bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancing a Wnt-Telomere Feedback Loop Restores Intestinal Stem Cell Function in Dyskeratosis Congenita
Authors: Lengner Christopher 
Published: October 2019

Abstract
Patients with dyskeratosis congenita (DC) suffer from stem cell failure in numerous organs, including the skin, intestine, blood, lung, and liver, due to hypomorphic loss-of-function mutations in proteins that promote telomere elongation or capping. Few therapeutic options exist for this disorder, and while patients are treated with bone marrow transplantation to restore hematopoietic function, this does not address the multi-organ failure, and in some cases can exacerbate it. We generated isogenic DC patient and disease allele-corrected induced pluripotent stem (iPS) cell lines using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated gene correction to model the stem cell failure characteristic of DC in multiple organ systems through the directed differentiation. We focused first on the intestinal epithelium, as GI manifestations of DC (enteropathy/enterocolitis ) are often the first and most severe symptoms in pediatric patients. We demonstrate that DC tissue has suboptimal Wnt pathway activity causing intestinal stem cell failure and that enhanced expression of the telomere-capping protein TRF2, a Wnt target gene, can alleviate DC phenotypes. Treatment with the clinically relevant Wnt agonists LiCl or CHIR99021 restored TRF2 expression and reversed gastrointestinal DC phenotypes, including organoid formation in vitro, and maturation of intestinal tissue and xenografted organoids in vivo. These findings establish the existence of a feed-forward loop between telomerase/telomere capping and the canonical Wnt pathway which is broken in DC, but can be restored by promoting capping and/or Wnt pathway agonists. Moving forward, we have begun to extend these investigations into the lung and liver, where fibrosis and organ failure are major clinical concerns in DC. Thus, the isogenic DC iPS cell model provides a framework for therapeutic discovery and identifies Wnt modulation as a potential strategy for treatment of DC patients.

Disclosures
No relevant conflicts of interest to declare.
High Neuropilin-1 Expression in Acute Myeloid Leukemia Is Mainly Associated with Monocytic Subtypes and Extramedullary Invasion
Authors: ElNahass Yasser H , Samra Mohamed Abdel Mooti , Fahmy Omar A , Elrefaey Fatma A , Eltokhy Soad , Mahmoud Hossam K 
Published: October 2019

Abstract
Introduction: Neuropilins are single-pass transmembrane glycoproteins acting as receptors for the vascular endothelial growth factor (VEGF) family that mediates angiogenesis and vascular development. In Acute Myeloid leukemia (AML), Neuropilin-1 high expression was found to contribute in disease evolution.
Aim of Work: To evaluate Neuropilin-1 (NRP-1) expression in AML patients especially monocytic subtypes and assess its role in disease progression and extramedullary invasion (EMI).
Patients and Methods: We measured NRP-1 expression level in 50 denovo AML patients who presented to the National Cancer institute, Cairo university. Expression was assessed by Real time quantitative PCR (RQ-PCR) using normalized copy number equation (2 -ΔΔ CT) in relation to normal healthy controls. AML patients were characterized according to their Bone marrow and peripheral blood morphology, karyotype, immunophenotyping and FLT3 internal tandem duplication (FLT3-ITD) by polymerase chain reaction (PCR). Patients were classified into 2 groups according to median NRP-1 expression into low ≤60 and high >60-fold expression.
Results: 33 males (66%) and 17 females (34%) with a median age of 34 years (18-73) were included. Cytogenetic risk categories were low in 12 (24%), intermediate in 34 (68%) and high in 4 (8%) patients. No correlation was found between high NRP-1 and cytogenetic risk classes or FLT3-ITD.
Out of 26 patients showing high NRP-1 expression; 19 (73%) were <40 years vs. 7(27%) >40 years (p=0.049) and 24 (92%) showed BM blasts >50% vs. 2 (8%) with < 50% BM blasts (p<0.001). A positive correlation was found between NRP-1 Fold -change and BM blasts (r=0.653, p=0.004). Out of 19 monocytic FAB subtypes (M4, M5), high NRP-1 expression was expressed in 16 (84%) vs. 10/31 (32%) patients presenting with other FAB subtypes (p=0.042). Out of 26 patients showing high NRP-1 expression, extramedullary invasion (EMI) was found in 23/26 (88%) vs. 3/26 (12%) patients only with no EMI (p=0.001).
Conclusion: Neuropilin-1 is useful as a prognostic marker of extramedullary invasion for AML patients especially in monocytic subtypes . Its role in disease progression and severity is still to be evaluated in our patients.
Key Words: Neuropilin-1, AML, extramedullary invasion
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
Efficacy and Adverse Reactions of Gemcitabine Combined with Cyclophosphamide, Vinblastine and Prednisone Hydrogenation Regiments in Relapse and/or Refractory Non-Hodgkin's Lymphoma
Authors: Wang Baiyan , Liu Jie , Chen Yin-Xia , Cao Xing-Mei , Zhao Wan-Hong , Wang Jian-Li , Ma Xiao-Rong , Yang Yun , Zhang Peng-Yu , Wang Fang-Xia , Gu Liu-Fang , Lei Bo , Wang Jin , Bai Ju , Zhang Yi-Lin , Xu Yan , He Ai-Li , Zhang Wang-Gang 
Published: October 2019

