bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neonates with Asymptomatic Central Venous Catheter-Related Thrombosis - a Systematic Review
Authors: Allahyani Bader , Alanazi Abdullah , Feder Joshua , Simpson Ewurabena 
Published: November 2020

Background:
Central venous catheters (CVCs) are the most frequent cause of thrombosis in acutely unwell neonates. The natural history CVC-RT remains unclear. The current guideline for symptomatic CVC-related thrombus suggests that anticoagulation likely leads to minimizing complications while the recommendation for pediatric patients with asymptomatic deep vein thrombosis (DVT) is equivocal.
Objective:
This systematic review was undertaken to summarize evidence from the pediatric literature on the prevalence of asymptomatic CVC-RT in the neonate and whether anticoagulation therapy (ACT) improves the outcomes of asymptomatic CVC-RT in the neonate.
Methods:
We searched CENTRAL, MEDLINE, Embase, CINAHL, the Web of Science, and clinical trial databases. We considered data from retrospective and prospective cohort studies, case series, and randomized controlled studies evaluating the prevalence and outcomes of CVC-RT following the use or non-use of ACT. Data were analyzed using Fisher exact and Chi-square statistics.
Results:
In total 762 articles were identified and screened, of which 16 articles included (1 RCT, 4 prospective studies and 8 retrospective cohort studies, and 3 case reports) that met inclusion criteria and contained extracted case data; these studies reported on a total of 1909 neonates with CVC have been screened for thrombosis. All studies were considered at moderate or high risk of bias. Tau2 and I2 suggested a high degree of heterogeneity. Ultimately, 309 cases were identified with the prevalence of asymptomatic CVC-RT was 16%. Notably, only 6.5% of neonates with symptomatic CVC-RT had undergone ultrasound (US) screening. The majority of the cases were premature neonates. 45% of the neonate had Umbilical Vein Catcher (UVC). 114 (41%) of the cases received ACT, of which none complicated with major bleeding. Overall there was no difference following the use or nonuse of ACT in patency of the asymptomatic CVC-RT, recurrence, and thrombosis related mortality. The frequency of each outcome according to therapy is shown in Table1.
CONCLOSION:
This systematic review has provided additional evidence supporting the favorable outcome of asymptomatic CVC-RT in the neonate regardless of the use of ACT. Further well-designed, prospective, multi-center clinical trials are needed to establish evidence-based treatment recommendations for neonates with asymptomatic CVC-RT.
Figure

Disclosures
No relevant conflicts of interest to declare.
The Current Practice of Management of Asymptomatic Central Venous Catheters Associated Venous Thromboembolism in Children: A Result of Saudi Arabian Pediatric Hematology/Oncology Society Survey
Authors: Allahyani Bader , Ali Abdullah , Feder Joshua , Alshahrani Mohammad , Alsultan Abdulrahman , Alzahrani Azzah 
Published: November 2020

Introduction:Central venous catheters (CVCs) are the main cause of venous thromboembolism (VTE) in critically ill children. The optimal first-line treatment for children with asymptomatic CVC-related VTE is unknown. Due to a paucity of clinical trials, clinical practice guidelines can offer only weak recommendations for the management of asymptomatic CVC- related VTE. This case-based survey was designed to assess current trends in local management strategies for pediatric patients with an asymptomatic CVC- related thrombosis. The survey focused on the use of the thrombophilia testing, management approach, duration of anticoagulation, and the use of secondary prophylaxis. We hypothesize that there will be significant variation in these four management areas, in large part due to the aforementioned paucity of available data.
Method:After Institutional Review Board approval, REDCap® questions were sent to members of the Saudi Arabian Pediatric Hematology/Oncology Society (SAPHOS) clinical forum/email database. We used a hypothetical case to assess management strategies for asymptomatic CVC-related VTE and secondary prophylaxis.
Result:Seventy-one (30%) physicians responded to the survey. The majority of the respondents (83.3%) did not use thrombophilia testing. 95% treated with anticoagulation, of which 20% treated only if clot propagation was identified on follow-up and 3.3% treated only if a thrombophilia was identified. In contrast, the survey respondents varied widely in the duration of anticoagulation (19% for 6 weeks, 41.4% for 12 weeks, 29.3% until CVC removal). Secondary prophylaxis was used by 20% of the respondents, whereas 21.4% did so, only if there was a previously identified thrombophilia.
Conclusion:Asymptomatic CVC-related VTE is a common clinical entity with limited data guiding management. In Saudi Arabia there remains considerable variability in clinical management; particularly, in the duration of treatment and use of secondary prophylaxis. These findings will help identify crucial knowledge gaps in the management of asymptomatic CVC-related VTE and facilitate clinical trials that will help establish evidence-based treatment guidelines.

