bluuebunny/crossref_metadata_2025_split huggingface dataset:
A GUT Microbiota Score Predicting for ACUTE GRAFT-Versus-Host Disease
Authors: Han Lijie , Peng Jie , Zhao Ke , Fan Zhiping , Jin Hua , Zhang Haiyan , Sun Hui , Liu Qifa , Jiang Zhongxing 
Published: November 2019

Although some studies have reported that intestinal microbiota is associated with aGVHD, they inadequately lacked a satisfactory method for precisely predicting aGVHD occurrence. We collected stool and blood samples at day 15 post-transplantation from 150 patients, who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from two independent centers. Stool microbiota was detected by 16S rRNA gene sequencing, inflammatory factors in blood were detected by multiplex immunoassays, and T lymphocyte subsets were examined by flow cytometry. A gut microbiota score (GMS) from a LASSO (least absolute shrinkage and selection operator) model using the gut microbiota was developed and validated to predict aGVHD. The discovery cohort included most of the identified bacterial families. As determined by area under the curve (AUC) analysis of ROC plots, the GMS could predict aGVHD in grades II-IV (AUC = 0.904, P < 0.0001). Furthermore, the GMS model in the validation set also demonstrated a high AUC that was consistent with the discovery set (AUC = 0.887, P < 0.0001). The results also indicated that the ratio of Treg/Th17 cells in the low GMS subgroup was higher compared with the high GMS subgroup (P = 0.012), and the validation set was consistent with the discovery set (P = 0.003). In addition, high cytokine levels (including IL-1β, IL-6, IL-17, and TNF-α) were associated with high GMS. In conclusions, the GMS at neutrophil engraftment could predict the subsequent aGVHD, and it is a potential and novel method. The GMS was associated with the inflammatory factor levels and Treg/Th17 balance.

Disclosures
No relevant conflicts of interest to declare.
Comprehensive Genomic Profiling of Adult T-Cell Lymphoblastic Lymphoma in Chinese Patients
Authors: Chen Feili , Guo Hanguo , Huang Ling , Jiang Xinmiao , Wei Xiaojuan , Li Wenyu 
Published: November 2019

Background:
T-cell lymphoblastic lymphoma (T-LBL) is a rare, aggressive neoplasm of precursor T cells that occurs mostly in adolescents and young adults. Extensive genomic analyses of T-LBL have discovered genes encoding adhesion molecules and extracellular matrix proteins in samples from T-LBL patients, with most studies being performed on patients in the Western hemisphere. We sought to define the mutational profile of T-LBL in Chinese patients.
Methods:
We collected 15 adult T-LBL biopsies from one center in China with confirmed pathologic diagnosis and treatment information. Median cohort age at diagnosis was 26.0 years. The male/female ratio was 13/2. DNA was extracted from formalin-fixed paraffin embedded samples, and targeted deep next generation sequencing (NGS) analyses were performed.
Results:
Mutation features were revealed in this Chinese T-LBL analysis. NOTCH1 mutations were found in 67% (10/15) of T-LBL patients (pts) with the highest mutation frequency. PHF6 mutations were seen in 53% (8/15) of cases. TP53mutations were seen in 53% (5/15) of T-LBL cases. JAK1 and JAK3 mutations were seen in 27% (4/15)of T-LBL cases respectively. Mutations at histone modification genesincluded SUZ12 (20%, 3/15), EZH2(13%, 2/15), and EP300 (7%,1/15). Other mutations included PTEN(27% 4/15), DNM2 (27% 4/15).
Discussion:
The aim of our study was to reveal the genomic landscape of Chinese T-LBL. The cohort collection was unbiased, the patients' features were in concordance with previous reports that the disease of T-LBL is mostly found in the young patients and shows male predominance. The most predominant somatic mutation wasNOTCH1, which is also usually seen in T-ALL. Mutations at histone modification genes were also seen in our study. NGS studies have identified epigenetic modifiers mutations as a hallmark of T-LBL, highlighting an attractive therapeutic target in this disease. In summary, this effort has identified novel mutation features in Chinese T-LBLs that can potentially lead to more effective treatments in Chinese population.

