bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility of Population Scale Comprehensive Identification and Analysis of Complex Structural Variations in Cancer Genome Using Nanochannel Array
Authors: Hastie Alex , Lam Ernest , Dai Heng , Andrews Warren , Pang Andy , Anantharaman Thomas , Saghbini Michael , Sadoski Henry , Austin Michael , Dickinson Todd , Yang Xing , Dzakula Zeljko , Rossi Michael R. , Kwok Pui , Xu Xun , Cao Han 
Published: October 2019

Abstract
Diseases with complex traits such as hematological cancer are known to be associated with large structural variations (SV > 1 kb). Techniques such as karyotyping, FISH and aCGH have been common tools for gross chromosomal lesion analysis. Yet population scale comprehensive SV analysis with these tools remains impractical, tedious or incomplete such as missing balanced lesions by aCGH. Recently, high throughput Next Generation Sequencing (NGS) has generated a large amount of sequencing reads that have rapidly reduced costs and are effective in detection of SNPs and small indels; however, complicated by the fact that large structural variations, often spanning tens to hundreds of thousands of base pairs or involving complex rearrangements throughout the genome, are hard for current short read sequencing technology to assemble or infer. Therefore, there is a blind spot in effectively detecting SVs within this range (1 kb ~ 1 Mb) due to insufficient tools.
Here we demonstrate a technology that rapidly linearizes very long strands of genomic DNA (100 kb to Mbs) through NanoChannels to directly visualize large SVs and rearrangements preserved within intact genomic DNA at the single molecule level. Through specific sequence motif labeling, de novo genome physical maps are assembled within hours and hundreds to thousands of SV events, balanced or imbalanced, are called with no a priori knowledge of the samples. Preliminary testing data from a group of cancer samples and multiple trio families will be shown to demonstrate this highly comprehensive and cost effective approach, with results validated by direct single-molecule images and multiple orthogonal methods. We also show long spanning molecules would provide very valuable information of precise mapping of viral genomic sequence integration in human genomes that are potentially associated with malignant cell transformation. For the first time, it is now feasible to do large population-based comprehensive genome structural variation studies on a single platform. This innovations will transform the biomedical research, diagnosis and treatment of hematological cancers that result from structural variations and chromosomal lesions.

Disclosures
No relevant conflicts of interest to declare.
Meta-Analysis of Pharmacotherapy Vs. Observation for Management of Smoldering Multiple Myeloma
Authors: Vijayakumar Jayanthi , Jackson Jeffrey , Ahn Kwang W , Hari Parameswaran N. 
Published: October 2019

Abstract
Introduction:
Asymptomatic or smoldering multiple myeloma (SMM) is usually 10-15% of all patients with multiple myeloma. Currently, national guidelines do not recommend early treatment of SMM though the majority of patients progress to active disease over time. Multiple trials have been conducted to evaluate implications of early therapy for SMM. Some of these trials, most notably, Mateos et al. (N Engl J Med 2013; 369:438-447) have shown benefit for treating SMM. However, there is lack of consensus as to whether early treatment of SMM prior to symptomatic disease progression is superior to observation alone. Hence we conducted a meta- analysis to determine if observation or treatment is superior in the management of SMM.
Methods:
We searched MEDLINE, the Cochrane database and hand-search of articles to identify 12 clinical trials which allocated SMM patients to treatment. Study quality was assessed using the Cochrane risk of Bias tool. Our main outcomes were progression free survival (PFS) and overall survival (OS). Sub-analysis examined the difference in treatment with antineoplastic agent (C), bisphosphonates (B), or their combination (CB). Data were pooled using a random effects meta-analysis using STATA (College Station Texas, V13.2).
Results:
Among the 12 trials, 4 trials were excluded due lack of survival curves for OS, PFS, TTP. Characteristics of the 8 included clinical trials are given in Table 1. Participants treated for early SMM had reduced mortality (HR: 0.64, 95% CI 0.4-1.0) and better PFS (HR=0.83, 95% CI, 0.64-1.07) compared to the observation group. In subgroup analysis, patients treated with either antineoplastic agents or the combination of antineoplastic agents and bisphosphonate had a better OS and PFS, whereas therapy with only bisphosphonate did not impact OS or PFS (Figures 1, 2).
Conclusion:
We conclude that antineoplastic treatment or a combination of antineoplastic agents and bisphosphonates is better than observation in improving overall survival in SMM patients. A similar trend is seen with PFS. This conclusion merits caution given the limited data available and the differences in the agents used for therapy.
Figure 1 Figure 1.
Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
A Comparison of Human CMVpp65-Specific Central Memory and Effector Memory CD8 T-Cells When Stimulated in-Vivo with IL-2 or IL-15/IL-15Rα Complex in a Murine Xenograft Model of Adoptive Cell Therapy
Authors: Kuo Tzu-Yun , Hasan Aisha , O'Reilly Richard J 
Published: October 2019

