bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-6 and IGF-1 Act in Synergy with HGF in Myeloma Cells by Modulating the Ras-MAPK Pathway.
Authors: Hov Håkon , Tian Erming , Waage Anders , Børset Magne , Sundan Anders 
Published: October 2019

Abstract
Multiple myeloma is an incurable malignancy of plasma cells homing to the bone marrow. Myeloma cells are dependent on factors in their microenvironment for survival and expansion. HGF may be produced both by myeloma cells and the bone marrow microenvironment and serum levels of HGF are known to be a prognostic factor in multiple myeloma. Both IL-6 and IGF-1 are known growth factors for myeloma cells. In the human myeloma cell line (HMCL) INA-6, HGF alone had low effect, but together with IL-6 and IGF-1 it became a potent growth factor increasing thymidin incorporation two- to three-fold above the levels obtained with IL-6 or IGF-1 alone. Similar results were obtained for the myeloma cell line OH-2. The ANBL-6 cell line harbours an autocrine growth promoting HGF-loop. When inhibiting this autocrine HGF loop with a specific c-Met receptor tyrosine kinase inhibitor (PHA-665752), IL-6- and IGF-1-induced proliferation was reduced by 80% and 50% respectively. Thus, in the prescence of HGF, both IL-6 and IGF-1 are dependent on the HGF-receptor c-Met for full effect on cell proliferation. There seems to be two interconnected explanations for the synergy between HGF- and either IL-6- or IGF-1-signalling in myeloma cells. IL-6 and IGF-1 treatment increased the expression of c-Met in INA-6 cells Secondly, we found that HGF was unique among the three growth factors in activating both Ras and p44/42 MAPK in INA-6 cells. Also in ANBL-6 cells, IGF and IL-6 was dependent on functional c-Met signalling to fully activate this pathway. Thus, the reason for synergy between HGF and IL-6 or IGF-1 seemed to be that full activation of the Ras-Mapk pathway through Gab1 and SHP-2 by these cytokines was dependent on operating c-Met signalling. Taken together, HGF and c-Met signalling would be attractive targets for therapy of multiple myeloma.
Recombinant Human Erythropoietin May Negatively Influence Survival in Newly Diagnosed Patients with Multiple Myeloma: A Single Center Experience in 246 Patients.
Authors: Katodritou Eirini , Verrou Evgenia , Banti Anastasia , Gastari Vassiliki , Mihou Dimitra , Hadjiaggelidou Christina , Markala Dimitra , Lazaridou Anna , Terpos Evangelos , Zervas Konstantinos 
Published: October 2019

Abstract
Anemia is a common clinical problem in patients with multiple myeloma (MM), which adversely affects their quality of life. The administration of recombinant human erythropoietin (r-HuEPO) improves anemia in about 2/3 of patients. However, it has not been clarified if r-HuEPO has any beneficial or adverse impact on the overall survival, particularly in a clear population of MM patients. The aim of this study was to examine the impact of r-HuEPO administration on the overall survival of newly diagnosed patients with MM. Two hundred forty-six newly diagnosed symptomatic MM patients, 139 males and 107 females, with a median age of 67 years (range 29–90) were studied. R-HuEPO was administered according to standard criteria, when Hb levels were less than 10.5g/dl and it was titrated and discontinued when Hb level reached 13g/dl. The parameters evaluated for predicting survival were: Age, sex, Hb, platelets, bone marrow infiltration, serum creatinine, serum ferritin, ISS score, B2-microglobulin and r-HuEPO administration. Cox regression was used for the univariate and multivariate analysis. One hundred forty-two patients received r-HuEPO and 105 did not. The median duration of r-HuEPO administration was 6 weeks (range 4–10) and the median hemoglobin level of patients who received r-huEPO, was 9.2g/dl (range 7.3–10.5 g/dl). The median follow up was 31 months (range 1–231). The univariate analysis showed that, age, Hb, platelets, serum creatinine, serum ferritin, ISS score, B2-microglobulin and r-HuEPO administration predicted for survival (p<0.05). The multivariate analysis demonstrated that, age, ISS score and r-HuEPO administration were statistically significant for predicting overall survival (p<0.05). The median survival of patients in the r-HuEPO group was 22 months (SD 22.7mo) whereas in the group without r-HuEPO administration it was 40 months (SD 35.8mo) (p=0.02). These results, suggest that r-HuEPO administration may negatively influence overall survival in newly diagnosed patients with MM and therefore, within this context, it should be used with caution. The large number of exclusively MM patients with a long follow up included in this study, highlights the importance of these results.
Tandem Autologous Transplant Versus Reduced Intensity Conditioned Allogeneic Transplant (Allo-RIC) as Second Intensification in Chemosensitive Patients with Multiple Myeloma (MM) Not Achieving Complete Remission (CR) or Near-CR with a First Autologous Transplant. Results from a Spanish PETHEMA/GEM Study.
Authors: Blade Joan , Rosinol Laura , Lahuerta Juan Jose , Sureda Anna , de la Rubia Javier , Garcia-Larana Jose , Hernandez-Garcia Miguel , Hernandez-Ruiz Belen , Perez-Simon Jose Antonio , Bello Jose Luis , Carrera Dolores , Penarrubia Maria Jesus , Abella Eugenia , Leon Angel , Poderos Concepcion , Garcia-Ruiz Juan Carlos , Besalduch Joan , Martinez-Martinez Rafael , Perez-Fernandez Isabel , Ribas Paz , Miguel Jesus San 
Published: October 2019