Disclosures
Li: Guangdong Province Hospital: Employment.
A Phase II Study of Lenalidomide Plus Rituximab in Patients with Newly Diagnosed Follicular Lymphoma: An Interim Analysis
Authors: Zheng Zhong , Wang Li , Cheng Shu , Xu Pengpeng , Zhao Weili 
Published: November 2019

A Phase II Study of Lenalidomide Plus Rituximab in Patients with Newly Diagnosed Follicular Lymphoma: An Interim Analysis
Zhong Zheng1, Li Wang1,2, Shu Cheng1, Peng-Peng Xu1, Wei-Li Zhao1,2
1State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China
Abstract
Background: Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma (iNHL). Rituximab plus chemotherapy for FL significantly improves the outcome of the patients, nevertheless, most patients ultimately relapse. Therefore, novel agents along with Rituximab have been applied to increase treatment efficacy in this subset of iNHL patients. Tumor immune eascape plays a crucial role in lymphoma progression. Through modulating tumor microenvironment, lenalidomide, are emerging as effective therapeutic approaches to affect tumor immunity and inhibit lymphoma cells proliferation. However, its anti-tumor activity activity has not yet been assessed in de-novo chinese FL patients. This prospective phase II study is to evaluate the efficacy and safety of lenalidomide in combination with Rituximab (R2) in newly diagnosed FL patients (NCT 03715309).
Methods: Patients with newly diagnosed FL (grade 1 to 3a), aged 16 to 75 years, Eastern Cooperative Oncology Group performance status of 0 to 2 are enrolled. The doses and administration schedule are as follows: rituximab 375 mg/m2 on day 0, lenalidomide 25mg from day 1 to day 10 every 3 weeks for 6 cycles. The primary endpoint is complete response (CR) rate assessed by PET-CT, and secondary endpoints include progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and main adverse events (AEs).
Results: To date, eighty-six patients have been enrolled, with median age of 48 years (range, 22-73). At diagnosis, Seventy-seven patients (89.5%) presented advanced Ann Arbor stage and 19 cases (22.0%) showed elevated serum LDH level. Twenty-nine patients (33.7%) had multiple extra-nodal sites involving bone marrow, bone, gastrointestinal, and spleen. Twenty-one patients (24.4%) had IPI scores ≥ 3. For Sixty-four patients available for response evaluation, the CR rate was 81.2% (52/64) and the ORR was 90.1% (58/64). Grade 3-4 neutropenia was found in 18 cases (20.9%). No grade 3-4 thrombocytopenia and grade 3-4 anemia were observed. For non-hematological AEs, cutaneous reactions and tumor flare reaction were observed in 12 cases (13.9%) and in 1 case (1.16%), respectively, while no grade 4 non-hematological AEs were presented.
Conclusion: Lenalidomide Plus Rituximab as first-line therapy for de novo patients with FL showed encouraging response and good tolerability.

Disclosures
No relevant conflicts of interest to declare.
AAV8-Specific Immune Adsorption Column: A Treatment Option for Patients with Pre-Existing Anti-AAV8 Neutralizing Antibodies
Authors: Kruzik Anita , Raim Roland , Voelkel Dirk , Weiller Markus , Hoellriegl Werner , Scheiflinger Friedrich , Rottensteiner Hanspeter , Reipert Birgit M , de la Rosa Maurus 
Published: November 2019

Background: Pre-existing neutralizing antibodies (NAbs) are a major hurdle in adeno-associated virus 8 (AAV8) gene therapy and result in patients being excluded from clinical trials. Prevalence data published by Kruzik et al. suggest that up to 50% of patients have biologically relevant NAbs against AAV8, excluding them from current clinical trials. We developed a strategy to circumvent pre-existing anti-AAV8 immunity and specifically remove anti-AAV8 antibodies.
Aim: Develop an AAV8-specific immune adsorption column (IAC) to specifically remove anti-AAV8 antibodies.
Methods: An AAV8-specific IAC was developed. Protocols were optimized to couple AAV8 capsids to activated sepharose. All procedures complied with regulatory requirements to accelerate clinical development. Accompanying mouse studies tested potential concomitant immune suppressive regimens in Bl/6 mice using AAV8-FIX vectors. NAbs were assessed using validated NAb assays of confirmed biological relevance. Titers of AAV8 binding antibodies were assessed by ELISA and T-cell responses by IFN-g ELISpot.
Results: Optimized coupling protocols revealed that AAV8 empty capsids can be linked in a stable way to resin. IAC was tested in vitro and in macaques: An IAC could be developed fitting into approved and marketed platforms for immune apheresis. By applying standard experimental procedures for apheresis column development, we showed an IAC can deplete AAV8 binding antibodies and NAbs with greater efficacy than a pan-Ig adsorber (Therasorb-IgOmni). We mimicked treatment of patients in vitro by applying different treatment cycles to plasma reservoirs and showed anti-AAV8 titers of 1:5260 could be depleted to undetectable levels in 4 to 5 treatment cycles. These data are supported by in vivo studies. The IAC is part of a strategy that uses concomitant immunosuppressants to block potential anti-AAV8 T-cell responses.
Conclusion: IAC is an enabler for treatment of patients with pre-existing immunity against AAV8 and would also facilitate re-administration. IAC is intended to be applied in combination with Takeda's AAV8 based hemophilia programs.

