bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resveratrol As a Novel Treatment for Recurrent Epistaxis in SMAD4+ Hereditary Hemorrhagic Telangiectasia
Authors: Gill Shahbegh , Swaidani Shadi , Parambil Joseph , McCrae Keith R. 
Published: November 2021

Abstract
Introduction
Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by the development of arteriovenous malformations or telangiectasias that may affect any organ system, but are most prevalent in the nose and gastrointestinal tract. Nasal telangiectasia account for epistaxis, the most frequent manifestation of HHT, which may be frequent, debilitating and lead to decreased quality of life. Epistaxis is quantified by the Epistaxis Severity Scores (ESS), which ranges from 1-10 with higher scores associated with more severe bleeding. The diagnosis of HHT is based on clinical criteria and requires three or more of the following features: epistaxis, mucocutaneous telangiectasis, visceral AVMs, and/or a family history of HHT. HHT is associated with several mutations that may involve ENG, ACVRL1, or SMAD4; the latter occurs in only ~2% of HHT patients, which is also associated with the Juvenile Polyposis Syndrome (JPS), another autosomal dominant disorder associated with an increased risk for colorectal, stomach, small intestine, and pancreatic cancers.
Methods
Case report with serial ESS scores, hemoglobin and hematocrit monitoring.
Results
A 25-year-old male was diagnosed with JPS/HHT and a c.1081C&gt;T mutation in SMAD4 leading to an R361C missense mutation was diagnosed in 2013. The patient had a longstanding history of frequent epistaxis leading to severe iron deficiency anemia and requiring at least two 750 mg iron infusions annually (total of 14), and did not improve with oral iron supplements. In December 2020, the patient initiated a 1 g daily dose of resveratrol for general anti-aging and health benefits. His epistaxis improved immediately, and his ESS decreased from 6 (consistent with severe bleeding) to 1 (no bleeding) over a two week period. The frequency, severity and duration of epistaxis all improved dramatically (Figure). No additional iron therapy has been required since initiation of resveratrol. Recent serum iron and ferritin values (6/2021) were both within normal limits.
Of interest, in parallel with the resolution of epistaxis, the patient also had a dramatic reduction in colonic polyposis after starting resveratrol.
Conclusions
There are no approved therapies for the treatment of HHT, and patients with this disorder may suffer from a markedly reduced quality of life due to unpredictable epistaxis and other manifestations. While a responses to bevacizumab have been reported in 60-70% of patients, treatment is expensive and may be associated with thromboembolic events, and patients may become refractory over time. Invasive approaches such as sclerotherapy may be initially, but only temporarily effective. Thus, there is an urgent need for better HHT therapies.
Figure 1 Figure 1.

Disclosures
McCrae: Sanofi, Novartis, Alexion, and Johnson & Johnson: Consultancy, Honoraria; Dova, Novartis, Rigel, and Sanofi Genzyme: Consultancy.
Haploidentical Stem Cell Transplantation Can be Fully Conducted on an Outpatient Basis
Authors: Murrieta-Álvarez Iván , Olivares-Gazca Juan Carlos , Cantero-Fortiz Yahveth , León-Peña Andrés A. , Priesca-Marin José Manuel , Ruiz-Delgado Guillermo J. , Ruiz-Argüelles Guillermo J. 
Published: November 2021

