bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-Throughput Chemical Screen on Acute Myeloid Leukemia Stem Cells Identifies Novel Anti-LSC Compounds
Authors: Iasenza Isabella Angela , Safa Safia , Barabe Frederic , Cellot Sonia , Wilhelm Brian T. , Eppert Kolja 
Published: November 2021

Abstract

Acute myeloid leukemia (AML) is an aggressive form of blood cancer defined by the uncontrolled proliferation and clonal expansion of immature myeloblast cells in the blood and bone marrow, leading to hematopoietic failure. Despite the use of aggressive and cytotoxic standard-of-care drugs, patients often relapse and succumb to the disease partially due to the inability of medically unfit patients to withstand the cytotoxic treatments, regrowth from minimal residual disease and the chemo-resistant nature of leukemic stem cells (LSCs) which can remain in a quiescent state and reside in a protective bone marrow niche. Hence, novel therapies targeting unique leukemic stem cell biology are highly needed to eliminate and avoid reoccurrence.
High-throughput screens of human AML LSCs are not performed due to technical issues such as low LSC frequency within primary samples, an inability to purify LSCs, and the difficulty maintaining and expanding primary patient samples and LSCs in vitro. We were able to optimize conditions for a 4-week in vitro large-scale expansion (&gt;600 million bulk) of the primary human AML sample 8227 (OCI-AML-8227), functionally validated to be enriched for LSCs in long-term xenotransplant assays (Eppert et al., 2011). These optimized conditions enabled the isolation and maintenance of the LSC-containing fraction for a chemical screen. We isolated the CD34+ LSC-containing fraction (&gt;90% purity) and performed a high-throughput screen of 11,166 chemical molecules using a CellTiter Glo assay followed by a counter screen against normal CD34+ cord blood (CB) hematopoietic stem and progenitor cells.
From this HT screen, a total of 61 hits had &gt;70% inhibition on CD34+ 8227 cells and &lt;30% inhibition on CD34+ CB cells. We also identified glucocorticoids, which were also identified in our prior small-scale anti-LSC screen where they were found to specifically drive human LSCs to terminally differentiate (Laverdière & Boileau, et al., 2018).
We then performed dose response assays for each candidate compounds and confirmed 35 potent anti-LSC compounds with IC 50 &lt; 1 μM. This refined the types of compounds to including anti-apoptotic inhibitors, GSK inhibitors, protease inhibitors, metabolism inhibitors, HDAC inhibitors, BET inhibitors, nucleic acid synthesis inhibitors, cell cycle inhibitors and Wnt/β-catenin inhibitors. This is interesting as some of the classes of these compounds (inhibitors of GSK, BET, nucleic acid synthesis, Wnt/β-catenin and metabolism) have been shown to target bulk and leukemic stem cells in AML in vitro and in vivo.
We now aim to examine LSC eradication in a panel of genetically defined primary AMLs confirmed through in vitro and in vivo assays. Our goal is to be able to understand and establish the molecular mechanisms and biomarkers on primary functional LSCs.

Disclosures
No relevant conflicts of interest to declare.
Diagnosis and Treatment of Acquired Hemophilia: One Single-Center Experience from PR. China
Authors: Zhou Rong-Fu , Xu Yueyi , Gao Wenjin 
Published: November 2021