Abstract
One randomized trial showed that tandem transplant resulted in a significantly longer EFS and OS in patients failing to achieve CR or near-CR with a single transplant. However, other studies failed to show benefit from a second transplant. The aim of our study was to investigate the efficacy in terms of response improvement and survival from a second transplant intensification in patients with chemosensitive disease who failed to achieve CR or near-CR with a first high-dose procedure. Patients diagnosed with MM from Oct 1999 to Dec 2004 younger than 70 years received 6 courses of VBMCP/VBAD and responding patients were intensified with busulphan/melphalan or MEL-200 followed by stem cell support. Patients not achieving CR or near-CR were planned to undergo a second transplant (second auto with CVB - cyclophosphamide, etoposide and BCNU - or MEL-200 intensification or an allo-RIC with Fludarabine/MEL-140 conditioning, if sibling donor available). Eighty-eight patients received a second autologous transplant while 26 underwent an allo-RIC. Thirty-seven percent of the patients given a second autologous transplant improved their response status (CR 11%, near-CR: 6%, PR: 9% and MR 11%) while 63% showed “no change”, progressive disease or early death. A response was observed in 45% of patients undergoing the allo-RIC (CR: 33%, PR: 4%, MR: 8%). The CR rate was significantly higher with allo-RIC (33% vs. 11%, p= 0.02). There was a trend towards a higher TRM with the allo-RIC (5% vs. 16%, p=0.09). Although the median EFS (26 vs 19 m) and OS (57 m vs not reached in allo-RIC) from the second high-dose procedure were not significantly different, there is a plateau in the “allo-RIC” group beyond 3 years of the second procedure not observed in the autologous arm.
Conclusions:
an allo-RIC transplant after an autologous procedure results in a significantly higher CR rate than a second autologous transplant, and despite the lack of significant differences in survival between the two transplant modalities, there is a plateau in the allogeneic group not observed in the autologous arm.
Induction of Raf-1 Kinase Inhibitory Protein (RKIP) by the Proteasome Inhibitor NPI-0052 and Reversal of B-NHL Resistance to Apoptosis.
Authors: Baritaki Stavroula , Yeung Kam , Chatterjee Devasis , Palladino Michel , Bonavida Benjamin 
Published: October 2019

