bluuebunny/crossref_metadata_2025_split huggingface dataset:
LILRB4 Signaling in Leukemia Cells Mediates T Cell Suppression and Tumor Infiltration
Authors: Deng Mi , Gui Xun , Kim Jaehyup , Zheng Junke , Zhang Ningyan , An Zhiqiang , Zhang Chengcheng 
Published: October 2019

Abstract
Immune checkpoint blockade therapy has been successful in treating some types of cancers but has not shown clinical benefits for treating leukemia. This result suggests that leukemia exploits unique escape mechanisms. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukemia cells. It remains unknown whether these receptors can initiate immune-related primary signaling in tumor cells. Here we show that LILRB4, an ITIM-containing receptor and a monocytic leukemia marker, supports tumor cell infiltration into tissues and suppresses T cell activity via ApoE/LILRB4/SHP-2/uPAR/Arginase-1 signaling axis in acute myeloid leukemia (AML) cells. Blocking LILRB4 signaling using knockout and antagonistic antibody approaches eliminated AML development. Thus, LILRB4 orchestrates tumor invasive pathways in monocytic leukemia cells by creating an immune-suppressive microenvironment. LILRB4 represents an attractive target for treatment of monocytic AML.

Disclosures
Deng: Immune-Onc Therapeutics Inc.: Patents & Royalties. Gui:Immune-Onc Therapeutics Inc.: Patents & Royalties. Kim:Immune-Onc Therapeutics Inc.: Patents & Royalties. Zheng:Immune-Onc Therapeutics Inc.: Patents & Royalties. Zhang:Immune-Onc Therapeutics Inc.: Patents & Royalties. An:Immune-Onc Therapeutics Inc.: Patents & Royalties. Zhang:Immune-Onc Therapeutics Inc.: Patents & Royalties.
Thiotepa-Based Conditioning Regimen Compared to Non-Thiotepa Conditioning Regimen Prior to Allogeneic Stem Cell Transplantation in β Thalassemia Major: Impact on Survival
Authors: Tan Wanxia , He Yuelin , Feng Xiaoqin , Wu Xuedong , Li Chunfu , Jianyun Liao , Peng Zhiyong , Ruan Yongsheng , Hui Ge , Liu Xiaoting , Ren Yuqiong 
Published: October 2019

Abstract
This study is to investigate the survival impact of thiotepa as part of the conditioning therapy for β thalassemia major (TM) patients, undergoing HSCT from haploidentical and sibling cord blood transplant. We retrospectively analyzed 262 transplant patients and compared outcomes between Cyclophosphamide -fludarabinebusulfan - thiotepa (with TT group)and Cyclophosphamide fludarabine -busulfan(without TT group) regimens from July 2014 to July 2018. Transplantation was performed from 86 matched sibling (32.8%), 103 unrelated (39.3%) ,13 matched parent(5%), 41 haploidentical (15.6%), and 19 sibling cord blood (7.3%) donors, with a median follow-up of 27 months(1months-72months) and median age of 7 years old(2 ys-18ys). The overall survival (OS), thalassemia free survival (TFS), graft rejection (GR) and transplantation related mortality (TRM) among TT group and without TT group in matched sibling transplant patients was 97.6%, 97.6%, 0%, 2.4% and91.6%, 91.6%, 0%, 8.4% (P=0.355 in TFS), respectively; in unrelated transplant patients was 97.9%, 97.9%, 0%, 2.1% and 95.2%,93.3%, 1.9%, 4.8% (P=0.256 in TFS), respectively; in matched parent transplant was 90.9%, 90.9%, 0%, 9.1% and 100%. 100%, 0%, 0%;( P=0.546 in TFS), respectively; whereas, in haploidentical transplant was 100%, 96.9%, 3.1%, 0% and 88.9%, 77.8%, 12.5%, 11.1%(P=0.043 in TFS); and in sibling cord blood transplant was 100%, 100%, 0%, 0% and 100%, 62.3%, 29.9%, 0% (P=0.035 in TFS). Our data suggest that thiotepa-based conditioning regimen in TM is effective and safe and survival outcome of thiotepa-based regimen in haploidentical transplant and sibling cord blood transplant are encouraging. Thiotepa-based regimen may improve survival outcome in haploidentical transplant and sibling cord blood transplant.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
Confirming the Presence of a Smoldering T and B PLL Associated with Improved 5 Year OS: Using the National Cancer Data Base
Authors: Parsons Benjamin , Peter Polewski , Go Ronald S. , Borgert Andrew , Gaddam Mamatha , Narayana Swapna 
Published: October 2019