Abstract
Objective: To explore the clinical efficacy and adverse reactions of gemcitabine combined with cyclophosphamide, vinblastine and prednisolone (GCVP regiments) in the treatment of relapse and/or refractory non-hodgkin's lymphoma (NHL) in adults patients. Methods: 27 relapse and/or refractory non-hodgkin's lymphoma adult patients (Median:58 years old; range:47-72 years old) were diagnosed and previously treated with regimens such as R-CHOP(E), CHOP(E), MAED (Mitoxantrone, Cytarabine, Etoposide, Dexamethasone), FCM (Fludarabine, Cyclophosphamide, Mitoxantrone) based chemotherapy. There were 19 cases of diffuse large B cell lymphoma, 6 cases of follicular lymphoma, 1 case of NK/T cell type and 1 case of T cell NHL respectively. The GCVP chemotherapy (1000mg/m2 of gemcitabine, 750mg/m2 of cyclophosphamide, 25mg/m2 of vinblastine, intravenous drip on day 1 and day 8, prednisolone 50mg by intravenous drip on day 1 to day 5) were applied to these patients, safety and efficacy analyses were evaluated after two cycles. All patients provided written informed consent. Results: Among all the 27 patients who received GCVP chemotherapy, 3 patients achieved complete remission (CR) (11.11%), 15 patients achieved partial remission (PR) (55.56%), 9 patients with stable disease (SD) (33.33%), the overall response rate (ORR, CR+PR) was 66.67%. Patient's follow-up was continued after treatment, and the median duration of progression-free survival was 60 days. The main adverse events were bone marrow suppression, others were mild to moderate gastrointestinal reactions, a few had mild liver function damage, and it was reversible through hepatoprotection therapy. The most common grade ≥3 adverse events were leukopenia (33.33%, 9/27 cases), thrombocytopenia (40.74%, 11/27 cases), while anemia and gastrointestinal reaction were 11.11% (3/27 cases) and 3.70% (1/27 cases) respectively, no treatment-related death occurred. Discussion and conclusion: The overall outcomes for patients with lymphoma was improved, but there still part of NHL patients suffered form relapse or primary drug resistance, and the prognosis of these patients was poor. Gemcitabine combined with cyclophosphamide, vinblastine and hydrogenated prednisone has a good short-term efficacy in the treatment of relapse and/or refractory NHL. The main adverse reactions were hematologic toxicity and gastrointestinal reaction, mild liver function damage, and no treatment-related death was observed.

Disclosures
No relevant conflicts of interest to declare.
The Impact on Survival of EBV Positive Diffuse Large B- Cell Lymphoma, Not Otherwise Specified in Young Adults
Authors: Beltrán Brady E. , Castro Denisse A. , Vega Julio , Malaga Jose Manuel , Postigo Mauricio , Gallo Ali , Sotomayor Eduardo , Castillo Jorge J. 
Published: October 2019