Abstract
Initial clinical trials of adoptive immunotherapy have shown that the efficacy of adoptively transferred T-cells in man is often limited by the failure of cultured T cells, particularly cloned CD8 T cells, to persist in vivo. These studies demonstrated that the transferred T cells induced only transient responses and that persistence of the transferred T-cell clonotypes correlated with disease regression. A previous study suggested that CMV virus-specific CD8 T cell clones derived from central memory T cells (TCM), but not effector memory T cells (TEM), persisted long-term in non-human primates. On the other hand, another study comparing TCM and TEM derived SIV virus specific CD8 T-cell clones that were adoptively transferred in non-human primates demonstrated limited persistence of both TCM and TEM derived transferred T cells, and failed to show any difference between the two cell types. Because of these conflicting data, we have reexamed the persistence of adoptively transferred viral antigen specific T-cells derived from TCM and TEM population. Accordingly, we developed a NOG mouse model for studying the ability of human CMVpp65-specific T cells derived from central memory and effector memory populations to migrate to and accumulate in human tumor xenografts expressing CMVpp65, to alter the growth of these tumors and to persist in the tumors. This model also allows us to test immunomodulating agents and their ability to enhance targeted T-cell accumulations, antitumor activity and persistence. We analyzed CMVpp65-specific CD8 T cells derived from TCM and TEM precursors in vitro and in vivo. To tract the T-cells in vivo, we transduced membrane-bound Gaussia luciferase into TCM and TEM populations and monitored T cell trafficking by in vivo bioluminescence. Contrary to expectation, our results initially showed no differences between TCM and TEM derived CMVpp65-specific T-cell in mice co-treated with IL-2 in the time to accumulation, ultimate level of accumulation, degree of CMVpp65+ tumor regression or T-cell persistence. However, in mice cotreated with IL-15/IL-15Rα complex, both TCM and TEM exhibited more sustained engraftment and more prolonged accumulation in both the targeted tumor and in the marrow. In mice treated with IL-15/IL-15Rα, TCM and TEM derived T cells showed a similar effector memory phenotype and a similar level of regression of tumor growth. Thus, adoptive transfer of CMVpp65 specific TCM or TEM when combined with IL-15/IL-15Rα complex may support better persistence of antigen-specific T-cells following adoptive immunotherapy. Studies comparing IL-15/IL-15Rα complex with IL-15 alone are in progress.

Disclosures
No relevant conflicts of interest to declare.
Spontaneous Apoptosis of the Lymphocytes in Cord Blood of Late Preterm Newborns
Authors: Wasiluk Alicja , Zak Janusz , Warda Janusz 
Published: October 2019

Abstract
Background/Aims: Apoptosis plays an important role in shaping the repertoire of lymphocytes and in regulating the size of the mature lymphocyte pool. The best-defined regulators of apoptosis in T cells are members of the Fas and Bcl families. Fas/FasL pathway is critically involved in the elimination of mature, self-reactive lymphocytes. Bcl-2 protein is important for lymphocyte survival in response to growth factors and various activating stimuli. We have compared the role of CD4+, CD8+, Fas, FasL and Bcl-2 in spontaneous apoptosis of T lymphocytes from cord blood and tested there is or not relation to gender.
Patients and Methods: We have introduced 28 late preterm newborns to our studies, 15 females and 13 males. Blood was collected from umbilical artery immediately after cutting cord. We have determined the following parameters: the per cent of CD4+ and CD8+ lymphocytes, the Fas and FasL phenotype and Bcl-2 using flow cytometer Coulter PC 500, Krefeld, Germany.
Results: We have found the increase per cent of CD4+ in females 56.10 %, in relation to males 38.15 %. The same per cent was found for CD8+ in both gender: 19.60 % females, 17.35 % males.
The antigen Fas (CD95) was more expressed in females: on CD4+ 12.80 %, CD8+ 8.15 %, in comparison to males: CD4+ 9.89 %, CD8+ 6.06 %. FasL (CD95L) was lower per cent in females: both on CD4+ 6.92 %, CD8+ 5.68 %, in relation to males: CD4+ 8.94 %, CD8+ 7.04 %. Bcl-2 was a little lower in females on CD4+ 96.9 % and evidently lower on CD8+ 79.14%. In males we noted on CD4+ 97.40% and on CD8+ 93.01 %. Summarizing our findings we can underline T lymphocytes in females are more activated, what indicate Fas. Inhibitor of apoptosis Bcl-2 is less expressed in females, in comparison to males lymphocytes.
Conclusion: Our preliminary results seems to indicate spontaneous apoptosis of T lymphocytes is more expressed in female newborns.
Table I. Spontaneous apoptosis of the T lymphocytes in cord blood of late preterm newborns. N Gender Lymphocyte T % Fas % FasL % Bcl-2 % 15 Female CD4+ 56.10 12.80 6.92 96.90 13 Male 38.15 9.89 8.94 97.40 15 Female CD8+ 19.60 8.15 5.68 79.14 13 Male 17.35 6.06 7.04 93.01

