bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Significance of FDG-PET/CT on Determining Upfront Autologous Stem Cell Transplantation for the Treatment of Peripheral T Cell Lymphomas
Authors: Ahn Seo-Yeon , Jung Seung-Yeon , Jung Sung-Hoon , Ahn Jae-Sook , Lee Je-Jung , Kim Hyeoung-Joon , Kang Sae-Ryung , Han Yeon-Hee , Kwak Jae-Yong , Yhim Ho-Young , Yang Deok-Hwan 
Published: October 2019

Abstract
Purpose: The clinical role of 18F-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET/CT) in performing upfront high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains unclear in peripheral T cell lymphomas (PTCLs). This study investigated the prognostic relevance of interim and final FDG-PET/CT in predicting the outcome of upfront ASCT for the treatment of PTCLs.
Method: The study conducted newly diagnosed 96 patients with PTCLs who aged under 65 years between January 2005 and December 2016 from two independent institutions. For making a comparison of clinical outcome between transplant and non-transplant patients according to interim or final FDG- PET/CT, 37 transplanted and 59 non-transplanted patients with the same populations were evaluated as a comparative group (non-ASCT). The enrolled patients were treated with mainly anthracycline-based chemotherapy except patients with NK/T cell lymphoma who were treated with non-anthracycline-based. If achieved complete or partial remission after primary treatment, patients proceeded to upfront ASCT. FDG-PET/CT was performed at the time of diagnosis, interim, and after primary treatment. The response of interim or final FDG-PET/CT was analyzed by visual assessment using Deauville five-point scale (5-PS).
Results: The characteristics of transplant patients were similar to non-transplant patients except two features (IPI score, CT response). Final FDG-PET/CT response (P<0.001, Hazard ratio (HR) 3.51), CT response (P<0.001, HR 2.11) and age (P=0.005, HR 1.07) were significant prognostic factors of progression-free survival (PFS) in transplant patients on multivariate analysis. In non-ASCT patients, final FDG-PET/CT response (P<0.001, HR 9.65), prognostic index for T-cell lymphomas (PITs) score (P=0.001, HR 5.24), and CT response (P<0.001, HR 2.34) were prognostic for PFS. After a median follow-up of 60.8 months, 5-year PFS rates of ASCT and non-ASCT patients according to interim FDG-PET/CT response were 75.5 vs 74.5% of Deauville score 1-2, 20% vs 22.2% of Deauville score 3 and 33.3% vs 42.2% of Deauville score 4, respectively (P=0.092, P=0.005; Figure 1A, 1C). 5-year PFS rates according to final FDG-PET/CT response of ASCT and non-ASCT patients were 70.2% vs 80.5% of Deauville score 1-2, 22.2% vs 25% of Deauville score 3 and 0% vs 0% of Deauville score 4, respectively (P<0.001, P<0.001; Figure 1B, 1D).
Conclusion: Final FDG-PET/CT response based on Deauville 5-PS had prognostic significance on the treatment outcome of PTCLs regardless of upfront ASCT. However, patients with ≥ 3 of Deauville score assessed by interim or final FDG-PET/CT had poor prognosis even though performing upfront ASCT.

Disclosures
No relevant conflicts of interest to declare.
Thromboembolic Complications in Patients with Sickle Cell Disease
Authors: Alkindi Salam , Al-Ghadani Anwaar , Al-zeheimi Samah , Pathare Anil 
Published: October 2019

Abstract
Background and Purpose: Venous thromboembolism (VTE) is common in patients with sickle cell disease (SCD). Traditional risk factors such as central venous catheters, frequent hospitalization, orthopedic surgeries for avascular necrosis, and pregnancy often leads to an increased incidence of VTE in the SCD. In addition, SCD itself appears to be a hypercoagulable state with many SCD-specific factors such as genotype, splenectomy and thrombophilia modifying the risk of VTE. This study aims to assess the clinical and pathological characteristics of VTE amongst a cohort of patients with SCD at the Sultan Qaboos University Hospital and determine its relation to morbidity and mortality.
Methodology: In this retrospective case control study, medical details of all patients with SCD who developed thromboembolic complications over the past decade were retrieved from the hospital information system. SCD patients matched for age and gender (2:1 ratio) who did not have thromboembolic complications but had a thrombophilia screen performed served as controls. The study was approved by the local Medical Research and Ethics Committee.
Results & Discussion: A total of 53 SCD patients were enrolled [34 cases, 19 controls] in this study. Amongst the 34 cases (mean age-30 yrs.), 18 had pulmonary embolism, eight had deep venous thrombosis, whereas, three each had cerebral venous thrombosis and portal venous thrombosis and one each had cerebral arterial thrombosis and VTE. A higher incidence of autosplenectomy(69.7% v/s 52.6%) and central venous catheters(42.4% v/s 5.3%) were significantly associated with thrombosis (p<0.05, Chi Square test). High LDH levels, WBC and Platelet counts were significant risk factors(p<0.05) for VTE. 21 patients [63.6%] amongst the cases developed acute chest syndrome, where 3[9%] had cerebrovascular accident. Mortality was seen in seven cases [21%].
Conclusions: The study shows that thromboembolic complications in SCD has a high impact on the morbidity and mortality. It confirms PE as the leading cause for VTE in SCD with asplenia, central venous catheter, high LDH, WBC and Platelet counts being significant risk factors.

