bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Role for Rpl22 in Controlling Lymphoma Progression and Dissemination
Authors: Rao Shuyun , Cai Kathy , Stadanlick Jason , Lee Sang-Yun , Greenberg-Kushnir Noa , Solanki-Patel Nehal 
Published: November 2019

Abstract
Mutations in ribosomal proteins often cause bone marrow failure syndromes associated with increased risk for cancer development; however, in most cases, the basis by which they do so remains unclear. We have shown that Rpl22 is a haploinsufficient tumor suppressor in T acute lymphoblastic leukemia/lymphoma (T-ALL). Loss one Rpl22 allele accelerates T-cell lymphomagenesis in the murine Akt transgenic mouse model, by inducing the stem cell factor Lin28B in an NFkB-dependent manner. Here we employed two distinct murine T lymphoma models to uncover a new role for Rpl22 in lymphoma progression through effects on migration and angiogenesis. Compared with Rpl22+/+ mice, mice deficient for Rpl22 (Rpl22-/-) exhibited significantly increased thymic tumor size, which was associated with markedly enhanced angiogenesis through the activation of VEGF signaling. Unlike Rpl22 sufficient tumors, Rpl22-deficient lymphomas were retained in the thymus as a large mediastinal mass that did not disseminate to the periphery due to a defect in migration. The migration defect in Rpl22-/- tumors results from attenuation of S1P1 receptor expression through downregulation of the KLF2 transcriptional factor, which is responsible for its expression. Indeed, re-expression of S1P1 receptor in Rpl22 deficient tumor cells rescues the migration defect. Re-expression of Rpl22 into Rpl22 deficient cells rescues expression of both KLF2 and its target, S1P1 receptor, indicating that Rpl22 is regulating the KLF2/S1P1 receptor axis, rather than the changes in expression being an indirect consequence of transformation. Consistent with this idea, human T-ALL lines with in which Rpl22 is mutated, exhibit reduced expression of both KLF2 and S1P1 receptor, relative to that in T-ALL lines with intact RPL22 alleles. Collectively, we have defined a new role of Rpl22 in tumorigenesis through regulation of migration.

Disclosures
No relevant conflicts of interest to declare.
PET Adapted Salvage Therapy for Advanced Hodgkin Lymphomas: Towards the Suppression of Positive Interim PET Unfavorable Prognosis? a Report of the Goelams Multicentric Phase 2 Trial LH2007
Authors: Carras Sylvain , Dubois Benjamin , Senecal Delphine , Quittet Philippe , Vuillez jean-Philippe , peoc'H Michel , Jais jean-Philippe , Lamy Thierry , Molina Lysiane 
Published: November 2019

Abstract
Introduction: Continuous improvement in the management of Hodgkin Lymphoma (HL) has brought to favorable outcome for the majority of patients. However, patients with advanced stages still present unsatisfactory results with ABVD. The GOELAMS group conducted a prospective multicentric phase 2 trial for advanced stage HL with front-line therapy by VABEM and early salvage therapy followed by ASCT in case of absence of complete metabolic response to test a global PET adapted strategy with early salvage (LH 2007 trial, NCT00920153).
Patients & Methods: Patients with advanced stage according to prognostic system score (PSS>3) received VABEM in front-line and interim 18F-FDG PET restaging using visual analysis after 2 courses. In case of negative PET-2 patients continued their therapy with a third course. In case of positive interim PET they underwent early salvage therapy by platin, gemcitabine and dexamethasone combination followed by intensification in case of metabolic response.
Results: 51 patients were included in the advanced arm. Median age was 40.5 years (range 18.2-64.8). Ann Arbor stage was IV in 35 (78%). B symptoms were observed in 44 (88%) patients; bulky disease in 22 (43%) of cases. The complete remission rate at the end of the strategy was 88% (n=45/51), with 34/37 patients in CR after 3 VABEM courses and 11/12 patients in CR after salvage therapy and ASCT. The metabolic complete response rate after 2 VABEM courses was 76% (37 above 49 assessable patients). The median follow up is 4.2 years (range: 0.02-5.8). Estimated 2-yrs EFS and OS (n=51) were respectively 82.3% (IC95% 72.5% to 93.5%) and 92.1% (IC95% 85% to 99.8%). 9 events occurred during the first 2 years and led to 4 deaths. The comparison by the one sample log-rank test of the observed EFS to a reference curve with a 2years EFS of 70% was statistcally significant (p=0.0004). No difference was observed in 2yrs-EFS and OS depending on interim PET-2 status. 2yrs-EFS and 2yrs-OS were respectively 83.7% (IC 95 72.6%-96.5%) and 97.2% (IC95 92.0%-100.0%) for PET-2 negative population vs 91.7% (IC 95 77.3%-100%) and 91.7% (IC95 77.3%-100.0%) for PET-2 positive population.
Discussion & conclusion: VABEM is an efficient first line treatment choice for Advanced HL. We demonstrate here that a PET-guided strategy with early salvage therapy and intensification for interim PET-2 positive patients is safe and feasible and that this global strategy permits to obtain interesting results in a population of patients associated with poor prognosis. Finally, we suggest that salvage by non-cross-resistant drugs and intensification may erase the unfavourable prognostic of positive interim PET-2 status in HL.