Disclosures
No relevant conflicts of interest to declare.
NSD2 Regulates Pro-Metastatic Gene PTP4A3 through Chromatin Remodeling in Multiple Myeloma
Authors: Chong Phyllis SY , Chooi Jing Yuan , Lim Julia , Chng Wee-Joo 
Published: November 2020

Nuclear receptor-binding SET domain 2 (NSD2) is the primary oncogenic driver and represent a good druggable target due to its universal overexpression in t(4;14) MM. However, given the challenges in the development of small molecule inhibitors against NSD2, we took on a discovery approach to characterize NSD2 interactome as an alternative strategy to target NSD2. We employed SILAC-based mass-spectrometry coupled with gene ontology analysis to uncover the spectrum of NSD2-interacting proteins which are relevant in t(4;14) MM. Validation using in silico protein-protein interaction analysis and immunoprecipitation confirmed that SMARCA2, a bromodomain-containing chromatin remodeler, interacts with NSD2 independent of the SWI/SNF complex. SMARCA2 is primarily expressed in t(4;14) cell lines, and functional assays indicated that dual inhibition of SMARCA2 and NSD2 impairs growth of t(4;14)+ cells. Next, we performed RNA sequencing which led to the identification of PTP4A3 as a downstream target of NSD2 that is co-regulated by SMARCA2. Mechanistically, SMARCA2 is required for the recruitment of NSD2 to PTP4A3 promoter, leading to a transcriptionally permissive state for expression. Importantly, upregulation of PTP4A3 is sufficient for the activation of MYC, which is crucial for t(4;14) myelomagenesis. PFI-3, which belongs to the class of bromodomain and extra-terminal motif protein inhibitors (BETi), displaced SMARCA2 and NSD2 occupancy from PTP4A3 promoter, and selectively inhibited t(4;14) myeloma cell viability. Interestingly, PFI-3 treatment did not perturb the levels of NSD2 nor SMARCA2, rather, the targeting effect is achieved through their occupancy on oncogenes. Finally, high expression of NSD2 and SMARCA2 were predictive of poor survival outcome in a large cohort of myeloma patients. Collectively, we demonstrated a proof-of-concept of how histone modifying enzyme and chromatin remodeling complex cooperatively caused an altered epigenetic state in myelomagenesis through the regulation of an important myeloma gene. Our study proposed that the pharmacological inhibition of SMARCA2 may represent a novel strategy to target t(4;14) myeloma cells using BETi and also explore as combinational therapy with anti-myeloma agents that are currently in the clinics.

Disclosures
No relevant conflicts of interest to declare.
Leukemia Stem Cells Demonstrate Increased DNA Damage Repair and Chemoresistance in Acute Myeloid Leukemia
Authors: Egan Grace , Thomas Geethu Emily , Patel Parasvi , Hurren Rose , MacLean Neil , Hakem Razq , Schimmer Aaron D 
Published: November 2020