Disclosures
No relevant conflicts of interest to declare.
Critical Role for Apobec and Its Interacting Partners in Mediating Mutations and Cell Growth in Multiple Myeloma (MM)
Authors: Talluri Srikanth , Samur Mehmet Kemal , Shi Jialan , Prabhala Rao , Avet-Loiseau Hervé , Shammas Masood A. , Munshi Nikhil 
Published: October 2019

Abstract
The APOBEC family of cytidine deaminases include AID (activity induced deaminase) and 10 related APOBEC enzymes (A1,A2,A3A,A3B,A3C,A3D,A3F,A3G,A3H and A4). AID is well studied for its role in somatic hyper mutation and class switch recombination of immunoglobulin genes. APOBECs (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) have been shown to have roles in mRNA editing and in antiviral immunity. Recently, a causal role for the AID/APOBECs in inducing somatic mutations in myeloma has been proposed and we have previously published that APOBEC signature mutations as a frequent event in Myeloma. We have also observed that APOBEC-mediated mutations may account for mutations associated with progression of smoldering myeloma to MM.
We further investigated the role of APOBEC in genomic changes in MM and observed that APOBEC expression and activity is elevated in myeloma cell lines as well as patient samples. Using knockdown and over expression approaches, we showed that depletion of APOBECs in myeloma cell lines reduces genomic instability. Following APOBEC3G knock down we observed decreased DNA damage (by g-H2AX), decrease in acquisition of new copy number events over time, and reduced mutational load, strongly suggesting that inhibiting APOBECs could be a potential approach to reduce genome evolution in MM.
We next investigated the effect of APOBEC inhibition on myeloma cell proliferation. We observed that Sh-RNA-based APOBEC knock down in MM1S and H929 MM cell lines, led to significant inhibition of MM cell proliferation, and induction of apoptotic cell death. Associated with APOBEC knockdown, we also observed increased levels of Cyclin-dependent kinase inhibitor 1B (p27Kip1) at both RNA and protein level. By immunoprecipitation we found that APOBEC3G interacts and inhibits the RNA binding protein DEAD-END 1 (DND1), thereby preventing it from inhibiting miR-221-mediated targeting of p27 transcripts. Knockdown of DND1, or over-expression of miR-221 in APOBEC-depleted cells rescued the cell proliferation defects with concomitant decrease in p27 levels. These results show that APOBCs bind to and sequester DND1, leading to miR-221-mediated depletion of p27. In the absence of APOBEC, DND1 prevents the degradation of p27 mRNA, leading to elevated p27 levels and inhibition of cell cycle, suggesting a role for APOBECs in regulating MM cell proliferation that might be independent of its RNA/DNA mutator function. Taken together, these results indicate a significant functional role for APOBECs both in genome evolution as well as cell growth in myeloma and may constitute an important therapeutic target.

Disclosures
Munshi: OncoPep: Other: Board of director.
Survival Outcomes of Young Multiple Myeloma Patients: A Single Center Experience
Authors: Aytan Pelin , Yeral Mahmut , Gereklioglu Cigdem , Korur Aslı , Tanrıkulu Funda , Solmaz Soner , Buyukkurt Nurhilal , Kasar Mutlu , Asma Suheyl , Boga Can , Kozanoglu Ilknur , Ozdogu Hakan 
Published: October 2019