Abstract
Objective: To deepen the understanding of the clinical manifestations of acquired hemophilia A for timely and correctly treatment.
Methods: The clinical data of the acquired hemophilia A patients diagnosed in the hospital from Jan 2006 to Mar 2021 were retrospectively analyzed, and the relevant literature was reviewed.
Results: 17 patients with acquired hemophilia A, male: female =10: 7, median age 61 years (19 to 78 years), were diagnosed and treated in the hospital with the median time from the onset to diagnosis 21 days (2 days to 6 months). Six patients had comorbidity, including hepatitis B carrying, chronic myelomonocytic leukemia, diabetes, hypertension and positive autoantibodies, pemphigoid and gastric cancer, respectively. Other 11 patients were healthy before the onset. All patients had large large ecchymosis of skin, and one case was combined with hematuria, and one case with retroperitoneal hematoma. All patients had APTT extension (45s-144.7s) and the prolonged APTT could not be corrected with normal mixed plasma with and without incubation at 37℃ for 2 hours. FVIII activity was 1% - 8.9% and inhibitor titer 2 - 128 Bu/ml. All patients with bleeding were with prothrombin complex/recombinant activated coagulation factor VII, some of them with pd-coagulation factor FVIII preparations. Inhibitors were removed with prednisone acetate (1 case) + chemotherapy (1 case), prednisone acetate / + CTX (11 cases) + chemotherapy (1 case), prednisone acetate/prednisolone + mabthera (2 cases) + CTX (1 case), respectively. The removal time of inhibitor was from 8 days to 4 years. During the treatment process, two patients developed lower extremity venous thrombosis, and one patient was complicated with lung infection.
Conclusion: Patients with unexplained bleeding and prolonged APTT should be conducted normal mixed plasma correction test, coagulation factor activity and inhibitor titer examination. After correctly diagnosis, bypass agents /coagulation factor VIII preparations should be given timely for hemostasis, protocol based on glucocorticoid + CTX/mabthera to remove the inhibitor and symptomatic treatment for patients with primary comorbidity disease at the same time.

Disclosures
No relevant conflicts of interest to declare.
Ethnic Disparities in AL Amyloidosis Outcomes Among Hospitalized Patients in the United States
Authors: Al Hadidi Samer , Dongarwar Deepa , Salihu Hamisu , Schinke Carolina , Thanendrarajan Sharmilan , Zangari Maurizio , van Rhee Frits 
Published: November 2021

Abstract
INTRODUCTION
Health disparities in immunoglobulin light chain (AL) amyloidosis have not been well described. We aimed to assess if health disparities between non-Hispanic (NH)-Whites, NH-Blacks and Hispanics exist and to describe differences between different ethnic/racial groups.
METHODS
We conducted a retrospective cross-sectional analysis of in-patient AL amyloidosis hospitalizations from 2016 to 2018 using the Nationwide Inpatient Sample (NIS), a database which provides nationally representative information on hospitalizations in the U.S. The studied period was chosen to capture data from the ICD-10-CM codes to avoid misclassification of AL amyloidosis which was grouped with other cases of ATTR amyloidosis in the ICD-9-CM coding system. All hospitalizations in adults (age ≥18 years) were included. The exposure for the study was the occurrence of AL amyloidosis in the discharge records. Outcomes were [1] in-hospital death [2] chemotherapy use; [3] intensive care unit (ICU) utilization; [4] palliative care consultation. The analysis for this study was performed using R program version 3.5.1; a 5% type I error rate for all hypothesis tests (two-sided) was assumed.
RESULTS
Admissions related to AL amyloidosis constituted 0.03% of all hospitalizations in the study period (25,470 of 90,869,381). The prevalence of AL amyloidosis related hospitalizations was higher in NH-Blacks when compared with NH-Whites (42.8 vs.28.1 per 100,000 hospitalizations). AL amyloidosis related in-hospital mortality rate was higher in NH-Whites and Hispanics when compared to NH-Blacks (6.6%% and 6.2% vs. 4.9%). In-hospital mortality with AL amyloidosis was higher in older patients, males and those who self-paid for their treatment. Utilization of ICU care was more common in NH-Blacks when compared to NH-Whites (6% vs. 4.8%). Hispanics had the lowest inpatient chemotherapy use (1.7% vs. 2.9%). Multivariable adjusted association between race/ethnicity and various outcomes showed a trend towards lower in-hospital mortality in NH-Blacks when compared to NH-Whites (OR: 0.76, 95% CI: 0.55-1.05, p=0.09) and lower utilization of palliative care services in NH-Blacks when compared with NH-Whites (OR: 0.61, 95% CI: 0.42-0.88, p=0.01). Despite very low numbers of transplant related admissions, such admissions occurred only in NH-Whites.
CONCLUSIONS
Our findings highlight disparities in AL amyloidosis care for NH-Blacks and Hispanics. NH-Blacks tend to have lower in-hospital mortality with higher utilization of ICU care, nevertheless, they receive the lowest palliative care services. Despite the higher utilization of ICU care, data suggest possible superior outcomes of AL amyloidosis in NH-Blacks when compared to NH-Whites.