Abstract

Background:
Prolymphocytic leukemia (PLL) is a rare cancer with incidence of 0.48/1,000,000. It is comprised of 2 subtypes, T or B cell. It generally is associated with a poor median OS of 1-3 years. However, some patients have an initial smoldering course not requiring treatment. Limited population data exists describing the outcomes of PLL. We studied PLL patients who met a definition of smoldering, not requiring treatment within 180 days of diagnosis, using the National Cancer Data Base (NCDB).
Methods:
Patient level data were obtained from the NCDB Participant User File. The NCDB collects hospital cancer registry data representing 70% of newly diagnosed cancer cases in the US population. We identified PLL patients (ICD-O: 9832 PLL, NOS, ICD-O: 9833 B-PLL, and ICD-O: 9834 T-PLL) diagnosed in 2004-2015 for demographics, disease and treatment characteristics. We included patients diagnosed from 2004-2013 in the overall survival (OS) analyses. Patients who received no treatment as part of their first course of treatment and who did not have a subsequent treatment within 180 days were considered smoldering PLL.
Results:
From 2004-2015, 1606 patients were diagnosed with PLL and 451(28%) were smoldering PLL. Of the 1606 patients, T-PLL represented 781(49%), B-PLL 480(30%), and PLL, NOS 345(21%). Of the 451 smoldering PLL patients observed as T-PLL represented 48%(215), B-PLL 29%(133), and PLL, NOS 23%(103). The median age at diagnosis was 69 [59 - 78] years. There was a male predominance with 60 % males. The median OS for the entire cohort was 20.6 months. The % 5yr overall survival (OS) for smoldering PLL was 40% vs 29%(for non-smoldering). Within the PLL subtypes PLL, NOS and B-PLL were associated with better 5yr OS 38.56% and 35.53%, compared to T-PLL 12.89%. Only 65(4%) patients underwent an early stem cell transplant(SCT).
Conclusions:
We identified a population of patients not needing treatment within 180 days of diagnosis representing smoldering PLL with a significantly improved OS. Additionally, PLL, NOS and B-PLL were associated with an improved OS. The use of early SCT is low in PLL.

Disclosures
No relevant conflicts of interest to declare.
The Efficacy and Safety of Super High-Dose Cytarabine Based Strategies in Childhood Acute Myeloid Leukemia Treatment
Authors: WU Zelin , Liang Ming , Zhang Hui , Wu Ziliang 
Published: October 2019

Abstract
Objective The aim of this study was to evaluate the effect of super high-dose cytarabine (SHDAC), a regimen first created by the author, on the five-year overall survival (OS) and event-free survival (EFS) of children with AML. Methods From July 2001 to April 2016, a total of 25 pediatric patients with newly diagnosed AML (exclueding secondary AML、APL and Down Syndrome AML) were enrolled. Patients received consolidate chemotherapy with the same regimen of high-dose cytarabine (3g/m2 every 12 hours by continuous infusion for 6 days) after remission induction chemotherapy. Then phase II consolidation therapy (also known as early intensive treatment) was performed according to the regimen of high-dose cytarabine (3g/m2 every 12 hours on days 1, 3, and 5 for four cycles, a total of 108g/m2) in 16 cases, while the other 9 cases received the treatment with another regimen (H3A7, M3A7 and VP16 combined with cytarabine alternately at intervals ranging from 2 to 6 months). The total treatment course spanned about three years, with regular post-treatment follow-up tracking for more than five years. Results Originally 26 cases were enrolled, but 1 case was not relieved after two courses of treatment and quitted therapy, so only 25 cases were enrolled finally. The total remission rate was 96%. There were 12 cases (48%) achieving complete remission within one course, 12 cases (48%) within two consecutive remission course and one case (48%) ,only one case(4%) achieving complete remission within with in five courses. The five-year OS and EFS of these 25 AML patients in this study were 77±0.98% and 77±1.22% respectively. Four patients (16%) died (1 treatment-related (4%), 3 relapse (12%) including 3 marrow relapse and 1 combined with testicular relapse). The average relapse time was 29.6 months and the median time was 14.8 months. Conclusion The application of super high-dose cytarabine (a total of 108g/m2 cytarabine, with a regimen of 3g/m2 every 12 hours by continuous infusion for 6 days as consolidation chemotherapy and 3g/m2 every 12 hours on days 1, 3, and 5 for four cycles as the early intensive treatment) is clinically safe and effective, with minimal hospitalization expense index (HEI). For patients with financial difficulties, especially those in developing countries, super high-dose cytarabine shows landslide advantages and practicality. Therefore, there should be more collaborative clinical applications as well as research upon related mechanisms.