Disclosures
No relevant conflicts of interest to declare.
The "Platelet Boilermaker" Is an Option for Quickly Raising Platelet Counts in IVIG Refractory ITP
Authors: Deloughery Thomas G. 
Published: October 2019

Abstract
Most patients with immune thrombocytopenia (ITP) respond to first line therapy. Rarely there are patients who remain with very low platelet counts despite administration of intravenous immune globulin (IVIG). A protocol at our institution (colloquially known as the "platelet boilermaker") for these refractory patients is to give 1 gram/kg of IVIG continuously over 24 hours concurrent with one unit of plateletpheresis product given over 6 hours repeated times 4. We examined the charts of 10 patients in the past 6 years who have received combined therapy. 70% were male; all were refractory to steroids and IVIG. Results are in table: Abstract 5023. TableAgeGenderDiseaseBleedingPlts PreDay +1Day+2Day+3Results65MEvansGIB1110510Stopped bleeding59MITP, CLLBruising3656No response34FITPPregnancy2583175150Delivered81FITPEpistaxis15384167Splenectomy day +123FITPEpistaxis552165Splenectomy day +164MDITPEpistaxis, ruising252427Stopped bleeding89MITPEpistaxis4655046Splenectomy day +157MITPBruising9586946Splenectomy day +128MITPICH14133325326No extension78MITPGIB27354498Splenectomy day +1
Plt = platelet count x 109/L
DITP = drug induced ITP, ICH - intracranial hemorrhage. GIB - gastrointestinal bleeding
9/10 patients had at least a transient rise in platelets greater than 30x109/L - 5 patients underwent emergent splenectomy with no bleeding complications. The patient with ICH had no extension and while the other patients who responded had cessation of bleeding. In summary for patients with IVIG refractory ITP who either have bleeding or need urgent splenectomy combined continuous platelets/IVIG is a therapeutic option.

Disclosures
Off Label Use: profilnine - warfarin reversal rVIIa - warfarin reversal.
Analysis of Using Low Dose 3 Factor PCC (Bebulin®) for INR Reversal in Patients with Warfarin Induced Severe/Life-Threatening Bleeding
Authors: Mekan Sabeen F. , Logdberg Lennart , Stein Arline , Nash Leah , Cohen Jessica , Rosenberg David 
Published: October 2019

Abstract
Background: 3 Factor Prothrombin Complex Concentrates have been used off label with plasma products for effective and timely reversal of INR in patients on Warfarin presenting with severe bleeding. The exact dosage required for this purpose has yet to be determined.
Methods: We conducted a retrospective review of all patients taking Warfarin who presented to our institution between January 1, 2013 to June 30, 2014 who received 3 Factor Prothrombin Complex Concentrate (PCC) Bebulin® for INR reversal for significant/lifethreatening bleeding. The dose of Bebulin was determined by clinical judgment by the blood bank and the treating physician in accordance with the patient’s weight, bleeding location and the presenting INR.
Results: A total of 116 patients were treated. Mean age was 72 years. Forty-two (36.21%) of patients were female. Most common bleeding site was intracranial (n=61), followed by systemic hemorrhage (n=24), GI bleeding (n=16), trauma (n=10) and other bleed (n=5). Some patients were also on other anticoagulants besides Warfarin – 28 patients (24%) were on Aspirin and 9 (7.8%) on Plavix. The mean INR prior to Bebulin treatment was 3.62 which dropped to 2.05 at an average of 2.2 hours post-treatment. Mean level at 12 hour post-Bebulin dropped to 1.57. The average patient received 2 units of plasma and 1 unit of packed red cell transfusions. The average Bebulin dose administered was 959 IU (SD +/-465 IU) with average patient weight of 82.9 kg (SD +/- 27kg). Based on this the average Bebulin dose administered was 11.57 IU/kg. Eighty-eight patients (76%) were able to be discharged home or to a skilled nursing facility.
Thirty-six patients (31.1%) required more than one dose of Bebulin®. Mean INR at presentation in this group of patients were not similar to the remainder of the group. Mean INR at average of 2.5 hours post-Bebulin in this group was 2.18 which dropped further to an average of 1.75 at 9 hours. The total average Bebulin dose incrementally administered was similar in both groups.
Conclusion: Low dose Bebulin at doses of approximately 12 IU/kg with 2 Units of plasma was effective in timely reversal of INR in majority of patients who presented with Warfarin induced bleeding.