Abstract
Multiple myeloma (MM) is a disease of the elderly. It shows rapidly increasing incidence with increased age. Although MM is rare in young people, patients diagnosed before the age of 50 years account for 10% of the overall incidence and approximately 2% are diagnosed before 40 years of age. The aim of the study was to assess the clinical results of the young MM patients diagnosed at the age of ≤45 years.
All the MM patients who were ≤45 years old at the time of diagnosis and who were admitted to our clinic between January 2004 and December 2017 were retrospectively assessed. There was a total of 31 patients and 14 (45.2%) of them were females and 17 (54.8%) of them were males. The mean age was 40.4±3.8 years. The most frequent myeloma types were Ig G Kappa (n:12, 38.7%) and Kappa light chain (n: 10, 32.3%). The remaining types were Ig A lambda (n:4, 12.9%), Ig G lambda (n:2, 6.5%), Lambda light chain (n: 2, 6.5%) and non-secretory myeloma (n:1, 3.2%). Before transplantation 12 patients (38.7%) were in complete remission, 11 patients (35.5%) were in very good partial remission, 4 patients (12.9%) were in partial remission state and 4 patients (12.9%) had refractory disease. VAD + VCD protocol was given to 12 (38.7%) patients. 6 (19.8%) patients had VCD, 3 (9.7%) got VCD + VRD, 2 (6.5%) got VAD and 8 (25.8%) got other chemotherapy protocols. Transplantation was done in 26 patients (83.9%). Overall 9 patients (29%) died during the study period. Second or tandem transplantation was performed to 10 patients and 30% (n:3) of these re-transplanted patients died. The overall survival for these patients was estimated to be 70% (95% CI: 64.2-75.8).
In conclusion MM in patients younger than 45 years is rare. In these patients Ig G Kappa and Kappa Light chain types are the most frequent types. Heterogeneous of individual patients may exist within these young myeloma patients. For those who are expected to show a poor response to current treatments despite their young age, the efficacy of an alternative therapeutic strategy such as front line allo-HSTC should be further investigated.

Disclosures
No relevant conflicts of interest to declare.
Identification and Characterization of EBV Genome in NKT Cell Lymphoma
Authors: Su Yi , Yang Xi , Yi Hai , Fan Fangyi , Sun Haoping , Lai Sihan , Niu Ting 
Published: October 2019

Abstract
Background: Epstein-Barr virus (EBV) is closely related to (Natural Killer/T) NKT cell lymphoma. However, the genomic characteristics of EBV genome in NKT cell lymphoma are poorly understood.
Methods: We targeted the EBV gene sequence of 5 samples of NKT cell lymphoma tissue and identified the genomic variation of EBV in NKT cell lymphoma, and compared with other EBV strains by bioinformatics.
Results: The EBV genome was successfully retrieved from 5 samples and the variation was detected. We found a total of 3220 mutations in 5 cases of NKT cell lymphoma, including 2996 substitutions, 105 insertion and 119 deletion, of which 2103 of the mutations in the gene coding region, others were in the non-coding region. The non-synonymous mutations in 5 samples were 563, 586, 596, 667 and 578, respectively. Most of them were located in the exons of tegument, membrane glycoprotein, transcription factor and replication. Phylogenetic analysis of LMP1, EBNA1, EBNA2, EBNA3A, BZLF1, BLLF1 were performed with other EBV strains. The results showed that the LMP1 and BZLF1 genes of EBV in NKT cell lymphoma were different from those of other EBV strains, suggesting that LMP1 and BZLF1 were specific in NKT cell lymphoma. The comparison of EBNA2 and EBNA3A between EBV in NKT cell lymphoma and other strains suggested that the EBV in NKT cell lymphoma was type I EBV. The characteristics of EBNA1 in different strains have no correlation and need further investigation.
Conclusion: By targeting sequencing technology, we had shown that there were many variations of EBV in NKT cell lymphoma, including substitutions, insertions and deletions, and most of the variations were located in the gene coding region. The EBV in NKT cell lymphoma was type I EBV. LMP1 and BZLF1 in the EBV genome of NKT cell lymphoma were tumor specific and might serve as potential biomarkers for EBV genotyping.

Disclosures
No relevant conflicts of interest to declare.
Evidence for Role of Enzymatic Operations in Shared T-Cell Receptors
Authors: Woodcock Mark , Buntzman Adam , Vincent Benjamin G. 
Published: October 2019