Disclosures
No relevant conflicts of interest to declare.
Modulation of the β2-Integrin Axis in Inflammatory Cell Trafficking By Fucosylated Ligands
Authors: Buffone Alex , Nasirikenari Mehrab , Neelamegham Sriram , Lau Joseph T. 
Published: November 2019

Abstract
Leukocyte trafficking to a site of inflammation, in which selectin-mediated recruitment is the well-established initial step in mouse and humans, requires α1,3-fucosylated carbohydrates as canonical selectin ligands. Disrupting these ligands mitigates leukocyte recruitment, and this pathway presents a choice target in managing inflammatory conditions. Here we report that fucose can act paradoxically in cell recruitment to select sites of inflammation. α1,3-Fucose deficient neutrophils lacking the fucosyltransferases Fut4 and Fut7 have severely impaired recruitment in the well-established selectin dependent acute peritonitis. By contrast they are preferentially recruited to inflamed airways, because α1,3-fucose deficiency augments CXCR2 mediated Rap1-GTP signaling and enhances the β2 integrin - ICAM-1 axis to promote neutrophil recruitment. Recognition of this newly identified role for α1,3-fucoslated carbohydrates in modulating the integrin axis of inflammatory cell recruitment illuminates the unique pathophysiology of the airway and new insights into therapeutic anti-inflammatory approaches.

Disclosures
No relevant conflicts of interest to declare.
Genetic Defects in 10 Index Cases of Inherited Vitamin K Dependent Clotting Factors Deficiency
Authors: Naz Arshi , Watzaska Mattiha , Oldenburg Johannes , Kristin Inga , Waryah Ali mohammad , Raza Ali , Nadeem Mohammad , Ahmed Nisar , Shamsi Tahir 
Published: November 2019

Abstract
Introduction: Vitamin K dependent factors i.e II, VII, IX and X plays an important role in the clotting mechanisms of the human body. Deficiency or defect in any of these factors, Vitamin K or Gamma glutamyl Carboxylase (GC) and Vitamin K Epoxide Reductase (VKOR) involved in the metabolism of these factors will compromise the clotting mechanisms and can lead to the bleeding disorder. 28 rare single mutations in VKORC1 coding sequence have been reported so far.
Objective: To investigate the biochemical, haemostatic and molecular basis of the Vitamin K dependent factor deficiency in Pakistani subjects.
Setting: NIBD &BMT, University of Bonn and Children hospital.
Method: For this purpose 10 subjects, 9 males and 1 female with age ranging from 7 months to 13years were included from selected region of Pakistan who had a history of bleeding disorder and low levels of all the Vitamin K dependent clotting factors. BT, PT, APTT, Factor II, VII, IX, X,Platelet count and fasted serum bile acids were analysed for exclusion of thromobocytopenia which cause of bleeding and bile acid for cholestatic liver disease respectively. DNA sequencing was done for the GCCX and VKOR encoding gene i.e. GCCX-1 and VKORC-1 respectively to understand the etiology at molecular level.
Results: Platelet counts of all the subjects were normal only in one case it was mild low 100x103/ul. Mean± S.E.M value of platelet was 440x103 ± 67. Factor II, VII, IX and X mean levels were 12.7%, 6.9%, 11.2%, 7.1% respectively. Out of ten subjects mean bile acid levels were increased in 3 patients (20 µmole/l) while 3 had low levels (1.2 µmole/l). 3 novel mutations identified in GCCX-1 gene in those patients who had normal levels of bile acids.
Conclusion: Out of ten only in three patients novel mutations were identified in GCCX-1 while other 6 patients had abnormal levels of bile acid may be a cause of vitamin K clotting factors deficiency.Better strategies for the diagnosis of vitamin K deficiency are needed.