Disclosures
No relevant conflicts of interest to declare.
A common polymorphism in the annexin V Kozak sequence (−1C>T) increases translation efficiency and plasma levels of annexin V, and decreases the risk of myocardial infarction in young patients
Authors: González-Conejero Rocio , Corral Javier , Roldán Vanessa , Martı́nez Constantino , Marı́n Francisco , Rivera José , Iniesta Juan A. , Lozano Marı́a L. , Marco Pascual , Vicente Vicente 
Published: October 2019

AbstractAnnexin V has phospholipid-binding capacity and plays a potent antithrombotic role. Recently, a C to T transition has been described in the Kozak region of this gene, affecting the nucleotide preceding the initiation ATG codon. We have developed a simple method to detect this genetic change, showing by analysis of 580 Mediterranean white subjects that the −1C to T transition (−1C>T) is a common polymorphism (allele frequency, 0.121). This polymorphism is in linkage disequilibrium with a new C>G polymorphism located 27 bp downstream in intron 2. We show that −1C/C carriers presented significantly lower plasma levels of annexin V than −1C/T subjects (0.45 ± 0.20 ng/mL versus 0.73 ± 0.28 ng/mL, respectively;P = .02). In vitro transcription/translation experiments support that the −1T allele increases translation efficiency. The clinical relevance of the −1C>T change was investigated in consecutive patients with nontraumatic spontaneous intracranial hemorrhage (n = 225), deep venous thrombosis (n = 151), and coronary heart disease (n = 101). Finally, we also studied 166 survivors of an acute myocardial infarction occurring at age of 45 or less. This polymorphism seems to have a minor effect in bleeding disorders, but to play a protective role against early myocardial infarction, reducing by 2-fold the risk of developing the disease (P = .006; odds ratio, 0.51; 95% confidence interval, 0.30-0.85).
Human fetuses are able to mount an adultlike CD8 T-cell response
Authors: Hermann Emmanuel , Truyens Carine , Alonso-Vega Cristina , Even Jos , Rodriguez Patricia , Berthe Aurélie , Gonzalez-Merino Eric , Torrico Faustino , Carlier Yves 
Published: October 2019

AbstractFetal/neonatal immune responses generally are considered to be immature and weaker than that of adults. We have studied the cord-blood T cells of newborns congenitally infected with Trypanosoma cruzi, the protozoan agent of Chagas disease. Our data demonstrate a predominant activation of CD8 T cells expressing activation markers and armed to mediate effector functions. The analysis of the T-cell receptor beta chain variable repertoire shows the oligoclonal expansion of these T lymphocytes, indicating that activation was driven by parasite antigens. Indeed, we have detected parasite-specific CD8 T cells secreting interferon-γ after coincubation with live T cruzi. This response is enhanced in the presence of recombinant interleukin-15, which limits the T-cell spontaneous apoptosis. These findings point out that the fetal immune system is more competent than previously appreciated, since fetuses exposed to live pathogens are able to develop an adultlike immune CD8 T-cell response.
Rituximab treatment of refractory fludarabine-associated immune thrombocytopenia in chronic lymphocytic leukemia
Authors: Hegde Upendra P. , Wilson Wyndham H. , White Therese , Cheson Bruce D. 
Published: October 2019