Disclosures
Kruzik: Baxalta Innovations GmbH, a Takeda company: Employment. Raim:Baxalta Innovations GmbH, a Takeda company: Employment. Voelkel:Baxalta Innovations GmbH, a Takeda company: Employment. Weiller:Baxalta Innovations GmbH, a Takeda company: Employment. Hoellriegl:Baxalta Innovations GmbH, a Takeda company: Employment, Equity Ownership. Scheiflinger:Baxalta Innovations GmbH, a Takeda company: Employment, Equity Ownership. Rottensteiner:Baxalta Innovations GmbH, a Takeda company: Employment, Equity Ownership. Reipert:Baxalta Innovations GmbH, a Takeda company: Employment, Equity Ownership. de la Rosa:Baxalta Innovations GmbH, a Takeda company: Employment.
Epigenetic Plasticity of Type II Innate Lymphoid Cells in the Lower Gastrointestinal Tract
Authors: Laurie Sonia J. , Bruce Danny W. , Bommiasamy Hemamalini , Noel Melodie P , Foster Joseph P. , Davis Ian J. , Pattenden Samantha G. , Serody Jonathan S 
Published: November 2019

Though hematopoietic stem cell transplantation (HSCT) is the preferred treatment for a variety of blood malignancies, its use is limited by the development of acute graft-versus-host disease (aGvHD). Type II innate lymphoid cells (ILC2s) are immune cells that play an important role in maintaining mucosal homeostasis, and our lab has previously shown that ILC2s in the gastrointestinal tract (GI) are sensitive to conditioning therapy prior to HSCT. Strikingly, we have demonstrated that the infusion of activated donor ILC2s markedly reduces aGvHD-associated mortality. We therefore wanted to investigate the mechanism of the loss of protective ILC2s from the GI tract. We hypothesized that ILC2s fail to repopulate the gut after HSCT due to inflammatory environmental cues that convert ILC2 precursors to an alternate, ILC1- or ILC3-like fate. Thus, we evaluated the impact of cytokines associated with commitment on murine ILC2s by exposing them to cytokines that may promote differentiation to an ILC1 or ILC3 fate (IL-1b/IL-12/IFN-γ and TGF-b/IL-6/IL-23, respectively). We found ILC2 cells acquired the ability to secrete TNF and IL-17 after in vitro skewing (with these lineage-defining cytokines. To test the ability of these "ex-ILC2" cells to home to other tissues in vivo, GFP-ILC2s were infused into recipients at the time of transplantation. We tracked GFP-ILC2s to the liver and spleen, where they made IFN-g and IL-17 and expressed transcription factors associated with the ILC1 and ILC3 lineages (Figure 1). Next we assessed the ability of cytokines alter ILC2 fate via epigenetic reprogramming by using ChIP-sequencing to evaluate the presence of histone marks that may underlie cellular plasticity. We show that these changes are associated with alterations in epigenetic marks around pioneer, lineage-determining factors. We therefore chose to test a screen of compounds known to modulate a variety of epigenetic targets to ask if they can maintain or convert ILC2s to alternate fates and identified a number of compounds that target bromodomains, methyltransferases, and histonedeacetylases, respectively, that alter the viability and differentiation of ILC2s into an "ex-ILC2"-like phenotype. Preliminary work suggests that maintenance ofG9a expression is able to rescue the loss of ILC2s, which is being tested in vivo. Taken together, these data provide new insights into mechanisms by which innate lymphoid cell precursors are epigenetically regulated, providing novel approaches to treating aGvHD following HSCT.
Figure 1