Abstract
Introduction
Haploidentical hematopoietic stem cell transplantation (haplo-SCT) has become an acceptable approach for many patients; however, the suitability of this procedure and outcomes regarding efficacy and safety remain unclear. Here we present a single-center experience using a conditioning regimen based on cyclophosphamide and fludarabine under outpatient conditions.
Methods:
Retrospective study evaluating the performance of haplo-SCT in a single center. The conditioning regimen was fludarabine 50 mg on days -6 through -4, cyclophosphamide (Cy) 500 mg/m 2 on days -7 to -4 and tacrolimus 1000 mg and post-transplant Cy (50 mg/kg) on days +3 and +4 (Figure 1). Donor cell collection was accomplished through apheresis in all patients and fresh cells were administered on same day of collection. All the procedures were started on an outpatient basis. Overall survival was defined as mortality for any reason, starting to count from the day of transplantation to the date of death. The survival function was calculated according to the Kaplan-Meier estimation method. All patients signed a consent to participate after a thorough interview and the study protocol was approved by Clínica Ruiz IRB.
Results:
We grafted 20 patients, (14 adults and 6 children) with haploidentical cells and found that in 11 cases (55%), the full procedure could be completed totally as outpatients; the diagnosis of the grafted patients were: 10 acute lymphoblastic leukemia, 3 acute myelogenous leukemia, 3 paroxysmal nocturnal hemoglobinuria, and one each non-Hodgkin´s lymphoma, Blackfan-Diamond syndrome and multiple myeloma. Nine patients (3 children and 6 adults) were admitted to the hospital after completing the conditioning, 1 to 8 days after day 0: the causes for admission were neutropenic fever (5 cases), cytokine-release syndrome (3 cases), and intraabdominal abscess (1 case). Patients remained in the hospital for a median of 9 days. Four patients failed to engraft and recovered endogenous hematopoiesis and acute graft versus host-disease developed in 5 of 16 engrafted patients; two patients relapsed after the haplo-SCT. The transplant-related mortality was 35%, whereas the 2-year overall survival (OS) was 37.5% (Figure 2); the causes of the 7 deaths were: Four granulocytopenic sepsis, 2 graft-versus-host disease and one multiple organ failure.
Conclusions
Haplo-SCT procedures can be conducted safely and effectively on an outpatient basis; however, questions remain regarding the selection of patients and managing of complications, especially in outpatient conditions in which full and timely availability of specialized care could be the pivotal factor to improve short-term outcomes.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Disparity Analysis and Prognostic Value of Pretreatment Whole Blood Epstein-Barr Virus DNA Load and EBER Status in Lymphomas: A Retrospective Multicenter Study in Huaihai Lymphoma Working Group
Authors: Shen Ziyuan , Hu Lingling , Qiao Jianlin , Xu Linyan , Xu Kailin , Zhang Hao , Sang Wei 
Published: November 2021

Abstract
Elevated Epstein-Barr virus (EBV) DNA load is common in lymphomas. However, it remains unclear whether the disparity in viral load and its prognostic value in lymphomas are correlated with EBER status. In this retrospective multicenter study, we collected the data of pretreatment whole blood EBV DNA (pre-EBV DNA) and EBER status and evaluated their disparity and prognostic values in lymphomas. A total of 454 lymphoma patients from December 2014 to August 2020 were retrospectively retrieved. Mann-Whitney U test, Kruskal-Wallis test, and Bonferroni's adjustment were used to explore the disparity of EBV DNA and EBER status in lymphomas. Time-dependent receiver operating characteristic analysis and MaxStat analysis were used to determine optimal cut-off points of pre-EBV DNA load. Univariable and multivariable Cox proportional hazards models were established for the estimation of prognostic factors. The positive rate of EBV-DNA in NKTL patients was higher than that in DLBCL, FL, and HL patients, and the median positive pre-EBV copy number of NKTL was also higher than that of FL and DLBCL. EBV-DNA could clearly distinguish the prognosis of DLBCL, NKTL, HL and PTCL, and the integration of EBER status and EBV DNA could differentiate the prognosis of HL patients. Multivariable results revealed that pre-EBV DNA load had an effect on the prognosis of NKTL, FL and DLBCL. The status of pre-EBV DNA and EBER were disparate. Whole blood pre-EBV DNA predicted the prognosis of lymphomas, and the integration of EBV and EBER status could differentiate the prognosis of HL

Disclosures
No relevant conflicts of interest to declare.
Correlation Analysis of DNA Methylation Level and Clinical Characteristics in JMML Patients
Authors: Cai Yuli , Zhang Jingliao , Yi Meihui , Liu Xiaoming , Zhang Xiaoyan , Wan Yang , Chang Lixian , Zhang Li , Chen Xiaojuan , Guo Ye , Zou Yao , Chen Yumei , Zhang Yingchi , Yang Wenyu , Zhu Xiaofan 
Published: November 2021