Abstract
Introduction: Epstein Barr virus-positive (EBV+) diffuse large B- cell lymphoma (DLBCL), not otherwise specified (NOS) is a new entity recognized by the WHO 2016. This entity was widely studied in older age patients, but in recent years there are few reports that show that EBV positive DLBCL, NOS can affect younger adults and there is a lack of evidence in this age group. The aim of this study is to evaluate the impact on survival in EBV+ DLBCL, NOS in young adults.
Methods: The study was retrospective, reviewing clinical records of patients treated at Rebagliati Martins Hospital between years 2002 - 2013. Patients of both sexes ≥ 18 years old, but ≤ 50 years old, with the diagnosis of EBV+DLBCL, NOS were included. IRB approval was obtained prior to research. Pathological samples were reviewed by hematopathologists at our institution to confirm the diagnosis. Pertinent clinicopathological data were collected through chart review and are presented using descriptive statistics. Overall survival (OS) was determinate according to the Kaplan -Meier method, the comparison of the survival curves were made with the log-rank test. Univariate and multivariate Cox proportional-hazard regression models were fitted to evaluate hazard ratios (HR) for OS.
Results: A total of 57 patients with a diagnosis of EBV+DLBCL, NOS were included in this analysis. The median age at diagnosis was 43 years (range 25-50 years), 61 % of patients were older than 40 years old and there was a slight female predominance (51%). Clinically, 55% presented ECOG >1, 57% had B symptoms, 68% had an extranodal disease as a primary tumor, 50% had stage III/IV and 26% had ≥ 1 extranodal site involved. EBV positivity was present in 16% of patients (9 patients). PDL-1 expression was present in 12% of patients. 92% received first-line treatment, but 7% of patients did not for progressive disease and death at diagnosis. During the treatment, 92% of patients received R-CHOP and 8% received other regimens. The overall response rate was 71%; 63% had a complete response and 7% had a partial response. The 5-year OS rate was 59%. In the univariate analysis, EBV positivity (<0.001) and ≥ 1 extranodal site involved (p=0.011) were associated with a poor prognosis. In the multivariate analysis, patients with EBV positive had a worse outcome (HR 7.8, 95% 2.2-25.9.2; p=0.001).
Conclusions: The prevalence of EBV in young adults with DLBCL is high compared with other series and there is an adverse impact on overall survival in this group of patients.
Figure. Figure.

Disclosures
Castillo: Genentech: Consultancy; Abbvie: Consultancy, Research Funding; Millennium: Research Funding; Beigene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding.
BCOR Regulates Cell Fate Transition, Myeloid Differentiation and Leukaemogenesis
Authors: Kats Lev M , Kelly Madison J , Gregory Gareth , Johnstone Ricky W , Vervoort Stephin J 
Published: October 2019

Abstract
Stem cell self-renewal and lineage specification are highly dynamic and tightly controlled processes that are essential for normal haematopoiesis and are dysregulated in cancer. The X-linked BCL6 Corepressor (BCOR) gene encodes a protein that is widely expressed across adult human tissues and is a component of a non-canonical Polycomb repressive complex 1 (PRC1). The BCOR gene is recurrently mutated in various malignant and non-malignant blood disorders, and we and others have recently provided experimental evidence that BCOR has cell-context dependent functions in regulating the proliferation, differentiation and survival of haematopoietic cells. To comprehensively examine the role of BCOR in haematopoiesis in vivo we used a conditional mouse model that mimics the truncating mutations observed in acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Using stem and progenitor populations isolated ex vivo we comprehensively analysed the role of BCOR in regulating gene expression, modifying chromatin and altering genome architecture. We demonstrate that BCOR has a pivotal role in down-regulating haematopoietic stem cell (HSC) associated transcriptional networks during the transition from multi-potent stem cells to lineage-committed myeloid progenitors. Inactivation of Bcor in HSCs results in expansion of myeloid progenitors and co-operates with oncogenic KrasG12D in the initiation of an aggressive and fully transplantable acute leukaemia. Mechanistically, Bcor regulates a subset of PRC1-target genes including key HSC super-enhancer-linked transcription factors that are normally down-regulated during myeloid differentiation. We used CRISPR/Cas9 to explore the function of Bcor target genes and identified those that are necessary for the proliferation of Bcor mutant leukaemic cells. This study provides a comprehensive mechanistic understanding of how BCOR regulates cell fate decisions and contributes to the development of leukaemia.

Disclosures
No relevant conflicts of interest to declare.
Composition of Classical Hodgkin Lymphoma Microenvironment Is Associated with Clinical Outcome
Authors: Novosad Olga , Skrypets Tetiana , Svergun Nataliia , Skachkova Oksana , Gorbach Oleksandr , Khranovska Nataliia , Krotevych Mykhailo , Skoroda Larisa , Koshubarova Maryna , Novikov Dmitry , Kriachok Iryna 
Published: October 2019