Disclosures
Davis: Triangle Biotechnology: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Pattenden:Triangle Biotechnology, Inc.: Equity Ownership, Other: Inventor on intellectual property. Serody:Merck: Research Funding; GlaxoSmithKline: Research Funding.
This Is a Title in Title Case: Prediction of CML Evolution By Telomere Length Analysis at the Single-Chromosome Level
Authors: Lu Jingyuan , Zhou Yingxing , Yan Xiaomei , Lu Quanyi 
Published: November 2019

Telomeresplay a vital role in DNA repair activities and protecting chromosomes from degradation[1]. Telomeres are shortened during each cell division because of the end replication problem. After several cell division, telomeres are shortened to a critical length (< 3 kb), and eventually lead to overall genomic instability and triggering the DNA damage response[2-3], which is related to the cancerization of numerous cancers. The commonly used method to estimate telomere length isterminal restriction fragment (TRF) basedon southern blot, which requires thousands of cells and provides only a crude estimate of the average telomere length of all cells analyzed. However, it is believed that the frequency of critically short telomeres, rather than the mean telomere length, is a crucial factor for telomere dysfunction. Therefore, analysis of telomere length at the single-chromosome level is necessary to determine the frequency of critically short telomeres.
Here, we describe the development of a high-throughput method for telomere length analysis at the single-chromosome level by using a laboratory-built high-sensitivity flow cytometer (HSFCM)[4] combined with targeted fluorescent peptide nucleic acid (PNA) probes. The unambiguous detection of the telomere signalsfrom a single chromosome was achieved via HSFCM analysis. The fluorescence intensity of single chromosome was converted to the probe number by a calibration curve, and was further transformed to the base pair number of the telomere. Five representative cell lines were analyzed to compare their telomere length and the ratio of critically short telomeres at the single-chromosome level. The potential of using frequency of short telomere for disease treatment monitoring is examined by analyzing the telomere length in lymphocyte of leukemia patients. The abundance of short telomeres was compared between healthy donors and patients with chronic myeloid leukemia (CML) to see whether it can be used to predict the efficacy of therapeutics. Moreover, the quantity of short telomeres was compared among patients with acute leukemia, patients in different phases of CML and healthy donors to see whether it can be used as a marker for disease progression prediction in CML.
Reference
[1] Blackburn E. H., Epel E. S., Lin J., Science,2015, 350, 1193-1198.
[2]Collado M., Blasco M. A., Serrano M., Cell, 2007, 130, 223-233.
[3] Deng Y., Chan S. S., Chang S., Nat. Rev. Cancer, 2008, 8, 450-458.
[4] Yang LL, Zhu SB, Hang W, Wu LN, Yan XM, Anal. Chem., 2009, 81, 2555-2563.
Figure 1

Disclosures
No relevant conflicts of interest to declare.
Invasive Fungal Disease Following Myeloablative Cord Blood Transplantation for Patients with Hematological Malignancies
Authors: Li Duihong , Jiafu Huang , Li Xiaofan , Jing Zheng , Fu Haiying , Xu Zhenshu , Chen Yuanzhong , LI Nainong 
Published: November 2019

Objective: Invasive fungal disease (IFD) is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). However, limited data is available on its clinical features after cord blood transplantation (CBT) for patients with hematological malignancies.
Method: We retrospectively reviewed 63 patients who underwent myeloablative CBT at our institution between July 2013 and June 2019 with a median follow-up of 14 months. Micafungin, Voriconzole or Posaconazole was used for IFD prophylaxis.
Results: Eight patients were identified as having an IFD, including 2 with proven IFD, 1 with probable IFD, and 5 with possible IFD. The most common prophylaxis regimen is micafungin (68.2%, 43/63). The incidence rate of IFD in the primary antifungal prophylaxis (PAP) and secondary antifungal prophylaxis (SAP) groups were 11.3% and 25% (P=0.488). The OS of day at +100, six months and +200 in the IFD and No IFD groups were 62.5% vs. 86.9% (P=0.1), 50 % vs.78.2% (P=0.07), and 50% vs.75.9% (P=0.094), respectively. The 3-year probabilities of overall survival (OS) in the IFD and No IFD groups were 50% and 60.5%, respectively (p=0.316). The incidence rate of Non-relapse Mortality in the IFD and No IFD groups were 42.9% and 30%, respectively (p=0.319).
Conclusion: Antifungal prophylaxis could help to reduce the incidence of IFD after CBT for patients with hematological malignancies.
Figure