Disclosures
Oldenburg: SOBI: Consultancy.
Haemophilia Care in Martinique: From 1982 to 2015
Authors: Pierre-Louis Olivier , Baudin Jacqueline Véronique , Joachim Clarisse Contaret , Marie-Nadiège Yerro , Sabine Molcard , Schved Jean-Francois , Pierre-Louis Serge 
Published: November 2019

Abstract
Introduction: Hemophilia A (HA) and B (HB) are the most common congenital bleeding disorders, characterised by missing clotting factor VIII (FVIII) for HA or factor IX (FIX) for HB, associated with specific mutations for the corresponding genes. This is the first article to focus on a localised specific hemophiliac population in the French West Indies.
Methods: Clinical, biological, genetic and socio-demographic data were collected at the Martinique Regional Centre for the Treatment of Hemophilia.
Results: Nowadays patients with hemophilia and von Willebrand diseases can benefit from clinical and paramedical care comparable to what prevails in mainland France. 130 hemophilia patients were diagnosed in Martinique. This study provides the first global report on epidemiological characteristics of hemophilia in Martinique. Hemophilia treatment center was established in 2000, implementation of care services, number and diagnoses of hemophilia patients, frequency of complications such as inhibitors, HIV and hepatitis C infection, and underlying genetic mutations are described.
Conclusion : These original data support that the French West Indies island of Martinique has the highest rate of HA and HB in the world compared to other countries. The establishment of a treatment center now provides standard of care to this population and may be a model for similar approaches in other French overseas regions.

Disclosures
No relevant conflicts of interest to declare.
The First Registry: Follow-up in Rivaroxaban Patients in the Setting of Venous Thromboembolism
Authors: Lang Kathryn Jane , Solis Vicente , Patel Jignesh , Czuprynska Julia , Roberts Lara N , Patel Raj , Arya Roopen 
Published: November 2019

Abstract
The direct oral anticoagulants (DOACs) are revolutionising the management of acute venous thromboembolism (VTE). Although favourable short term outcomes have been demonstrated with these agents, there is a growing need to improve our understanding of biological and clinical predictors of longer-term outcomes with all DOACs. In addition to reducing the need for dual anticoagulant coverage, the use of oral rivaroxaban, has accelerated the implementation of outpatient and early discharge treatment protocols for VTE, in particular for pulmonary embolism (PE).
Although clinical trials provide evidence of efficacy and safety, there is a need for ongoing assessment of outcomes in unselected populations treated in routine 'real-world' clinical practice. As for most drugs, conditions requiring special attention include advanced age, impaired renal or liver function, extremes of body weight, presence of multiple co-morbidities, and the need for concomitant therapies. Such conditions commonly co-exist, particularly in elderly patients. In clinical practice patients aged 80 years or older and requiring anticoagulation are becoming increasingly common. In addition, trials do not report long-term adverse outcomes after VTE; aside from bleeding, currently there are no long-term data that assess the impact of the DOACs as part of a single-drug treatment algorithm on long-term recurrence.
The FIRST registry will assess long-term outcomes of patients with acute VTE treated with rivaroxaban from diagnosis - our hypothesis is that the long-term outcomes for such patients will be favourable due to consistent anticoagulation intensity, particularly during the acute phase of thrombosis. There are currently no data describing post-thrombotic syndrome (PTS) or chronic thromboembolic pulmonary hypertension (CTEPH) incidence rates in patients treated with DOACs. Patients enrolled onto the FIRST registry will be followed up for five years with primary end-points defined as incidence of long-term sequelae (PTS and CTEPH, defined clinically) and secondary endpoints including recurrence, bleeding and anticoagulation related satisfaction and adherence scores. Analysis of these data may also contribute to improved risk stratification strategies to identify patients who have the greatest risk of adverse bleeding events, recurrence and long-term VTE-related morbidity. Recruitment is currently underway at 20 UK hospitals, with a target of 1500 patients, to be achieved by summer 2017.