Abstract
Background.
Classical Hodgkin's lymphoma (cHL) is characterized by only few malignant cells and an abundance of inflammatory cells.cHL infiltrating cells produce cytokines and growth factors that provide essential stimulatory signals for survival and proliferation of Hodgkin and Reed-Sternberg (HRS) cells. Moreover, clinical behaviour of cHL may be directly regulated by the cross-talk between HRS cells and other cells in their microenvironment. The aim of our study was to estimate the role of microenvironmental composition in clinical outcome of cHL.
Methods.79 patients (pts) with cHL were included in this study (median age: 41, range: 18-65 years; males: 26, females: 53).Patients were treated with ABVD or BEACOPP (14/esc) and radiation therapy. CR/PR was achieved in 86.1% of patients. 13.9% of pts had relapse or disease progression during the therapy.
Using IHC and qPCR techniques, we analyzed lymph-node biopsy obtained from patients during diagnostic to determine cellular and cytokine signature (CD3, CD19, CD11b, PD-L1, PD-L2, IDO, TGF-β, IL-13) that correlates with cHL treatment outcome.
Results. Expression level of tested markers was heterogeneous across the samples and did not correlate with histological variant or stage of cHL. For most of cytokines as well as immunomodulatory molecules we did not notice significant independent effect on cHL clinical outcome, except IL-13, which appeared to be a strong and independent marker of cHL prognosis. High expression of IL-13 was associated with lower EFS and OS rates comparing to IL-13 low/negative group (p<0.05).
We found that the presence of myeloid CD11b+ cells in cHL microenvironment correlates significantly with shortened EFS rate (p<0.05). Multivariate analysis has shown that the negative impact of presence of myeloid cells increases gradually when combined with elevated expression of one or more following markers - PD-L1, IDO or TGF-β (p<0.05). At the same time, we did not find any significant associations between cHL outcome and B- or T-cells populations
Conclusion.In summary, our study showed the presence of CD11b+ myeloid cells together with increased expression of checkpoints molecules and cytokines (PDL1, IDO, TGF-β and IL-13)in diagnostic lymph-node samples is associated with cHL clinical outcome.

Disclosures
No relevant conflicts of interest to declare.
"Ultrasensitive Reactive C-Protein As an Affordable Biomarker of Quantitative Expression of the BCR-ABL Transcript in Chronic Myeloid Leukemia. an Exploratory Study."
Authors: Villela Luis , Otañez Arce Melani , Best Carlos , Guzman Alicia , Estrada Elva Gabriela , Rivera Mendoza Laura , Lopez Hernandez Juan Carlos , Robles Arianna , Gomez-Almaguer David 
Published: October 2019

Abstract
INTRODUCTION
Real-time PCR (PCRq) quantification of the BCR-ABL transcript is the most reliable response marker in Chronic Myeloid Leukemia (CML), its levels have proven prognostic implications. However, in some centers it is still a difficult diagnostic tool to access. The ultrasensitive C reactive protein (pcrU) is an exquisite marker of inflammation and contextually the increased activity of the BCR-ABL transcript is associated with an inflammatory state mediated among others by IL-6. Here we explore the association between the molecular response (RM) induced with Imatinib mesylate and the serum levels of pcrU as a possible biomarker of leukemic activity.
OBJECTIVE
To explore the association between the quantitative expression of the BCR-ABL transcript and the serum levels of pcrU by turbidimetry.
PATIENTS AND METHODS
15 patients with CML were studied, in 14 of them the BCR-ABL transcript was determined after 1 year of treatment by PCRq together with the serum levels of pcrU, any inflammatory state present during the sampling was ruled out. As a control 1 patient was studied at diagnosis as described.
RESULTS
There is a significant concordance between molecular status and serum levels of pcrU in 13 of the 15 patients studied (87% true negatives and 13% false positives). Table 1. When the diagnostic test was performed to evaluate pcrU as a possible MRI biomarker, we observed that it presents a sensitivity of 100%, specificity 84.6% (in an area under the curve of 93%), Positive Predictive Value (PPV) 50% and Negative Predictive Value (NPV) 100%. The probability index (+) = 6.5 (IC95%: 1.8 to 23.2), while the probability index (-) = 0.
DISCUSSION
The inflammation promoted by the tumor and the escape of the immunologically mediated tumor destruction, have been recognized as the hallmark of cancer and the myeloid cells are key players in this process. Therefore, the detection of an ultrasensitive biomarker of inflammation theoretically has the potential to detect leukemic activity. In this exploratory study a remarkable association was found between the molecular status and the levels of pcrU, making an extension of this study a goal to be pursued.