Disclosures
No relevant conflicts of interest to declare.
Quantification and Characterisation of Nano-Sized Particles in Cryoprecipitate Units
Authors: Hwang Ji Hui , Tung John-Paul , Flower Robert L , Pecheniuk Natalie M 
Published: November 2021

Abstract
Background
Cryoprecipitate is an important blood product derived from fresh frozen plasma. It is primarily used to replenish fibrinogen levels in patients. Currently, there is a lack of studies characterising nano-sized particles, including extracellular vesicles (EVs) in cryoprecipitate. EVs play a key role in cell-to-cell communication in physiological and pathological conditions, through the transference of their bioactive cargo such as proteins, lipids, or nucleic acids. This study utilised modern techniques such as nanoparticle tracking analysis (NTA) to characterise these EVs.
Methods
We obtained ten individual cryoprecipitate units and determined their particle concentration and size distribution using optimised NTA parameters on the Nanosight NS300 instrument.
To prevent blockage of the Nanosight's micro-fluidics, samples are routinely filtered before sample injection. Therefore, we wanted to investigate if different filter materials could impact NTA measurements for cryoprecipitate. Samples were filtered with either regenerated cellulose (RC) or polytetrafluoroethylene (PTFE), with non-filtered samples as control. A one-way ANOVA with Tukey post hoc test was used to compare the particle parameters (particle concentration, mean, mode). Significance was set at p&lt;0.05.
Results
The results showed that different cryoprecipitate units varied in their particle concentration and size, with an average concentration of 2.501 x 10 11 ± 1.098 x 10 11 particles per mL and a particle mean of 133.8 ± 7.5 nm and mode of 107.9 ±11.06 nm. In addition, only samples filtered using RC were there no significant changes in the measured particle parameters (particle concentration, p=0.936; mean, p=0.999; mode, p=0.996) compared to the non-filtered samples. A significant difference was observed in the mean of particle size between PTFE and RC filters (112.7 ± 6.033 nm, 42 133.8 ± 7.503 nm, p =&lt;0.0001) and between PTFE and non-filtered (112.7 ± 6.033 nm, 133.7 ± 13.63 nm, p =0.0015). PTFE significantly reduced the particle mean compared to both RC and non-filtered.
Conclusions
Our findings revealed that NTA could be used as a novel method to measure particles in cryoprecipitate. Furthermore, RC filters are compatible with quantitative NTA analysis compared to PTFE filters.

Disclosures
No relevant conflicts of interest to declare.
Patterns of Family History of Cancer in Adults with Hematologic Malignancies
Authors: Seiter Karen , Swa Kyaw , Htun Kyaw , Baskind Paul , Liu Delong 
Published: November 2021

Abstract
Hematologic malignancies have generally been considered to be sporadic diseases. More recently several germ line mutations that lead to hereditary hematologic malignancies have been discovered, even in adults. We sought to evaluate the frequency of a family history of hematologic or other malignancy in pts admitted to the hospital for treatment of a hematologic malignancy. We also studied exposure history including use of cigarettes. All pts signed informed consent. Pts were entered prospectively and interviewed with a standard questionnaire. 702 pts (median age 61.9: range 16.3-91.3 years) were enrolled. Diagnoses were AML: 396 pts, aplastic anemia: 5 pts, ALL: 96 pts, CLL: 24 pts, CML 42 pts, CMML 10 pts, MDS 30 pts, MM 19 pts, MPD 10 pts, and NHL 70 pts. 473 pts (67.4%) had a family member with cancer. There was a total of 1037 cancers in these family members. The median number of family members with cancer was 1 (range 0-10). The frequency of each type of family member cancer is displayed in the table. 19.7% of pts had a family member with leukemia or other hematologic malignancy (leukemia: 12.0%, other hematologic: 7.7%). Compared to pts with a hematologic malignancy other than AML, pts with AML were more likely to have a family member with any type of cancer (72.4% vs 60.7%, p=0.001). Pts with AML were also more likely to have a family member with a history of any type of hematologic malignancy (22.4% vs 16.0%, p=0.03), but not specifically a history of leukemia (13.4% vs 10.1%, p=0.11). Compared to pts with hematologic malignancies other than AML, pts with AML were also more likely to have a family member with prostate cancer (16.2% vs 9.5%, p=0.01), or breast cancer (29.5% vs 21.9%, p=0.02). 51.4% of pts had a history of smoking (either current or prior). Pts with AML were more likely to be current or former smokers compared to pts with other hematologic malignancies (55.8% vs 45.8%, p=0.008). These data support the role of genetics and exposure in adults with AML.
Figure 1 Figure 1.