Abstract
Objective: As a rare, aggressive pediatric myeloproliferative disease, juvenile myelomonocytic leukemia (JMML) encompassed both biological features of myelodysplastic syndrome and myeloproliferative neoplasm. Studies have shown that the methylation level in JMML patients is closely related to prognosis, and patients with high methylation level have poor prognosis. This study aimed to find clinical indicators that were associated with different methylation levels and prognosis.
Methods: The clinical information of 24 JMML patients with DNA samples admitted to our center from December 2013 to May 2020 was retrospectively analyzed, and the DNA methylation level of their whole genome was detected.
Results: The median age of onset was 14.5 months (0.1-153 months) among the 24 cases, including 17 males and 7 females. At diagnosis, the median WBC count was 27.1×10 9/L (6.2-98.1×10 9/L), and the median platelet count was 38×10 9/L (10-277×10 9/L). Chromosome karyotype abnormalities were found in 12.5% (3/24) of patients. Next-generation sequencing results showed that 79.2% (19/24) patients had at least one Ras pathway-related classical gene mutation, and 41.7% (10/24) patients had two or more somatic mutations. Genomic DNA methylation levels were divided into three groups: 10 cases in the hypomethylation group, 4 cases in the moderate methylation group, and 10 cases in the hypermethylation group. There were significant differences in age, platelets, PTPN11 gene mutation and the number of somatic mutations ≥2 in different methylation groups (P&lt;0.05). The age of hypomethylated group was significantly lower than that of hypermethylated group (P&lt;0.05), and the platelets of hypomethylated group was significantly higher than that of hypermethylated group (P&lt;0.05). Patients ≤12m and platelets＞32×10 9/L had lower DNA methylation level (P&lt;0.0001). The number of patients with PTPN11 gene mutation in the hypomethylated group was significantly lower than that in the hypermethylated group (P&lt;0.05), and the number of patients with ≥2 mutations in the low and medium methylated groups was significantly lower than that in the hypermethylated group (P&lt;0.05). Correlation analysis showed that hypermethylation level was significantly correlated with PTPN11 gene mutation and ≥2 somatic mutations (P&lt;0.001).
Conclusions: JMML patients with high methylation level in the DNA genome at diagnosis were older and with lower platelet levels, and hypermethylation were significantly correlated with high-risk prognostic factors such as PTPN11 gene mutation and ≥2 somatic mutations.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.

OffLabel Disclosure:
Decitabine for treatment of children with JMML
Concordance Study of CD30 Expression Detected By Multiple Immunohistochemistry Assays and Ventana CD30 Assay in Chinese Lymphoma Patients
Authors: Jiang Xiang-Nan , Shi Yang , Li Xiao-Qiu 
Published: November 2021

Abstract

Background: CD30 is emerging as an important biomarker guiding the clinical diagnosis, treatment, and evaluating the efficacy and prognosis of lymphoma. However, there is no standard procedure for specification and interpretation of the pathological detection of CD30 in China. This study intends to evaluate the staining and interpretation concordance of CD30 expression detected by the VENTANA CD30 assay and other multiple immunohistochemistry (IHC) assay in Chinese malignant lymphoma patients.
Design: This is a multi-center, observational study enrolling 1,000 adult patients with a diagnosis of histologically confirmed malignant lymphoma in China. Patients, aged 18 years or older at diagnosis and who provided available formalin-fixed paraffin-embedded (FFPE) samples stored within 2 years, with diagnosis of classical Hodgkin's lymphoma, anaplastic large-cell lymphoma, large cell transformation of mycosis fungoides, diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, extranodal NK/T-cell lymphoma, peripheral T cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, and pcCD30+ T-cell lymphoproliferative disease were eligible to participate. Exclusion criteria included sample insufficiency for CD30 testing, incomplete sample information, lack of written informed consent.
Methods: Each eligible patient provides an available r FFPE sample. Tissue slides obtained from each eligible FFPE sample will be stained by the VENTANA CD30 assay and at least one of the following IHC assays [umAB256 (zhongshanjinqiao) + Ventana BenchMark; Ber-H2 (Maixin) + Ventana BenchMark；Ber-H2 (Maixin) + DAKO; Ber-H2 (DAKO) + DAKO; Ber-H2 (DAKO) + Ventana BenchMark;umAB256 (Zhongshanjinqiao) + Leica; JCM182 (Leica) + Ventana BenchMark;JCM182 (Leica) + Leica; Ber-H2 (DAKO) + Leica]. CD30 expression of all immunostained slides will be independently interpreted as a percentage of CD30 positive cells by trained pathologists. The primary endpoint will be the staining concordance of percentages of positive cells for CD30 expression detected by each of the nine IHC assays and VENTANA CD30 assay (interpreted by expert panel) Secondary endpoints will be the interpretation concordance of pathologists at sites and the expert panel by assessing CD30 expression detected by various IHC assays. Both primary and secondary endpoint will be evaluated by intraclass correlation coefficient ICC, Bland-Altman, and Pearson correlation method.
Discussion: This planned study will explore more equivalent testing methods to detect the expression of CD30 in Chinese patients with lymphoma.