Disclosures
Off Label Use: Bebulin (3 Factor PCC) is approved for use in Hemophilia patients; we discuss using low dose for INR reversal in Warfarin associated bleeding.
Down-Regulation of HO-1 Promoted Apoptosis Induced By Decitabine Via Increasing p15INK4B Promoter Demethylation in myelodysplastic syndrome
Authors: Wang Jishi , Ma Dan , Fang Qin , Wang Ping , Gao Rui , Sun Jia 
Published: October 2019

Abstract
Background: Decitabine, reverts hypermethylation of p15INK4B gene in vitro, was used to improves cytopenias and blast excess in over 50% of patients with high-risk myelodys plastic syndrome (MDS). In this study, over-expression of Heme Oxygenase-1(HO-1) was found in MDS cells line SKM-1 cells, and it was closely related to resistance to apoptosis induced by decitabine.
Objective: we aimed to further investigated what role of HO-1 exactly played in apoptosis induced by low-does of decitabine in MDS.
Method: CCK-8 kits was used to determine the proliferation inhibition of SKM-1 cells. Flow cytometry was used for analyzing cell proliferation rate and apoptosis. The methylation status and expression of P15INK4B in mRNA and protein levels were measured by methylation-specifc polymerase chain reaction (PCR [MSP]). Apoptosis relative factors expression were detected by real-time transcription and Western blot.
Result: Up-regulation of HO-1 by transfected it into SKM-1 cells via lenti-virus vector promoted proliferation and protected cells against apoptosis. In contrast, down-regulation of HO-1 enhanced decitabine-induced apoptosis but reduced accumulation of S phase in cell cycle. To explore the mechanism, we detected cell cycle relative protein expression after SKM-1 cells were treated by decitabine in each group. As a result, over-expression of p15 INK4B and CDK4 were observed in SKM-1 cells which HO-1 was inhibited. And p15 INK4B and CDK4 expression-dependent apoptosis was related to caspase3 pathway. Even though HO-1 was silenced, but apoptotic rate never increased as caspase3 pathway was blocked.
Conclusion: As we known that p15 INK4B is a keypoint to regulate S phase of cell cycle, in our study, more obvious demethylation of p15 INK4B was seen in group of SKM-1 cells in which HO-1 was down-regulated. It’s equally in patients’ mononuclear cells who suffered from MDS. The worse the prognosis of MDS was judged, the more the mRNA level of HO-1 expressed. In conclusion, over-expression of HO-1 indicated resistance to demethylation of p15 INK4B induced by decitabine.

Disclosures
No relevant conflicts of interest to declare.
Wogonin Inhibits Angiogenesis Via a c-Myc/Hif-1α–dependent Pathway in Multiple Myeloma
Authors: Fu Rong , Guo Qinglong , Chen Yan , Song Huihui , Chen Baoan 
Published: October 2019

Abstract
Wogonin, a plant-derived flavone, has been shown to inhibit tumor angiogenesis. Angiogenesis is associated with multiple myeloma (MM) progression. However, the mechanisms that Wogonin inhibits angiogenesis in MM microenvironment are not well known. In this study, we investigated Wogonin inhibited tumor angiogenesis that correlated with the inhibition the secretion of vascular endothelial growth factor (VEGF) in MM cells. The c-Myc/Hif-1α–dependent pathway was essential to regulate MM cell-mediated angiogenesis and contributed to tumor growth. Wogonin inhibited c-Myc activation and down-regulated the expression of c-Myc and Hif-1α. Functionally, based on transient knockdowns and overexpression, our data delineate Wogonin inhibited VEGF production and secretion mediating tumor angiogenesis via c-Myc/Hif-1α–dependent pathway. Our data, therefore, identify Wogonin as a novel anti-angiogenesis compound to inhibit tumor promotion in MM.