Abstract
Patients with B-cell malignancies initially respond to conventional cytotoxic therapies. However, many patients experience relapses and recurrences. Novel therapeutics are being explored in the reversal of resistance such as TRAIL. TRAIL has been shown to be selectively cytotoxic to few tumors and both TRAIL and agonist TRAIL-R1 (DR4) and TRAIL-R2 (DR5) antibodies are currently being explored clinically in unresponsive cancer patients. We have recently found that treatment of TRAIL resistant B-NHL cell lines such as Ramos with the novel proteasome inhibitor NPI-0052 (Nereus Pharmaceuticals) sensitizes tumor cells to TRAIL-induced apoptosis. The concentration of NPI-0052 achieving optimal sensitization to TRAIL was in the range of 1–5 nM. In contrast 400 fold more VelcadeTM (bortezomib) was necessary to achieve a similar level of apoptosis. The mechanism of NPI-0052- mediated sensitization to TRAIL was examined. Treatment of Ramos with NPI-0052 inhibited significantly the constitutively activated NF-κB concomitantly with inhibition of the DR5 transcription repressor Yin Yang 1 (YY1) resulting in up-regulation of DR5 expression. The role of YY1 in NPI-0052-induced sensitization to TRAIL was corroborated by the use of YY1siRNA as treatment with the YY1siRNA mimicked NPI-0052 induced DR5 up-regulation and sensitization to TRAIL. Studies examining the inhibition of the NF-κB pathway by NPI-0052 revealed a novel finding demonstrating the induced expression of the metastatic suppressor gene, Raf-1 kinase inhibitory protein (RKIP). RKIP has been reported to inhibit NF-κB activity and, thus, its induction by NPI-0052 contributed to the inhibition of NF-κB activity. The role of RKIP in NPI-0052 induced sensitization to TRAIL was corroborated by the use of RKIPsiRNA and transfectants mimicked NPI-0052 mediated inhibition of YY1, DR5 upregulation and sensitization to TRAIL mediated apoptosis. The above findings suggest that NPI-0052-induced inhibition of NF-κB results at least from two distinct mechanisms, namely, inhibition of p-IκBα degradation by the proteasome and by the induction of RKIP expression. The apoptosis induced by combination of NPI-0052 and TRAIL was the result of the activation of the type II mitochondrial pathway. It has been reported that the RKIP levels are reduced in many tumors (e.g. breast, prostate, ovarian) and the expression levels are of prognostic significance. Hence, the present findings demonstrating NPI-0052 induced RKIP expression may be therapeutically relevant in the prevention of metastasis. In addition, NPI-0052 should facilitate the reversal of tumor resistance when used in combination with subtoxic levels of cytotoxics.
Maintenance Treatment with Azacytidine for Patients with High Risk Myelodysplastic Syndromes or Acute Myeloid Leukaemia in Complete Remission after Intensive Chemotherapy.
Authors: Grövdal Michael , Khan Rasheed , Aggerholm Anni , Antunovic Petar , Astermark Jan , Bernell Per , Engström Lena-Maria , Kjeldsen Lars , Linder Olle , Nilsson Lars , Olsson Anna , Wallvik Jonas , Tangen Jon Magnus , Öberg Gunnar , Jacobsen Sten Eirik , Hokland Peter , Porwit Anna , Hellström-Lindberg Eva 
Published: October 2019

Abstract
Patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) secondary to MDS may reach complete remission (CR) following intensive chemotherapy but the CR-duration is usually very short. Promoter hypermethylation of e.g. tumour suppressor genes is considered to be important in cancerogenesis and a negative risk factor for survival in patients with MDS. We designed a prospective clinical trial to assess the impact of methylation status on the outcome of induction chemotherapy and to evaluate the effect of maintenance treatment with 5-azacytidine (aza) on CR duration. Sixty patients with a median age of 68 years (54–83) with high risk MDS (n=23) or AML (n=37) following MDS were treated with standard doses of daunorubicin and ara-C. Standard prognostic variables, and methylation status of the P15ink4b (P15), E-cadherin (CDH) and Hypermethylated in Cancer 1 (HIC) genes were analyzed before treatment. Patients in CR were given low dose aza subcutaneously for 5 days/4 weeks until relapse. The CR rate was 40%; significantly lower in patients with high white blood cell counts (P=0.03) and high CD34 expression on bone marrow cells (P=0.02). While P15 status alone was not associated with CR rate (P=0.25) patients with CDH methylation showed a lower CR rate (P=0.008). Moreover, no patient with hypermethylation of all three genes achieved CR (P=0.03). CDH methylation retained its prognostic value in the multivariate analysis. Hypermethylation was associated with increased CD34 expression but not with blast count or cytogenetic risk group. Median duration of CR was 13 months (2 to +37) and 7/ 23 patients (30%) had a CR duration >20 months. Three of four patients with trisomy 8 had CR >20 months. The overall survival of patients reaching CR was 17 months (6 to +40). Methylation status before treatment did not correlate with CR duration. We demonstrate for the first time a significant impact of methylation status on the outcome of conventional chemotherapy in high-risk MDS and MDS-AML and propose that this variable should be further evaluated in prospective studies. CR duration is promising, with a substantial portion of patients showing durable responses.
ATR Dependent Phosphorylation of FANCM Is Required for the Fanconi Anemia Pathway.
Authors: Singh Thiyam R. , Ali Abdullah M. , Du Chang-hu , Meetei Ruhikanta A. 
Published: October 2019