Disclosures
Seiter: Delta FLY: Research Funding; Novartis: Honoraria; Rafael: Research Funding; Sun Pharma: Research Funding; Jazz: Honoraria, Research Funding; Glycomimetics: Research Funding; Incyte: Honoraria; Forma: Research Funding; Celgene (BMS): Honoraria, Research Funding. Liu: Beigene: Honoraria, Speakers Bureau; Pfizer: Research Funding; Astellas: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau; Incyte: Honoraria; Celgene: Research Funding.
Follicular Lymphoma Grade 3A Is Different from Grade 1/2 in the Real World
Authors: Li Chunyuan , Yang Ping , Wan Wei , Liu Shuozi , Jing Hongmei 
Published: November 2021

Abstract
Background: follicular lymphoma (FL) is histologically subdivided into grades 1/2(FL1/2), 3A(FL3A), and 3B(FL3B). FL3B is more like diffuse large B-cell lymphoma (DLBCL), while the clinical approach to FL1/2 and FL3A has been debated. We aim to explore the clinical, biological characteristics and outcomes between them.
Methods: A retrospective analysis of 195 de novo FL patients within the same time frame (1999 to 2020) was identified. 141 patients were FL1/2, and 54 patients were FL3A.
Results: Comparing with FL1/2, FL3A patients tend to present ECOG≥1, B symptoms, bone marrow involvement, digestive tract involvement, elevated LDH, Ki-67≥30%, CD10 negative, and multiple myeloma oncogene-1(MUM1) positive, while Ann Arbor stage I or II was usually seen in FL1/2. After received CHOP±R (cyclophosphamide, doxorubicin, vincristine and prednisone ±rituximab), the 5-year overall survival (OS) was 89.5% for FL1/2 and 61.1% for FL3A [ HR =3.742(95%CI:1.838-7.620),P &lt;0.0001], the 5-year progression-free survival (PFS) was 62.5 for FL1/2 and 47.6% for FL3A [ HR =2.113(95%CI:1.297-3.443),P =0.003].
Conclusion: FL3A is more aggressive both clinically and biologically compared with FL1/2, and more attention should be paid to the difference of treatment between them.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
The Comparison of Dasatinib 70 Mg/Day to 100 Mg/Day in Newly Diagnosed Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP): A Multicenter, Prospective, Randomized Controlled Study
Authors: Yu Dan , Yang Zhuangzhi , Cheng Hui , Jiang Rui , Guo Jingming , Wan Chucheng , Qin Jun , Zhang Youshan , Yuan Guolin , Jiang Daozi , Zhang Chun , Liu Fang , Zhang Min , Chen Shiming , Liang Caixia , Zou Jing , Wu Zhiwei , Zou Xiuping , Han Danlei , Chen Xu , Wang Li , Lv Tingting , Tian Xiaolong , Xie Yanping , An Hongyu , Yan Li , Zhang Yicheng , Li Weiming 
Published: November 2021