Abstract
Background:
There exist shared T cell receptors (TCR) found in the circulating repertoires of healthy individuals. The exact mechanism for why some sequences are more commonly shared is unclear, but it has been hypothesized that the number of recombination permutations of V, D and J segments that produce a particular shared sequence is predictive (i.e. the "convergent recombination" hypothesis). An alternative hypothesis is that sharing is driven by decreased biochemical energy required to generate the shared sequences (i.e. the "enzyme proxy" hypothesis).
Methods:
Circulating T cells were collected from 100 healthy donors and TCR repertoires were profiled. Using a novel algorithm, the number of recombination events that could produce each TCR was calculated ("path count"). Sequence features associated with enzymatic operations - such as V and J region chewback and non-templated nucleotide addition - were calculated as well ("enzymatic" parameters). Multivariable regression was used to identify TCR sequence features associated with TCR clonotype sharing between individuals.
Results:
Nearly 38 million unique TCR sequences from the donor cohort were profiled. Based on regression coefficient analysis of significance, enzymatic parameters were overall negatively associated with TCR sharing (betas [-1.24x10-2 - 3.88x10-3], average -5.67x10-3, maximum p<0.001), while path count had a positive association (beta 1.73x10-2, p<0.001). When these parameters were used to predict sharing, a model using enzymatic parameters had similar performance to a model using only path count. The creation of a model with both enzymatic and path count parameters led to a significant improvement in predictive ability over both models (minimum delta LR 56950, p<0.001). The enzymatic variables and path count had a weak negative correlation (pearson correlation [-0.518 - -0.407]).
Conclusions:
Our findings indicate that TCR sharing is inversely related with increasing complexity of enzymatic operations required during VDJ recombination, and is predictive of receptor sharing between circulating T-cell repertoires in humans. The number of recombination paths is positively associated with TCR sharing, and carries predictive information indepenent of enzymatic operation. This suggests that shared TCRs are favored due to a combination of enzymatic kinetics as well as available recombination paths.

Disclosures
Buntzman: - An Autoimmune Research Fund: Membership on an entity's Board of Directors or advisory committees. Vincent:Merck: Research Funding.
A Reciprocal Interaction between Immune Reconstitution and Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Xiao Min , Luo Xiaofeng , Ren Jinhua , Yang Xiaozhu , Zhu Haojie , Lin Kangni , Chen Minmin , Chen Shaozhen , Li Qian , Chen Zhizhe , Hu Jianda , Yang Ting 
Published: October 2019

Abstract
Background
Hemorrhagic cystitis (HC) is one of the serious complications of allogeneic hematopoietic stem cell transplants (allo-HSCT), with the potential to cause significant morbidity. However, the underlying mechanism of HC is not yet clear.
Objective
To explore the reciprocal interaction between immune reconstitution and HC after allo-HSCT.
Methods
101 patients undergoing allo-HSCT in our department during July, 2014 to April, 2017 were analyzed. JC virus(JCV), BK virus (BKV), cytomegalovirus (CMV) by quantitative real-time PCR were performed on all blood or urine samples post-HSCT. Non-specific T and B cell immune reconstitution were assessed by the expression of CD3, CD4, CD8, CD56, CD10, CD19, CD20 and CD22 with multiparametric flow cytometry, and specific T cell phenotype and cytokine production were determined by the expression of CD3, CD4, CD8, CD69, IL-2, IFN-gamma and TNF-alpha on PBMCs after the stimulation with one of four BKV peptides (tAg,Tag,VP-1,VP-2,VP-3).
Results
62 out of total 101 patients were male and 39 were female. The median age was 27 years (range, 1-54). 85 patients were diagnosed as malignancy hematologic disease (AML=44, ALL=26, MDS=4, CML=6, NHL=5), while 16 were non-malignancy hematologic disease (SAA = 14, fanconi=1, thalassemia=1). Through the cox regression analysis, the hazard ratio (HR) of HC (95% confidence interval) for BKV viruria was 4.866 (1.908-12.406), with a P-value of 0.001. Those with primary malignance disease also had higher odds of developing HC, with an HR of 5.101. Both of them were independent risk factors in multivariate analysis. There was no significant difference on the expression of CD3, CD4, CD8 and CD56 representative the non-specific T cell immune reconstitution between BK+ and BK- group, but the non-specific B cell immune reconstitution stained with CD19+, CD20+, CD22+ was significant delayed in BK+ group. Moreover, the specific T cell immune reconstitution performed in 6 cases were significant delayed in BK+ group as well compared to that in BK- group.
Conclusion
HC is correlated to BKV viruria and primary malignance disease in allo-HSCT. Poor specific immune reconstitution post-HSCT increased the risk of BK virus reactivation, and BK virus infection delayed the immune reconstitution after transplantation vise versa.