While most patients with AML achieve remission with standard induction chemotherapy, the majority ultimately relapse. Relapsed AML is due, at least in part, to the persistence of chemoresistant leukemia stem cells (LSCs). The mechanisms of chemoresistance in LSCs are not fully understood. Here, we explored DNA damage repair in LSCs.
8227 cells are low passage primary AML cells that maintain a hierarchical organization with functionally defined stem cells in the CD34+CD38- fraction. We FACS sorted 8227 cells into stem and bulk fractions and measured expression of DNA repair genes. LSCs were primed for DNA repair with increased expression of genes associated with homologous recombination (RAD51, XRCC2, XRCC3) and non-homologous end joining (XRCC4, XRCC5, PRKDC). Next, we treated the cell fractions with daunorubicin, an intercalating anthracycline that causes double stranded breaks. DNA damage and repair were evaluated by measuring foci of 53BP1, RAD51 and γH2AX by fluorescent microscopy and quantified using image J. Compared to bulk cells, 8227 stem cells demonstrated enhanced DNA damage repair with increased foci of 53BP1 and RAD51 and decreased γH2AX foci, compared to their basal levels. Similar findings were noted after exposing the stem and bulk cells to radiation.
We recently discovered that the metabolic enzyme hexokinase 2 (HK2) localizes to the nucleus to maintain stem cell number and function. Therefore, we selectively over-expressed HK2 in the nucleus of 8227 and NB4 cells by tagging HK2 with a nuclear localizing sequence (PAAKRVKLD). We confirmed selective over-expression of HK2 in the nucleus by immunoblotting and confocal microscopy. Over-expressing HK2 increased stem cell function as shown by clonogenic growth assays and engraftment into mouse marrow. We then treated these cells with daunorubicin and measured DNA damage repair. Over-expression of nuclear HK2 increased 53BP1 and RAD51 foci with decreased γH2AX foci, similar to the phenotype observed in LSCs. In addition, over-expression of nuclear HK2 conferred resistance to daunorubicin as measured by clonogenic growth assays.
In summary, LSCs appear to be primed for DNA repair with increased levels of DNA damage repair genes. After exposure to chemotherapy and radiation, LSCs have increased repair of double strand DNA breaks compared to more differentiated blasts. This accelerated DNA damage repair may partly explain the increased chemoresistance seen in LSCs.

Disclosures
Schimmer: Takeda:Honoraria, Research Funding;Novartis:Honoraria;Jazz:Honoraria;AbbVie Pharmaceuticals:Other: owns stock ;Otsuka:Honoraria;Medivir AB:Research Funding.
Nuclear Protein DEK Governs Quiescence and Metabolic Homeostasis of Hematopoietic Stem Cells By Shaping Chromatin Accessibility
Authors: Chen Zhe , Li Lei , Chen Jieping , Hou Yu 
Published: November 2020

Hematopoietic stem cells (HSCs) must achieve a balance between quiescence and activation that fulfils the demands for hematopoiesis without compromising long-term maintenance of HSCs. DEK, a chromatin architectural factor, is involved in chromatin remodeling, transcriptional regulation and DNA replication, and is implicated in genetic and epigenetic regulation of gene expression. Here, we identified that DEK is a critical regulator of HSCs quiescence. Deletion of DEK in mice resulted in abnormal hematopoiesis with an obvious decreased HSC pool size (~3700 to ~1700 cells/mouse), associated with apparent reduction in the proportion of HSCs in G0 phase as compared to control HSCs (~72% to ~57%). As shown by serial bone marrow transplantation and competitive repopulation assays, deletion of DEK impaired the self-renewal capacity of HSCs. Mechanistically, deficiency of DEK in HSC altered chromatin accessibility landscape, resulting in increased transcription of activation-specific genes (including Akt1/2,Ccnb2, and Rps6) and decreased transcription of quiescence-specific genes (including p21 and Gata2), leading to excessively activated Akt-mTOR signaling and elevated metabolism of HSC. Targeting the Akt-mTOR pathway efficiently abrogated the impaired quiescence and the increased metabolism of HSC in DEK-deficient mice, and partially rescued the long-term functions of HSC. Further, DEK regulated chromatin accessibility of HSC by recruiting the co-repressor NCoR1 to repress acetylation of histone 3 at lysine 27. Collectively, our findings revealed crucial functions of DEK in HSC quiescence maintenance and disclosed a new link between chromatin remodelers, epigenetic modification, gene transcription, and HSC homeostasis.

Disclosures
No relevant conflicts of interest to declare.
Efficacy and Safety of Direct Oral Anticoagulants in Extremes Weights
Authors: Huang Julie , Chin Jamie , Hindenburg Alexander , Davenport Lilia , Willner Debra 
Published: November 2020

Background: The clinical use of Direct oral anticoagulants (DOACs), as opposed to warfarin, has become more prevalent in patients with extremes in body weight. However, both the International Society on Thrombosis and Haemostasis' (ISTH) and anti-thrombotic therapy guidelines state that DOACs should be avoided in patients with a body mass index (BMI) &gt;40 kg/m2, weight &gt;120 kg, or weight &lt; 50 kg. The purpose of this study was to analyze the efficacy and safety of DOACs in extremes of weight compared to patients treated with warfarin. Warfarin may be a safer and more effective oral anticoagulant for patients in extremes of weight, due to the availability of dosing based on INR. DOAC standard dosing may either overdose/underdose in patients with low/high BMI respectively.
Study Design and Methods: A retrospective, single-institution study evaluated patients with extreme weights receiving a DOAC or warfarin for either venous thromboembolism (VTE) or atrial fibrillation/atrial flutter between October 2016 and October 2020. Inclusion criteria consisted of patients admitted to NYU Langone Hospitals continued on a DOAC or warfarin for VTE or atrial fibrillation/atrial flutter with BMI &lt; 18 kg/m2 or BMI &gt; 30 kg/m2. Patients newly initiated on oral anticoagulation or received anticoagulation other than atrial fibrillation/atrial flutter or VTE were excluded. Primary endpoints include incidence of VTE or bleeding events in anticoagulated patients who meet extreme weight criteria.