Disclosures
No relevant conflicts of interest to declare.
The Role of SMAD7 Downstream of TEL-AML1 Signalling in t(12;21) Acute Lymphoblastic Leukemia
Authors: Sundaresh Aishwarya , Mangolini Maurizio , de Boer Jasper , Hubank Mike , Goulden Nicholas , Williams Owen 
Published: November 2019

Abstract
The single most frequent chromosomal translocation associated with childhood ALL is the t(12;21) rearrangement that creates a fusion gene between TEL (ETV6) and AML1 (RUNX1). Although TEL-AML1+ patients have very good prognoses, relapses occur in up to 20% of patients and many patients face long-term side effects of chemotherapy.
Recent data has shown that TEL-AML1 has a direct role in inducing signal transducer and activator of transcription 3 (STAT3) activation in human t(12;21) leukemia. This activation has been shown to transcriptionally induce MYC and is critical for survival of TEL-AML+ leukemia cells. Here, we demonstrate that STAT3 also regulates SMAD7 gene expression. SMAD7 is an antagonist of TGF-β signaling, functioning through a negative feedback mechanism, but is also known to function in other biological pathways. Interestingly, SMAD7 has also been shown to play a role in promoting self-renewal of hematopoietic stem cells. We show that both pharmacological and mechanistic inhibition of STAT3 results in down regulation of SMAD7 gene expression in TEL-AML1+ cell lines. This result was specific to TEL-AML1+ cells and not found in cells of other ALL subtypes. To understand the role played by SMAD7 in TEL-AML1+ cells, we used lentiviral vectors expressing shRNA targeting SMAD7. Interestingly, SMAD7 silencing was found to inhibit proliferation of TEL-AML1+ cell lines, eventually leading to growth arrest and apoptosis. Furthermore, we have established that this effect is not mediated through TGF-β signalling. This poster highlights the results of RNA-seq performed on TEL-AML1+ cells with SMAD7 knockdown and in vivo xenograft model of SMAD7 shRNA in TEL-AML+ ALL.

Disclosures
No relevant conflicts of interest to declare.
Effect of Expression of Multidrug Resistance Genes on Efficacy the Treatment of Multiple Myeloma By Proteasome Inhibitor
Authors: Chernykh Yulia , Golenkov Anatoly 
Published: November 2019

Abstract
Background: Increased expression of efflux protein, such as P-glycoprotein, multidrug resistance protein, lung resistance protein, breast cancer resistance protein are a major reason for resistance to existing or previously effective therapy multiple myeloma (MM). Effect of the expression of genes of multidrug resistance (MDR) - MDR1, MRP1, LRP, and BCRP on the efficacy of therapy with proteasome inhibitor is currently not well understood.
Aim: Determination of mRNA expression of genes responsible for the development of drug resistance, such as MDR1, MRP1, LRP, BCRP in bone marrow aspirates in patients with newly diagnosed and refractory / relapsed MM before start bortezomib-containing chemotherapy programs.
Materials and methods: We studied bone marrow aspirates of 29 patients (12 men and 17 women) aged 48 to 77 years (median 60 years) with stage 3 MM by classification Durie-Salmon. 14 of studied patients made a group of newly diagnosed MM. 15 patients made a clinically refractory / relapsed group MM. The bone marrow in this group of patients was studied after treatment with alkylating agents at the time of registration of resistance to the given therapy. In the future, all patients were treated by bortezomib - containing chemtheapy regimens. mRNA expression studied genes was determined by semi-quantitative polymerase chain reaction reverse transcription.
Results: In both groups of patients had comparable expression of all studied MDR`s genes. In the group of newly diagnose patients the MDR 1 mRNA expression was detected in 93% (13/14) of the samples, the mRNA of the gene MRP 1 was detected in 79% (11/14). The BCRP mRNA expression was detected in 100% of the investigated samples. The expression of mRNA of the gene LRP was identified in 71% of the studied cases (10/14). In the group of patients after treatment with alkylating agents the expression of mRNA of MDR1 was detected in 87% (13/15) of samples, MRP 1 was detected in 93% (14/15), BCRP was in 100% of cases, and the LRP mRNA was detected in 13/15 (87%) of the samples.Treatment efficacy was assessed by Iinternational Unified Response Criteria for multiple myeloma after the 6 cycles of treatment. Evaluation of treatment efficacy in patients previously non-treated with chemotherapy as well as in the group of clinical resistance patients showed comparable results by the number of objective response rate (57% and 60% respectively).
Conclusions: The expression of MDR genes does not determine the resistance of tumor cells to bortezomib. The proteasome inhibitor bortezomib can overcome the MDR gene activity, attaching it to alkylating drugs increases the sensitivity to them of resistant tumor cells.