Disclosures
Best: Novartis: Consultancy; AbbVie: Consultancy. Gomez-Almaguer:AbbVie: Consultancy; Novartis: Consultancy.
Novel Thyrointegrin αvβ3 Antagonist for the Treatment of Acute Myeloid Leukemia
Authors: Mousa Shaker A , Sudha Thangirala Institute , Godugu Kavitha , Rajabi Mehdi , Tipu Nazeer , Davis Paul J 
Published: October 2019

Abstract
Acute myeloid leukemia accounts for up to one-third of the more than 60,000 leukemias diagnosed annually in the U.S. Primary AML cells express membrane αvβ3 integrin, which is associated with adverse prognosis and resistance to chemotherapies used in AML. A macromolecule Polyethylene glycol-conjugated bi-TriAzole Tetraiodothyroacetic acid (P-bi-TAT) acts with high affinity (Ki 3.1 nM) and specificity for the thyrointegrin αvβ3 receptors, without nuclear translocation and has demonstrated effective suppression of cancer cell proliferation, NF-kB expression and invasion in leukemic cells.
We evaluated P-bi-TAT in two different AML models against two forms of acute leukemia (monocytic and myelocytic) that are largely resistant to existing therapy, by grafting human leukemia cells in immunocompromised male and female mice. IVIS imaging scans revealed that leukemic colonies were extensively established in bone marrow throughout the control (untreated) grafted animals, as well in liver, lung and kidney. Smears of bone marrow aspirates from untreated animals were found to contain multinucleate myeloblast and monoblast leukemic cells, and peripheral blood smears contained blast cells, multinucleated megakaryocytes, giant platelets and platelet aggregates, which are hallmarks of acute leukemia. IVIS imaging scans revealed 95% reduction in bone marrow colonies and resolution of liver, kidney and lung colonies in animals treated with P-bi-TAT at daily doses ranging from 1-10 mg/kg, subcutaneously for 2-3 weeks. Peripheral blood smears from treated animals were normal. Normal myeloblasts, which are the source of functional white blood cells, were found in the marrow smears, but leukemic cells were not detected in P-bi-TAT treated animals. Thus, against two forms of leukemia models, P-bi-TAT was extraordinarily effective, with the potential in treating most AML sub-types because αvβ3 receptors are expressed in the majority of AML. Among genes targeted by multiple laboratories for pharmacological downregulation of expression in AML are BCL2, VEGF, AKT1, KIT, IDH2, CDK4/6, TIMP1, VEGF, EGFR, and PD-L1. In that regard, P-bi-TAT has been shown in various tumor cell models to downregulate transcription of each of the genes listed, which are relevant to AML disease progression. Additionally, the pro-apoptotic P53 gene transcription is enhanced by P-bi-TAT.
In conclusion, P-bi-TAT is a promising lead clinical candidate that warrants clinical trials in AML patients.

Disclosures
Mousa: NanoPharmaceuticals LLC: Equity Ownership, Patents & Royalties. Davis:NanoPharmaceuticals LLC: Employment, Equity Ownership.
Evaluation of Anticoagulant Use during Pregnancy in Mothers with Antiphospholipid Syndrome: An Observational Cross-Sectional Study
Authors: Pandjaitan Inolyn , Tambunan Karmel L , Atmakusuma Tubagus Djumhana 
Published: October 2019

Abstract
Introduction: Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by vascular thrombosis and/or pregnancy morbidity with persistent elevated concentration of antiphospholipid antibody. The use of anticoagulant in pregnant women with APS has reduced implantation failure, reduced rate of placental insufficiency, increased rate of delivery of live infant, and reduced rate of abortion. However, compared to its beneficial effects, anticoagulant therapy during pregnancy can be challenging because of the burden of the treatment (self-injecting anticoagulant for 9 months, cost of the treatment) and potential anticoagulant side effects. The purpose of this study was to evaluate the outcome of pregnant women with APS with anticoagulant.
Method: We searched through medical records of pregnant women who visited hematology oncology clinic of Cikini CCI Hospital from year 2000 to 2017. Pregnant women with positive antiphospholipid antibodies who were treated with anticoagulant and followed up until presence of outcome were included in the study. Main outcome was any delivery of live infant above 22 weeks gestational age. Activated partial thromboplastin time (aPTT), d dimer level, birth weight and length were also documented.
Results: We identified 92 pregnancies in 88 mothers diagnosed with antiphospholipid syndrome who were prescribed anticoagulant. From 92 pregnancies, 67 (73%) and 25 (27%) patients were prescribed low molecular weight heparin (LMWH) and unfractionated heparin (UFH), respectively, with combination of low dose antiplatelet agent. APTT and d dimer level of every patients were monitored monthly. 80% of the pregnancies successfully resulted in live births. The proportion of successful delivery of healthy infant in patients treated with UFH (21 out of 25; 84%) was greater than LMWH (53 out of 67; 79%) but not statistically different (p = 0,708) (Figure 1). Birth weight and length between groups were similar.
Conclusion: UFH may be used as safe and cost-effective alternative treatment to LMWH in pregnant women with APS. Despite the use of anticoagulant and antiplatelet agents, 20% of patients still had adverse pregnancy outcome.

Disclosures
No relevant conflicts of interest to declare.