Disclosures
No relevant conflicts of interest to declare.
Recovery Blasts in the Peripheral Blood in AML Patients Who Obtain a Complete Remission Is a Favorable Prognostic Indicator
Authors: Cook Nathaniel M. , Butera James N. , Reagan John L 
Published: October 2019

Abstract
Introduction: Many patients with Acute Myelogenous Leukemia (AML) will transiently develop blasts in the peripheral blood upon recovery of induction chemotherapy, despite going on to obtain a complete remission. These are presumably non-leukemic marrow blasts. Recovery blasts can sometimes reach over 20% in the peripheral blood in remission patients. The significance of recovery blasts cells after induction chemotherapy in patients with AML is not clear. We sought to define the incidence of recovery blastocytosis (RB) and determine if the presence of RB has prognostic relevance.
Methods: We performed a retrospective analysis of 72 patients with newly diagnosed AML who underwent induction chemotherapy with 7+3 (cytarabine and daunorubicin) with or without etoposide between the years of 2006 and 2013 at our institution. Patients were included in the analysis as having RB only if their blasts resolved by day 14 of induction chemotherapy, blasts reappeared upon recovery after day 14, recovery blasts were > 5% in the peripheral blood of a duration of >5 days, and subsequently resolved by day 45 and remission was obtained. We recorded patient's absolute and percentage peripheral blast counts on presentation, upon nadir and throughout recovery of induction chemotherapy. The incidence and level of RB in patients who achieved a remission was tabulated. This group (group 1) was compared to the patients who achieved a remission whom did not develop RB (group 2).
Results: 45/77 AML patients obtained a CR after induction chemotherapy. Recovery blasts were seen in 9/45 (20%) remission patients (group 1), with a median RB of 9% for a median duration of 8 days. Of these 9 patients, 4 developed RB > 10%, and 2 developed RB >20 % Group 1 did not differ in respect to age, gender, cytogenetic profile, etoposide use, or whether the patient received 1 or 2 induction therapies from the 36/45 remission AML patients who did not develop RB (group 2). Median survival for group 1 was = 1,376 days, and 1,036 days for group 2 (p= .035).
Conclusion: Recovery Blasts in the peripheral blood after induction chemotherapy is seen commonly in AML patients who obtain a complete remission. RB can be seen even as high as > 20% in remission patients. AML patients who develop RB on their way to remission after induction chemotherapy have a better overall survival then patients who do not develop RB.
Figure 1 Figure 1.
Graph 1. Kaplan-Meier survival curves for AML patients with RB (group 1) and without RB (group 2).

Disclosures
No relevant conflicts of interest to declare.
TGFβ and IL10 Have an Impact on Risk Group and Prognosis in Childhood ALL
Authors: Wiegering Verena , Taschik Julia , Haubitz Imme , Eyrich Matthias , Winkler Beate , Schlegel Paul Gerhardt 
Published: October 2019

Abstract
Introduction: Considering that cytokines play an important role in immune response and that many infectious, autoimmune and malignant diseases are influenced by cytokine production, we hypothesized that genetically determined cytokine gene polymorphism might have an important influence on prognosis in pediatrics acute lymphoblastic leukemia (ALL).
Methods: In this study, 95 pediatric ALL-patients were examined with regard to cytokine gene polymorphisms (TNFα, TGFβ, IL10 and IFNγ) and their potential association with prognosis. Moreover we analyzed the intracellular production of theses cytokines in patient T-cells.
Results: TGFβ high-producer-haplotypes were associated with high-risk ALL-patients (Codon 10: T/T) and with the tendency of a reduced overall survival, whereas IL10 high-producer-genotypes were associated with a reduced relapse rate and a superior overall survival compared to IL-10-low-producer patients. Gene-polymorphisms of the pro-inflammatory cytokines IFNγ and TNFα did not show an impact on prognosis and risk-group of ALL in our cohort. On a functional basis TNFα and IFNγ expression of T-cells at initial diagnosis was significantly reduced in high-risk- and T-ALL-patients in comparison to healthy controls.
Summary: Cytokine gene-polymorphisms of the regulatory/anti-inflammatory cytokines TGFβ and IL10, but not of the pro-inflammatory cytokines IFNγ and TNFα seem to have an impact on prognosis of pediatric ALL patients. Reduced capacity to produce pro-inflammatory cytokines at diagnosis may serve as a functional risk factor. These data may help in further risk stratification and adaptation of therapy-intensity.

Disclosures
No relevant conflicts of interest to declare.