Disclosures
No relevant conflicts of interest to declare.
Potent and Timed Epigenetic Repression of PD-1 in Human T Cells
Authors: Pearl Jocelynn , Urnov Fyodor D , Stamatoyannopoulos John A 
Published: October 2019

Abstract
T cell exhaustion mediated by checkpoint genes - most prominently PD-1 - is believed to play a major role in limiting the efficacy of chimeric antigen receptor (CAR) T cell therapies of hematologic malignancies. Clinically durable responses to CAR-T therapy of B cell malignancies almost invariably occur in patients who achieve a complete remission by day 28 post infusion. Accumulating data indicate that the impact of T cell exhaustion is most prominent during the early post-infusion interval. PD-1 has recently been found to function as a tumor suppressor in T cells; as such permanent disablement of PD-1 expression via genetic knockout may thus increase long term adverse events from cell therapy.
We sought to develop an approach for increasing the potency and efficacy of CAR-T cell therapy of B cell and other hematologic malignancies by timed epigenetic abrogation of PD-1 expression that was limited to the critical early (21-28d) therapeutic interval. To accomplish this we engineered synthetic transcription factors coupled to a modified KRAB repressive domain that densely tiled the transcriptional regulatory regions of PD-1 at up to single-base resolution.
To identify TF-repressors that were both potent and specific, we transiently transduced each engineered TF-repressors separately into primary total CD3+, CD4+, or CD8+ human T-cells. These experiments revealed striking position dependence of TF-repressor activity, indicating that spatial and rotational positioning of the repressive domain was critical for function. We identified several TF-repressors that exhibited highly potent repression (>90%), and screened these for gene selectivity using transcriptome-wide deep RNA-seq. These studies yielded a TF-repressor with both high potency (>90%) and true single-gene (PD-1) specificity on a genomic scale.
Next we examined the durability of expression. Transduction of TF-repressor mRNA resulted in rapid expression and activity, with PD-1 repression observable beginning at 12 hours and peaking by 48 hours post transduction. Experiments with tagged TF-repressors revealed that substantially all translated protein had dissipated within 72 hours post transduction. Remarkably, however, potent PD-1 repression reliably persisted for >3 weeks post-transduction.
Collectively, our studies show the feasibility of generating highly potent and single-gene-selective epigenome editing reagents capable of reprogramming clinically relevant genes over a defined temporal interval. This approach should be broadly applicable to other key regulators of clinical response to produce genome-targeted medicines without incurring the genotoxic consequences of double-stranded DNA breaks.

Disclosures
No relevant conflicts of interest to declare.
LAMTOR2 Is Dispensable for T Cell Receptor-Mediated Signaling of Thymocytes but Controls Medullary Thymic Epithelial Cells
Authors: Wendeler Lina , Huber Lukas A , Klein Christoph , Kotlarz Daniel 
Published: October 2019

Abstract
Human LAMTOR2 deficiency is characterized by severe congenital neutropenia, growth failure, partial albinism, as well as B and T cell deficiencies (Bohn et al., Nat Med 2007). To determine the role of the endosomal adaptor LAMTOR2 in T cell development and homeostasis we used conditional knockout mouse models.
Mx1-Cre-driven knockout of Lamtor2 resulted in reduction of thymus weight and total thymocyte numbers. Immunophenotyping revealed an impaired T cell development characterized by a partial block at the double negative CD4-CD8- T cell precursor stage after 7 and 21 days of poly I:C injection that induced deletion of the Lamtor2 gene. Since Mx1-Cre-driven knockout does not allow a discrimination between T cell intrinsic and extrinsic effects, we next generated pre-TCRα-iCre conditional knockout mice. In contrast to Mx1-Cre-Lamtor2fl/fl mice, mice with T cell-specific knockout of Lamtor2 showed normal frequencies of total thymocytes and T cell progenitor subsets. Furthermore, LAMTOR2-deficient thymocytes exhibited normal TCR signaling (p-ERK, p-LAT, p-LCK, p-PLCγ, Nur77) and internalization of TCRβ upon stimulation with anti-CD3ε +/- anti-CD28, indicating that LAMTOR2 in T cells is dispensable for thymocyte development.
To assess whether T cell developmental defects in Mx1-Cre-Lamtor2fl/fl mice are caused by a dysfunctional thymic epithelium, we analyzed thymic epithelial cells (TECs) after 4 days of poly I:C injection by flow cytometry and detected a reduced ratio of CD45-EpCAM+UEA-1+Ly51- medullary TECs (mTECs) to CD45-EpCAM+UEA-1-Ly51+ cortical TECs in LAMTOR2-deficient mice. Further studies are underway to determine the role of LAMTOR2 in mTECs.
Taken together, our findings show that LAMTOR2 is not required for TCR-mediated signaling but plays a critical role in controlling mTEC homeostasis.

Disclosures
No relevant conflicts of interest to declare.