Abstract
Fludarabine can exacerbate idiopathic thrombocytopenia (ITP) in chronic lymphocytic leukemia (CLL). We report 3 CLL patients with refractory fludarabine-associated ITP who responded to rituximab. The patients had Rai stages III, III, and IV disease. Before fludarabine treatment, the platelet counts were 141 000/μL, 118 000/μL, and 70 000/μL. ITP developed within week 1 of cycle 3 in 2 patients and within week 2 of cycle 1 in 1 patient. Platelet count nadirs were 4000/μL, 1000/μL, and 2000/μL, respectively, and did not respond to treatment with steroids or intravenous immunoglobulin. Rituximab therapy (375 mg/m2 per week for 4 weeks) was begun on days 18, 23, and 20 of ITP. Patient 1 achieved a platelet count of more than 50 000/μL at day 21 and more than 133 000/μL at day 28, patient 2 achieved a platelet count of more than 50 000/μL at day 4 and more than 150 000/μL at day 10, and patient 3 achieved a platelet count of more than 50 000/μL at day 5 and 72 000/μL at day 28 of rituximab therapy, with platelet response durations of 17+, 6+, and 6 months. These results suggest rituximab can rapidly reverse refractory fludarabine-associated ITP.
Generation of Tumor-Specific Cytotoxic T Lymphocytes in Multiple Myeloma Using Dendritic Cells Pulsed with Tumor-Derived Heat Shock Protein gp96.
Authors: Yi Qing , Qian Jianfei , Xie Jin , Wang Siqing , Freeman Muta E. , Barlogie Bart 
Published: October 2019

Abstract
To develop more effective immunotherapy strategies for patients with multiple myeloma (MM), it is important to identify novel tumor antigens. Heat shock protein gp96, a highly conserved glycoprotein, is a chaperon molecule that carries intracellularly processed peptides from proteins synthesized by the cells, including those of tumor-specific or -associated proteins. Recent studies in solid tumors have shown that tumor-derived gp96 is immunogenic and potent at stimulating the generation of tumor-specific cytotoxic T lymphocytes (CTLs). In this study, we examined whether myeloma-derived gp96 can be used as potent myeloma antigen. To generate myeloma-specific CTLs, immature dendritic cells (DCs), obtained from cultures of blood monocytes from HLA-A2+ healthy individuals or patients, were pulsed with gp96 protein purified from the myeloma cell line U266 (A2+), and induced maturation using the cytokine cocktail. Autologous T cells were then stimulated every two weeks with these DCs, and cytotoxicity was examined against gp96-pusled DCs, myeloma cell lines, and primary myeloma cells isolated from patients. After several cycles of in vitro stimulation, specific CTL lines were obtained, which consisted of both CD4+ and CD8+ T cells. These CTLs demonstrated not only specific cytotoxicity against gp96-pusled DCs and the cell line U266, but also significantly killed A2+ primary myeloma cells. No killing was observed against A2+ normal lymphocytes including B cells or A2− myeloma cell lines and primary myeloma cells from patients. Using the cold target inhibition assay, we showed that the same CTLs mediated the killing of both gp96-pulsed DCs and myeloma tumor cells. The cytotoxicity was MHC class I- and, to a lesser extent, class II-restricted, indicating that the gp96 contained both class I- and II-restricted tumor-derived peptides and that myeloma cells naturally present these peptides in the context of their surface MHC molecules. Upon antigen stimulation, these CTLs secreted predominantly interferon-g, detected by the ELISPOT assay and intracellular staining, indicating that they belong to the type-1 T-cell subsets. Furthermore, the CTLs lysed the target cells mainly through the perforin-mediated pathway because Concanamycin A but not Brefeldin-A, the selective inhibitors for perforin- or Fas-, respectively, mediated pathways, abrogated the cytolytic activity of the cells. These results therefore show that myeloma-derived gp96-specific CTLs are able to lyse myeloma tumor cells including primary myeloma plasma cells from patients and, thus, provide a rationale for gp96-based immunotherapy in MM.
Identification of a New Population of Human Cord Blood Cells with Lymphoid-Restricted Reconstituting Potential in Sublethally Irradiated Immunodeficient Mice.
Authors: Christ Oliver , Smith Clayton , Leung Karen , Hamilton Melisa , Eaves Connie J. 
Published: October 2019