Disclosures
No relevant conflicts of interest to declare.
Clinical Utility of Flow Cytometry Immunophenotyping in Acute Myeloid Leukemia
Authors: Oliveira Gustavo Henrique de Medeiros , Júnior Lenilton Silva DA Silva , Silva Antonia Eduarda Martins Oliveira Elói , Lima João Pedro Andrade , Soares Victor lima , Freitas Rodrigo Villar , Oliveira Taissa Moura , Silva Dany Geraldo Kramer Cavalcanti , Sales Valéria SF , Paiva Hugo Diogenes De Oliveira , Araujo Rafael Santiago , Paiva Aldair Sousa , Cavalcanti Geraldo Barroso , Silva Alessandra Suelen Jardim 
Published: November 2019

INTRUDUCTION: Acute myeloid leukemia (AML) is a heterogeneous group of clonal disease of hematopoietic tissue, characterized by proliferation of abnormal myeloid progenitor cells, suppressing the normal hematopoietic activity and constituting a great diagnostic challenge. With the advent of immunophenotyping by flow cytometry, the diagnosis of these neoplasms became more faithful, facilitating the treatment and follow-up of the patients. METHODS: In this study a flow cytometric immunophenotyping study was performed in bone marrow aspirate and / or peripheral blood samples from 38 patients with AML, using a panel of monoclonal antibodies specific for acute leukemias, also investigating clinical, laboratory and demographic data of these patients. RESULTS AND DISCUSSION: Of the 38 subjects studied, 23 were male and 15 females. In relation to the age, we found a higher number of cases in adult patients. According to clinical data, splenomegaly and hepatomegaly were present in most cases. The immunophenotyping demonstrated a characteristic profile of AML with expression of CD13 and CD33 in all cases and CD34 and CD117 in most cases. The CD14 was reactive in monocytic leukemia (M4 and M5-AML). Were observed negativity for lymphoid antigens CD19, CD10 and CD3 and positivity to CD7, CD56 and CD2, present in 10, 5 and one cases respectively. Regarding cytomorphology, there was a direct correlation with FAB classification, with the prevalence of type myeloid-monocytic (AML-M4). CONCLUSION: These data demonstrate the importance of immunophenotyping in the differential diagnosis of AML and monitoring of these neoplasms.

Disclosures
No relevant conflicts of interest to declare.
One-Year Outcomes with Once or Twice Daily Enoxaparin
Authors: Klil-Drori Adi J. , Nazha Sara , Gharib Marlene , Perreault Sylvie , Tagalakis Vicky 
Published: November 2019

Background: Enoxaparin given once daily (QD) for thrombotic disorders is less burdensome than twice-daily (BID) dosing. However, long-term outcomes when enoxaparin given as QD monotherapy are unknown.
Methods: We did a population-based cohort study. New users of enoxaparin alone (2005-2014) were identified in the linked healthcare databases of Quebec, Canada, and followed up for up to one year. The number of dispensed syringes divided by prescription length determined QD or BID enoxaparin by intention to treat. Cumulative rates of major bleeding and re-treatment with anticoagulants at one year were compared between enoxaparin groups. Re-treatment was initiation of anticoagulation after at least 30 days of no dispensed anticoagulants. The duration of enoxaparin monotherapy was the sum of prescriptions until discontinuation.
Results: The cohort included 504 patients; QD and BID enoxaparin users were 445 and 59, respectively. Mean (SD) age was 78.0 (6.6) years, 43.8% were males, and 61.9% had cancer. At 12 months, major bleeding occurred in 21 (4.7%) and 4 (6.8%) among QD and BID enoxaparin users, respectively (Figure 1A, P = 0.49). Re-treatment with anticoagulants occurred in 37 (9.6%) and 5 (9.4%) of QD and BID users, respectively (Figure 1B, P = 0.98). The duration of enoxaparin monotherapy was on average 13.9 (95% CI, 4.4-23.4, P = 0.005) days longer with QD vs BID use.
Conclusions: Monotherapy with QD enoxaparin was common and longer than BID enoxaparin with no apparent differences in bleeding or re-treatment with anticoagulants.
Figure 1

Disclosures
Klil-Drori: Sanofi Canada: Research Funding. Nazha:Sanofi Canada: Employment. Gharib:Sanofi Canada: Employment. Perreault:Sanofi Canada: Research Funding. Tagalakis:Servier: Other: participated on ad boards; Bayer: Other: participated on ad boards; Pfizer: Other: participated on ad boards; Sanofi Aventis: Other: investigator initiated grant;participated on ad boards; BMS-Pfizer: Other: participated on ad boards.