Disclosures
Shi: Takeda Pharmaceuticals: Current Employment. Li: Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Receiving lecture fees.
Autosomal Recessive Congenital Dyserythropoietic Anemia Type III Is Caused By Mutations in the Centralspindlin RACGAP1 Component
Authors: Romero-Cortadellas Lídia , Hernández Gonzalo , Ferrer-Cortès Xènia , Venturi Veronica , Olivella Mireia , Pérez de Soto Concepción , Morales-Camacho Rosario M. , Villegas Ana , Gonzalez-Fernandez F. Ataulfo , Morado Marta , Pérez-Montero Santiago , Tornador Cristian , Sánchez Mayka 
Published: November 2021

Abstract

An autosomal dominant form of congenital dyserythropoietic anemia type III (CDA III) is caused by a missense mutation in the KIF23 gene whose protein product, mitotic kinesin-like protein (MKLP1), is part of the centralspindlin complex involved in cytokinesis. Several case reports suggested the existence of an autosomal recessive inheritance form of CDA III so far not genetically characterized. By means of whole exome sequencing in a Spanish CDA III family with healthy parents, we identified in the male proband a novel homozygous missense mutation p.Pro432Ser in the RACGAP1 gene, which encodes for the RACGAP1 protein (Rac GTPase-activating protein 1, also known as MgcRacGAP or CYK-4), the partner of MKLP1 in the centralspindlin complex. A second CDA III Spanish patient has a different rare and novel homozygous missense mutation, p.Thr220Ala, in the RACGAP1 gene. Both patients presented with macrocytic anemia, aberrant multinucleated erythroblasts in the bone marrow typically seen in CDA III cases, no iron overload and skull defects secondary to severe anemia. Silencing of RACGAP1 using siRNA in HeLa cells mimics the cytokinesis defect observed in the bone marrow of our patients. Both mutations disrupt normal cytokinesis and alter the GTPase balance in patients' cells. We conclude that the autosomal recessive form of CDA type III is caused by mutations in the RACGAP1 gene, encoding for RACGAP1 protein, which is the partner of MKLP1 in the centralspindlin complex critical for cytokinesis and now both proteins are associated with CDA type III.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Systematic Construction of an Autophagic Risk Model in Bone Marrow for Prognostic Prediction in Multiple Myeloma
Authors: Shu Lingling , Huang Han-Ying , Liu Yang , Li Yang , Wang Weida , Li Jinyuan , Chen Shuzhao , Wu Xiaoping , Wang Yun , Lin Huan-xin , Liang Yang 
Published: November 2021

Abstract
Autophagy is an intracellular self-degradative process that balances cell energy source and regulates tissue homeostasis, which plays critical role in the pathogenesis of multiple myeloma (MM). However, the prognostic role of autophagy-related genes (ARGs) in MM remains undefined.
In the present study, the ARGs were obtained from Gene Expression Omnibus datasets (accession GSE24080, GSE136337, GSE57317), which contains 1038 samples of patients with MM. Univariate Cox regression analysis identified 38 ARGs that were significantly associated with overall survival of MM. Furthermore, a risk score model with 11 prognosis-associated ARGs was developed using multivariate Cox regression analysis, including ARNT, ATG4D, BIRC5, BNIP3L, CDKN1A, EIF2S1, IRGM, ITGA3, NCKAP1, NRG1 and TM9SF1. The 3-year area under the curve (AUC) values for the receiver operating characteristic curves were 0.717(0.662, 0.758), 0.646(0.587, 0.703) and 0.906(0.694, 1.000) for GSE24080, GSE136337, GSE57317 prognosis predictions, respectively (Figure A-C). Using this prognostic signature, patients with MM could be separated into high- and low-risk groups with distinct clinical outcomes (Figure D-F). Moreover, autophagy risk score was an independent prognostic factor by multivariate analysis. KEGG revealed that most pathways were related to autophagy and metabolism. Furthermore, we validated the expression of 11 genes and ARNT in bone marrow of MM patients (Figure G-I) and showed the critical role of ARNT-mediated autophagy in the proliferation and drug resistance of bortezomib in myeloma cells (Figure J-M).
In conclusion, we constructed ARGs-based prognostic model to predict the prognosis of MM, targeting specific autophagic gene such as ARNT might provide therapeutic clues for MM treatment.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Posttransplant Cyclophosphamide-Based Haploidentical Vs Matched Unrelated Donor Peripheral Blood Hematopoietic Stem Cell Transplantation Using Myeloablative Targeted Busulfan-Based Conditioning for Pediatric Acute Leukemia
Authors: Hong Kyung Taek , Park Hyun Jin , Kim Bo Kyung , An Hong Yul , Choi Jung Yoon , Kang Hyoung Jin 
Published: November 2021