Abstract
Fanconi anemia (FA) is a rare, recessive disorder characterized by progressive bone marrow failure, developmental abnormalities, chromosome instability, cellular hypersensitivity to DNA cross-linking agents, and predisposition to cancer, mainly leukemias and squamous cell carcinomas of the head and neck. We have shown that FANCM which is one of the FA core complex proteins is hyperphosphorylated in response to DNA damage suggesting that it may serve as a signal transducer through which the activity of the FA-core complex is regulated. The cell cycle checkpoint kinase, ATR has been shown to act upstream of the FA pathway, however, its substrate within the FA-core complex has not been identified yet. FANCM contains multiple predicted ATR phosphorylation sites suggesting that FANCM could be a direct ATR target. In this study, we examined the roles of ATR in regulating FANCM phosphorylation in response to DNA damage:
by kinetics study we found that phosphorylation of FANCM is concurrent with FANCD2 monoubiquitination; siRNA mediated suppression of ATR activity abrogates both phosphorylation of FANCM and monoubiquitination of FANCD2; and ATR knock out HCT116 cells display defective phosphorylation of FANCM as well as defective monoubiquitination of FANCD2 indicating that DNA damage induced phosphorylation of FANCM is ATR dependant.
Furthermore, we used mass spectrometry to identify the in vivo phosphorylation sites of FANCM and found a novel DNA damage-inducible phosphorylation site (S-1045; one of the potential ATR phosphorylation sites) within FANCM protein. Using ATR knock out HCT116 cells and the anti-p-S1045 antibody, we show that phosphorylation of FANCM at S-1045 is ATR dependant. The biological relevance of phosphorylation of FANCM at S1045 in FA pathway will be investigated by functional complementation analysis with non phosphorylatable FANCM mutants in FANCM deficient cells.
Phase I Study of Triciribine Phosphate Monohydrate, a Specific Inhibitor of AKt Phosphorylation, in Adult Patients with Advanced Hematologic Malignancies.
Authors: Ravandi Farhad , Lancet Jeffrey , Giles Francis , Plunkett William , Williams Betsy , Burton Michelle , Faderl Stefan , Estrov Zeev , Borthakur Gautam , Akinsanmi Lawrence , Kantarjian Hagop 
Published: October 2019

Abstract
Activation of Akt, a serine/thronine protein kinase downstream of PI3 kinase, promotes cell survival through phosphorylation of Bad as well as activation of IKKa-NFkB pathway. Aberrant activation of Akt, by its amplification and overexpression, as well as through the loss of the upstream tumor suppressor PTEN, has been reported in many human cancers and is associated with poor prognosis, resistance to chemotherapy and shortened survival; disruption of Akt pathways inhibits tumor cell growth, angiogenesis and metastasis, and induces apoptosis. Through high through put screening of a library of small molecules, it has been determined that Triciribine Phosphate Monohydrate (TCN-PM), a nucleoside analog, is an inhibitor of Akt activation, and inhibition of Akt activation may be one of its antiproliferative mechanisms. We have conducted a phase I study of TCN-PM in patients with advanced hematological malignancies. Cohorts of 3 patients receive escalating doses of TCN-PM at 15, 25, 35, and 45 mg/m2 administered IV on days 1, 8, and 15 of a 28 day cycle. Twenty four (19M, 5F) patients have been enrolled in 2 institutions and have received a median of 1 cycle (range, 1 – 3) of TCN-PM including 4 in cohort I, 4 in cohort II and 16 in cohort III. Median age of the patients is 60 (range, 30 – 79). Twenty two patients had AML, 1 CLL, and 1 MDS. Median number of prior therapy before inclusion in the study was 3 (range, 1 – 7). Ten patients were inevaluable including 1 in cohort I, 1 in cohort II, and 8 in cohort III due to disease progression (in 7) and other (in 3). Dose limiting toxicity of mucositis was observed in a patient on the third cohort resulting in expansion of that cohort. No further incidences of mucositis were seen in the expanded cohort. No other severe adverse events related to treatment have been observed. 2 patients have achieved major improvements in platelet count lasting 7 and 36 days. One patient achieved a minor improvement in platelet count. Four patients have achieved major improvements in neutrophil count lasting a median of 19 (range, 8 – 40) days while on therapy. Cell death, measured by annexin-5 staining was examined in pre and post treatment samples in 14 patients; in 2 patients there was a significant increase in apoptosis to 25% and 27% after TCN-PM but this did not correlate with response. Pharmacodynamic studies evaluating inhibition of Akt phosphorylation as well as pharmacokinetic data will be presented. Accrual to higher dose levels is continuing.
Purinergic Signaling Differentially Modulates Normal and Leukemic Hematopoiesis.
Authors: Salvestrini Valentina , Gulinelli Sara , Zini Roberta , Caione Luisa , Migliardi Giorgia , Piacibello Wanda , Ferrari Davide , Virgilio Francesco Di , Ferrari Sergio , Manfredini Rossella , Lemoli Roberto M 
Published: October 2019