Abstract
Throughout adult life, human hematopoiesis is sustained by the activity of a small compartment of pluripotent stem cells with extensive self-renewal potential. Available evidence suggests that these cells undergo a process of progressive lineage restriction similar to that described for murine hematopoietic cells, although many of the intermediate stages of human hematopoiesis have not yet been characterized. In human hematopoietic tissues, cells with short-term (<4 months) as well as long term (>4 months) repopulating activity (termed STRCs and LTRCs, respectively) are distinguished by their differential ability to engraft sublethally irradiated NOD/SCID-β2microglobulin null mice as well as their transient versus sustained output of differentiated cells. In previous studies, both a myeloid-restricted type of human STRC (STRC-M) and a type of STRC with lymphoid as well as myeloid potential (STRC-ML) have been identified. STRC-Ms are CD34+CD38+ and produce mainly erythroid progeny for the first 3–4 weeks post-transplant. In contrast, STRC-MLs are CD34+CD38− and produce progeny only between weeks 5 and 12 post-transplant which consist mainly of B-lymphoid cells plus some granulopoietic cells. We show here that both STRC-MLs and STRC-Ms are similarly distributed among lin- cord blood cells with intermediate to high levels of aldehyde dehydrogenase activity (ALDH-int/hi) as evidenced by staining with the fluorescent dye BAAA. In addition, BAAA-staining has allowed a previously undescribed primitive cell with low ALDH activity (ALDH-lo) and lymphoid-restricted repopulating activity to be identified. Assessment of NOD/SCID-β2microglobulin null mice transplanted with various subsets of cord blood cells further demonstrated that these “STRC-Ls” are CD38− and 10-fold more prevalent in the CD133+ subset of the low-density SSC-low ALDH-lo/neg population but, numerically, are equally distributed between the CD133+ and CD133− fractions because of the proportionately larger size of the CD133− subpopulation. Phenotype analysis of CD34+CD38− cord blood cells revealed a small and distinct ALDH-lo subset that expressed 10-fold higher levels of CD7 than any other CD34+CD38− cells. However, transplantation of this small CD7++ subset into NOD/SCID- β2microglobulin null mice revealed that they accounted for very few of the ALDH-lo STRC-Ls. The discovery of a CD38− ALDH-lo population of lymphoid-restricted human cells with in vivo reconstituting activity identifies a key step in the process of human hematopoietic cell lineage determination and the ability to prospectively isolate these progenitors separately from other types of short- and long-term repopulating cells present in normal human hematopoietic tissues should greatly facilitate future analysis of the mechanisms regulating their normal differentiation or malignant transformation.
Protein Signature of LMP1 Signaling in PTLDs Identifies and Mimics Inter/Perifollicular CD30+ EBV− B Blasts.
Authors: Shaknovich Rita , Basso Katia , Bhagat Govind , Alobeid Bachir , Cattoretti Giorgio 
Published: October 2019

Abstract
EBV-associated B-cell Post-Transpant Lymphoproliferative Disorders (PTLDs) represent a diverse group of lesions morphologically, in clinical presentation and behaviour, ranging from early reversible lesions to monomorphic aggressive lymphomas.
Polymorphic cases, which represent the focus of our analysis, contain a mixture of cells in various EBV latency stages, defined by EBNA1, EBNA2 and LMP1 immunostaining.
LMP1 is a key viral protein for cellular transformation and, analogously to CD40, engages TNF Receptor Associated Proteins and activates NF-kB and NF-kB-responsive genes.
We analyzed the protein signature of LMP1 in PTLDs and non-PTLD tonsils by double staining for LMP1, CD30, CD20, Pax5 and signaling molecules. A remarkably conserved set of proteins, associated with LMP1/CD40 signaling and NF-kB activation is expressed both in the EBV-infected lymphoid population in polymorphic PTLDs and in a normal B-cell subset(s) in reactive tonsils. These proteins include highly expressed CD30, JunB, nuclear cRel, TRAF-1, Bcl-XL, MUM1, CCL22 and downregulated BCL6 and CD10.
We observed that EBV infection, possibly through LMP1 and LMP2A signaling, results in varioius degrees of differentiation within the neoplastic clone. EBER+ terminally differentiated mucosa-associated IRTA-1+ marginal zone B-cells and CD138+ plasma cells were identified in most cases, including control post-transplant tonsils with no overt disease. We document for the first time in situ, in-vivo evidence of EBV latently infected post-Germinal Center B cells of marginal and plasma cell types in PTLDs. Polymorphic PTLD cases represent EBV-induced expansion of B cells, mimicking CD40L-like activated Peri/Interfollicular CD30+ normal B-cells.