Disclosures
No relevant conflicts of interest to declare.
Measles Reactivity in Windsor Patients Post Autologous Versus Allogeneic Hematopoietic Cell Transplantation: A Retrospective Review
Authors: Negus Kayla , Jarrar Mohammad , Woldie Indryas L. , Kanjeekal Sindu M. , McCann Kit , Hamm Caroline 
Published: November 2020

Background
As the antivaccine movement has increased, vaccine preventable illnesses have also increased. The resurgence of measles globally has been noted, specifically the United States received 1200 new cases of measles in 2019, which is the highest number of cases since 1994. Measles is a highly contagious pathogen; the virus has an attack rate of up to 90% in susceptible individuals. Standard of care for patients post hematopoietic cell transplant (HCT) includes repeating all childhood vaccinations. However, compliance with recommendations is unknown. No previous reports have been created measuring the difference in measles, mumps, and rubella (MMR) reactivity between autologous and allogeneic HCT patients post treatment.
Methods
A retrospective chart review investigated HCT patients between 2000-2019 from the Windsor Regional Hospital (WRH) cancer centre. Patients were excluded from data collection if they were deceased before an MMR reactivity test could be done or if they were lost to follow up. A total of 83% of autologous HCT (N=57) and 66% of allogeneic HCT (N=47) patients had serology tested to measure MMR reactivity post-transplant prior to live vaccinations. MMR titres were drawn from autologous patients a median of 395 days after HCT and a median of 907 days after HCT for allogeneic patients.
Results
Overall, allogeneic HCT patients had more reactivity than autologous HCT patients as seen in Table 1.
Conclusion
All patients not reactive to measles need to be re-vaccinated 24 months after treatment according to 2019 American Society for Transplantation and Cellular Therapy guidelines. Our patients are treated in a variety of transplant centers in Ontario, Canada as well as Detroit, Michigan; which is of concern because measles cases have been reported in Detroit. The majority (66%) of allogeneic HCT patients had a myeloid malignancy, while 70% of autologous patients has a diagnosis of multiple myeloma. As evidenced by the poor MMR response, less robust immune systems may be accounted for by multiple myeloma patients. This does emphasize the need for MMR vaccinations post HCT for multiple myeloma patients and raises the question regarding immunization for at risk non-transplant eligible patients. We suggest that it may be reasonable to assess MMR immune status in all myeloma patients to determine if this is a transplant effect or an effect of the underlying immune status of the myeloma patient. This study does emphasize the need to assess MMR status post transplant in all myeloma patients, as the vast majority in our study did not demonstrate immunity post stem cell transplant.
Figure

Disclosures
Hamm: Amgen: Consultancy.
RNA Sequencing Analysis in Primary Mediastinal B Cell Lymphoma: Identification of Different Gene Expression Related to Chemoresistance
Authors: Parvis Guido Eugenio , Incarnato Danny , Torti Davide , Familiari Ubaldo , Vassallo Francesco , Carrà Giovanna , Oliviero Salvatore , Volante Marco , Guerrasio Angelo , Saglio Giuseppe , Morotti Alessandro 
Published: November 2020