Abstract
Abstract 1436
Poster Board I-459
Extracellular nucleotides adenosine and uridine triphosphates (ATP and UTP, respectively) are emerging as ubiquitous molecules involved in a wide variety of biological responses and their biological effects are mediated by specific plasma membrane receptors, P2 receptors (P2R). Previously, we showed that extracellular nucleotides stimulate the proliferation and engraftment potential of normal human hematopoietic stem cells. In this study, we assessed whether P2R are expressed on acute myeloblastic leukemia (AML) cells and whether their engagement modulates leukemic cell functions. We show that AML cells express several functional P2R subtypes at the molecular and protein level. Stimulation of AML cells by extracellular nucleotides induced intracellular Ca2+ concentration increases. Furthermore, gene expression profiling revealed that leukemic cells stimulated with ATP underwent a down-regulation of genes involved in cell proliferation and migration whereas those involved in cell cycle inhibition were strongly up-regulated. At the functional level, the clonogenic efficiency of leukemic blasts and CD34+CD38− leukemic stem/progenitor cells was significantly inhibited by the addition of ATP and, to a higher extent, by the stable analogs INS415 and INS973. We also observed a pronounced inhibitory effect of triphosphate nucleotides on spontaneous migration of AML cells and in response to CXCL12.In vivo, xenotransplant experiments demonstrated that the homing and the engraftment capacity of human AML blasts and leukemic stem cells to NOD/SCID/IL-2RGamma-Null mice was significantly inhibited by pre-treatment with ATP, UTP and INS415 and INS973 analogues. Thus, our data show that purinergic signaling modulates leukemic cells in a opposite way than normal cells. Characterization of purinergic signalling in leukemia may help the better understading of the mechanism of neoplastic transformation and tumor progression.

Disclosures
Di Virgilio: F. Di Virgilio serves as a consultant for Cordex Pharma Inc. (USA) involved in the development of “P2 receptor-based drugs”.: Consultancy; F. Di Virgilio serves as a consultant for Affectis Pharmaceuticals AG (Germany), involved in the development of “P2 receptor-based drugs”.: Consultancy.
Quantitative Imaging of Femoral Bone Marrow Microenvironments Reveals a Heterogenous Distribution of Hematopoietic Stem and Progenitor Cells.
Authors: Nombela-Arrieta Cesar , Harley Brendan , Pivarnik Gregory , Mahoney John E , Levantini Elena , Protopopov Alexei , Tenen Daniel G. , Silberstein Leslie E. 
Published: October 2019

Abstract
Abstract 1455
Poster Board I-478
Sustained production of all mature blood cell types relies on the continuous proliferation and differentiation of a rare population of self-renewing, multipotent hematopoietic stem cells (HSCs). HSC maintenance and lineage differentiation are thought to be regulated by spatially confined niches, defined by cellular components, soluble regulators, and the extracellular matrix immediately surrounding stem cells. Identification of these microenvironments in which endogenous and transferred HSCs reside within the BM is a major challenge in stem cell biology with relevant clinical implications. Yet the extreme rarity of HSCs, their dynamic nature, and the lack of specific markers to identify them, have precluded an accurate definition of HSC niches to date. Quantitative imaging technologies such as Laser Scanning Cytometry (LSC) are designed for the automated analysis of large cell numbers at a single cell level with high resolution while preserving the morphological information lost in flow cytometry, therefore providing data of statistical significance even for rare cell populations such as HSCs. We have employed LSC to analyze the localization of both adoptively transferred and endogenous hematopoietic stem and progenitor cell (HSPC) populations inside whole longitudinal sections of murine femoral BM cavities.
Our results indicate that, as previously suggested, purified HSPC (Lin−c-kit+Sca-1+) significantly accumulate in endosteal regions (ER) of BM cavities (within 100μm of inner bone surface) upon transplantation. Nevertheless, analysis of sufficient numbers of more differentiated cell subsets (Lin−c-kit+Sca-1− progenitors, pro B cells and mature B cells) indicated that these areas serve as homing sites for most hematopoietic cells, highlighting the limitations of any conclusions drawn on HSC niche identity from studies performed with transferred HSPC populations. Immunofluorescent staining of endogenous cell populations revealed a gradient in distribution of early hematopoietic progenitors (c-kit+), which accumulated in but were not restricted to ER regions. Of note, a vast majority (>80%) of HSPC (Bmi-GFPhic-kit+, or Lin−c-kit+Sca-1+),were found inside ER, although not directly adjacent to endosteal surfaces. Our studies define endosteal areas as tissue regions where HSPC reside in close proximity, but not necessarily in direct contact with a dense vascular network, osteoblastic cells and other potential niche cell types and growth factors currently under investigation.

Disclosures
No relevant conflicts of interest to declare.