Abstract
Haploidentical related donor (HRD) is a common alternative donor strategy used when matched sibling or unrelated donors are not available for hematopoietic stem cell transplantation (HSCT). Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis is an attractive option when performing a HRD HSCT because of its promising outcomes and easy application. However, there have been no studies comparing HRD HSCT with PTCy and MUD HSCT with antithymocyte globulin, using similar busulfan-based myeloablative conditioning regimen in pediatric acute leukemia. Herein, we compared the outcomes in children and adolescents with acute leukemia after HRD HSCT with PTCy (n=35) and matched unrelated donor (MUD) HSCT (n=45) after targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic monitoring. The median follow-up times of the HRD and MUD groups were 3.7 and 4.6 years. No engraftment failure was observed. The cumulative incidence of GVHD grades II-IV (34.3% versus 48.9%, p=0.142), grades III-IV (2.9% vs. 8.9%, p=0.272), extensive chronic GVHD (11.4% vs. 18.3%, p=0.417), relapse (25.6% vs. 28.0%, p=0.832), and non-relapse mortality (0% vs. 2.2%, p=0.420) were not significantly different. The 3-year severe chronic GVHD-free/relapse-free, leukemia-free and overall survival rates in the HRD and MUD groups were 62.9±8.7% versus 49.8±7.6% (p=0.318), 74.4±8.0% versus 67.5±7.2% (p=0.585), and 88.6±5.4% versus 83.7±5.7% (p=0.968), respectively. In subgroup analyses of patients with acute lymphoblastic leukemia and acute myeloid leukemia, there were no significant differences in outcomes between the groups. Our results demonstrated that HRD HSCT with PTCy using a targeted busulfan-based myeloablative conditioning shows outcomes similar to those of MUD HSCT. HRD HSCT with PTCy could be considered for pediatric acute leukemia patients who lack an HLA-matched donor.

Disclosures
Kang: Cartexell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding.
Measuring H3K27me3 Reduction after in-Vivo Administration of Ftx-6058; A Potent Polycomb Repressive Complex 2 (PRC2) Inhibitor
Authors: Roth Mark , Xie Keqiang 
Published: November 2021

Abstract
FTX-6058 is an investigational drug for the treatment of Sickle Cell Disease (SCD). The molecule is a selective and potent binder of the embryonic ectoderm development protein (EED). Binding of FTX-6058 to EED inhibits PRC2, a histone methyltransferase which primarily methylates lysine 27 of histone H3. Inhibition of PRC2 results in the reduction of trimethylation at lysine 27 on histone H3 (H3K27me3). Because the level of trimethylation on lysine 27 is the immediate downstream consequence of PRC2 activity, we developed a flow cytometric assay to measure the relative level of H3K27me3 from in-vivo tissue samples. The flow cytometric assay measures the median fluorescence intensities (MFI) of H3K27me3 and total histone H3. The target engagement (TE) measurement is a ratio of H3K27me3 MFI to total Histone H3 MFI. The target cells for FTX-6058 in SCD treatment are the hematopoietic cells of the bone marrow. We demonstrate an FTX-6058 dose dependent decrease in the TE ratio of bone marrow, hematopoietic cells. Translating the TE assay from mouse pre-clinical studies to human clinical trials required use of a less invasive tissue type than bone marrow. In mice, a positive relationship between the TE ratio of hematopoietic, bone marrow cells and circulating monocytes was established. Therefore, a human monocyte TE assay for FTX-6058 was validated for human trials. Research use only (RUO) validation was completed by Q2 Solutions Laboratories. The monocyte FTX-6058 TE assay is currently being evaluated as an exploratory biomarker in Fulcrum Therapeutics' phase 1 clinical trial FIS 002-2020.

Disclosures
Roth: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Xie: Fulcrum Therapeutics, Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months.