Background: Primary mediastinal large B cell lymphoma (PMLBCL) is a rare subtype of non-Hodgkin lymphoma mostly diagnosed in young women and is currently recognized as a distinct clinical and biological entity. First line therapy with R-CHOP allows to achieve good remission rates even if chemoresistant cases remain highly challenging from the therapeutic standpoint. As such, we aimed to compare the transcriptome of R-CHOP resistant PMBCL patients to those of chemosensitive patients.
Methods:We extracted RNA from embedded paraffin samples and then we performed whole RNA sequencing on 7 patients. Four of them were selected as chemoresistant (Group A), while three of them were classified as responder to R-CHOP (Group B). A First bioinformatics analysis selected a panel of 200 genes significantly differentially expressed in chemoresistant (A) samples versus chemosensitive (B). An unbiased analysis based on different ontology of the genes led to easily identify common signatures that may better profile the two groups of patients. Finally, on a bias analysis, genes were divided into categories in order to identify potential new targets and/or mechanisms of chemoresistance.
Results:We identified three genes which may be frankly related to chemoresistance in PMLBCLs due to an overexpression in the group A or a suppression of expression in group B. We selected NFKBIA, the gene which encodes for the IκBα protein, mutated in numerous Hodgkin's lymphoma cells, which cause NFkB to be chronically active in the lymphoma tumor cells. For this reason, we imagine that it could have a major role in the modulation of PMLBCLs sensitivity to chemotherapy.
EPHB1 was selected for its very strong expression in the poor prognosis group, since it is one of the most expressed genes and for his association with numerous cancers. The kinase STK 33 appeared overexpressed in group A. A more thorough investigation of this gene might lead to new, significant findings.
Conclusions:
Our in-silico analyses allowed to identify in PMBCL an unique profile that may modulate sensitivity to chemotherapy. Further analyses may address whether this unique phenotype has clinical implications. We may expect to: i) develop specific therapeutic strategies to target NFkB, EPHB1 and STK33 pathways in PMBCL with a chemoresistant behaviour; ii) correlate the expression profile of resistant PMBCL to other transcriptomes, including those of Hodgkin Lymphomas, Diffuse Large B cell Lymphomas, in order to better profile clinical and biological overlapping features.

Disclosures
Saglio: Ariad:Research Funding;Incyte:Research Funding;Roche:Research Funding;Bristol-Myers Squibb:Research Funding;Pfizer:Research Funding;Novartis:Research Funding.
Bleeding Diathesis in Mice Lacking JAK2 in Platelets
Authors: Eaton Nathan , Subramaniam Saravanan , Schulte Marie L , Drew Caleb , Jakab David , Haberichter Sandra L , Weiler Hartmut , Falet Herve 
Published: November 2020

The tyrosine kinase JAK2 is a critical component of intracellular JAK/STAT cytokine signaling cascades that is prevalent in hematopoietic cells such as hematopoietic stem and progenitor cells (HSPCs), megakaryocytes (MKs), and platelets. Individuals expressing somatic activating JAK2 mutations such as JAK2V617F commonly develop myeloproliferative neoplasms (MPNs) associated with serious complications, including venous and arterial thrombosis, a leading cause of mortality. Here, we investigated the role of JAK2 in hemostasis and thrombosis using Jak2fl/flPf4-Cre (Jak2Plt-/-) mice specifically lacking JAK2 within the platelet lineage. Jak2Plt-/- mice developed severe thrombocytosis with a 5-fold increase in circulating platelet number, MK hyperplasia, and splenomegaly. Jak2Plt-/-platelets were of normal size and the expression of major membrane surface glycoproteins was indistinguishable from controls, except for the integrin β3, which was reduced by 20%. Despite the thrombocytosis, Jak2Plt-/- mice had a severe bleeding diathesis, as evidenced by: 1) prolonged tail bleeding time; 2) failure to occlude in a ferric chloride-induced carotid artery injury model; and 3) failure to form stable thrombi in a laser-induced cremaster muscle injury model. Jak2Plt-/- platelets spread poorly on immobilized collagen or on immobilized fibrinogen following GPVI stimulation with the collagen-related peptide (CRP). Jak2Plt-/- platelets had defective α-granule secretion and integrin αIIbβ3 activation following stimulation with CRP, but not thrombin, and showed aggregation defects with low-doses of CRP. Together, the data support a GPVI-specific impairment in platelets lacking JAK2, a notion that was supported by impaired intracellular signaling following GPVI stimulation, as assessed by protein tyrosine phosphorylation. Jak2Plt-/- platelets adhered poorly to type I collagen under arterial shear rates in whole blood. However, JAK2 deletion in platelets did not alter plasma von Willebrand factor (VWF) levels or botrocetin-mediated binding of plasma VWF to GPIbα. Together, the results underline a critical role for JAK2 in platelet GPVI signaling and hemostatic function, which likely contributes to venous and arterial thrombosis observed in patients with MPNs with the activating JAK2V617F mutation.

Disclosures
No relevant conflicts of interest to declare.