Disclosures
Golenkov: Novartis: Consultancy.
Incidence of Thrombotic Complications with Use of Peg-Asparginase in Treatment for Acute Lymphoblastic Leukemia (ALL) in Adults and Young Adolescent Patients
Authors: Routledge David JM , Tomlins Joanna , Bloor Adrian , Mamat Kaz , Dennis Michael , Cavet Jim , Somervaille Tim , Sommerfeld Sven Armin , Kulkarni Samar 
Published: November 2019

Abstract
Introduction: Peg-Asparginase is routinely used in the chemotherapy regimens used for treatment of ALL. Incidence of thrombotic complications is well established in children but there is limited data in adult and young adolescent patients. This is retrospective analysis to assess the risk of thrombotic complications with use of Peg-Asparginase.
Methods and Results: 100 patients with Acute Lymphoblastic Leukaemia treated between 2007-2015 who received Peg-Asparginase containing chemotherapy regimen were evaluated for development of thrombotic complications and pancreatitis. There were 69 male patients and 31 female patients. Median age was 29 yr. (range: 16-68 yr). Route of administration for Peg-Asparginase was intravenous in 51 cases and intramuscular in 49 cases. Peg-Aspraginase was administered during induction phase and consolidation cycles according to the relevant chemotherapy protocols. The adverse events included deep vein thrombosis (DVT) in 15 (15%), cerebral venous thrombosis in 7 (7%), Pancreatitis in 2 (2%), DVT and pancreatitis in 1 (1%) and 1 patient had clinically suspected DVT (1%). Complication rate was similar with IV or IM route of administration. 10 patients in IM group (20.4%) and 17 patients in IV group (33.3%) had at least one complication with Peg-Asparginase (P=0.31). Risk of individual complications was similar in both groups (DVT: 14.3% vs. 21.6%, p=0.34; Pancreatitis 2% vs. 3.9%, p=0.57; Cerebral venous thrombosis 4%% vs. 9.8%, p=0.25). There was no difference in the incidence of thrombotic complications with gender, age at diagnosis and use of central venous lines.
Conclusions: There is a significant risk of thrombotic events including PE (18% risk of thrombotic events excluding CNS). Risk of CNS events is 7% in this population. Risk appears to be higher with IV administration but this is not statistically significant due to small sample size. Incidence of CNS events is similar to that reported in adolescents participating in UKALL2003 study. The analysis will be extended to evaluate other toxicities especially hepatic toxicity and identify if there are any high risk patients for CNS or thrombotic events including blood counts, clotting, and cytogenetics. Use of LMWH prophylaxis seems reasonable in view of high incidence of thrombotic events even if CNS events are excluded.

Disclosures
Cavet: Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Somervaille:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.
Two Cases of Pediatric Acute Lymphoblastic Leukemia with t(5;14): a Challenging and Unique Entity
Authors: Fortin-Boudreault Renee-Pier , Leung Elaine W. , Bassal Mylene 
Published: November 2019

Background: Pre-B acute lymphoblastic leukemia (B-ALL) with the t(5;14) translocation occurs in less than 1% of B-ALL diagnoses. This translocation links the IGH on chromosome 14 with IL-3, which results in hypereosinophilia. Interestingly, circulating blasts or cytopenias usually don't accompany the eosinophilia. Patients often present with symptoms related to the eosinophilia, which can be quite morbid, and can delay the diagnosis of ALL. Few pediatric patients with this association have been described in the literature. The presentation and outcome can be quite variable, although it is thought that the prognosis in those patients is worse than standard ALL.
Objectives: To review the laboratory and clinical features of pediatric ALL with t(5;14).
Methods: Cases of pediatric patients with ALL and t(5;14) diagnosed at the Children's Hospital of Eastern Ontario between 1995 and 2003 were reviewed.
Results: We present two 11 year old children, a female and a male, who were diagnosed with B-ALL with t(5;14). The first one presented with a persisting low-grade fever and weight loss as well as asymptomatic lung infiltrates on the chest xray. The second patient presented with chest pain, fever, abdominal pain, as well as a petechial rash and splinter hemorrhages. His EKG showed ST depression, his troponins were elevated and an echocardiogram showed heart dysfunction. He went on and developed behavior changes and cerebral microinfarcts. Common to their presentation was the presence of hyperoesinophilia and absence of circulating blasts. Both had aggressive disease with persistent positive minimal residual disease (MRD) after consolidation and reinduction, which sent them to stem cell transplant.
Conclusion: ALL with t(5;14) is a rare entity that usually presents with hypereosinophilia. While eosinophilia can be asymptomatic, it can also be the cause of important morbidity. Diagnosis can be delayed because of the absence of blasts in the peripheral blood and lack of severe cytopenia. Finally, due to its rarity, there is very little information available on how this cytogenic abnormality impacts prognosis, which seems to be worse than ALL without this translocation.

Disclosures
No relevant conflicts of interest to declare.