Abstract
Background:
The purpose of this study is to compare efficacy and safety of patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline dasatinib 70 mg/day with those who received standard-dose dasatinib 100 mg/day.
Method:
From July 2019 to July 2021, 81 patients with newly diagnosed CML-CP were enrolled across 11 centers. All of the patients were randomly treated with dasatinib 70 mg/day (N=43) or standard-dose dasatinib 100 mg/day (N=38).
Results:
Among 81 enrolled patients, 16 patients were off study at different times for different reasons.All patients achieved hematological remission after 3 months of treatment, and the best response rates were 84.00% (21/25) and 88.89% (24/27) for 70mg/d and 100mg/d groups (P&gt;0.05).At 6 months, the best response, complete cytogenetic response (CCyR) and major molecular response (MMR) rate were 94.44% vs 92.86% (P &gt; 0.05), 94.44% vs 92.86% (P &gt; 0.05) and 55.56% vs 71.43% (P &gt; 0.05), respectively.At 9 months, the rates of CCyR and MMR were 90.91% vs 88.89% (P &gt; 0.05) and 66.67% vs 72.73% (P &gt; 0.05);CCyR and MMR by 12 months, respectively, were 90.91% vs 100.00% (P &gt; 0.05), 81.82% vs 80.00% (P &gt; 0.05).The adverse events (AEs) of the two groups were mild, and there was no significant difference (P &gt; 0.05).The most common grade ≥3 hematological AEs in 70 mg/d group were leukopenia (1/43), neutropenia (1/43) and anemia (2/43), and In 100mg/d group were leukopenia (4/38), neutropenia (6/38), anemia (3/38) and thrombocytopenia (3/38).
Conclusions:
Our study suggests that patients with newly diagnosed CML-CP treated with dasatinib 70 mg/day or 100 mg/day, there is no significant difference in efficacy and safety. Decreasing the dose of dasatinib can ensure the efficacy of patients, while reducing the economic burden of patients and increasing patient compliance.

Disclosures
No relevant conflicts of interest to declare.
Functional Verification of Novel ELMO1 Variants By Live Imaging in Zebrafish
Authors: Xue Rongtao , Wang Ying , Wang Tienan , Lyu Mei , Mo Guiling , Fan Xijie , Li Jianchao , Yen Kuangyu , Yu Shihui , Xu Jin , Liu Qifa 
Published: November 2021

Abstract
ELMO1 (Engulfment and Cell Motility1) is a gene involved in regulating cell motility through the ELMO1-DOCK2-RAC complex. Contrary to DOCK2 (Dedicator of Cytokinesis 2) deficiency, which has been reported to be associated with immunodeficiency diseases, variants of ELMO1 have been associated with autoimmune diseases, such as diabetes and rheumatoid arthritis (RA). To explore the function of ELMO1 in immune cells and to verify the functions of novel ELMO1 variants in vivo, we established a zebrafish elmo1 mutant model. Live imaging revealed that similar to mammals, the motility of neutrophils and T-cells was largely attenuated in zebrafish mutants. Consequently, the response of neutrophils to injury or bacterial infection was significantly reduced in the mutants. Furthermore, the reduced mobility of neutrophils could be rescued by the expression of constitutively activated Rac proteins, suggesting that zebrafish elmo1 mutant functions via a conserved mechanism. With this mutant, three novel human ELMO1 variants were transiently and specifically expressed in zebrafish neutrophils. Two variants, p.E90K (c.268G&gt;A) and p.D194G (c.581A&gt;G) could efficiently recover the motility defect of neutrophils in the elmo1 mutant; however, the p.R354X (c.1060C&gt;T) variant failed to rescue the mutant. Acts as a dominant-negative form, p.R354X (c.1060C&gt;T) which failed to rescue the elmo1 mutant and inhibited neutrophil movement in siblings. Based on those results, we identified that zebrafish elmo1 played conserved roles in cell motility, similar to higher vertebrates. Using the transient-expression assay, zebrafish elmo1 mutants could serve as an effective model for human variant verification in vivo.

Disclosures
No relevant conflicts of interest to declare.
NL-201, a De Novo Agonist of IL-2 and IL-15 Receptors, Demonstrates Synergistic Antitumor Activity with Anti-PD-1 Checkpoint Inhibitor Therapy in a Preclinical Non-Hodgkin Lymphoma Model
Authors: Huard Justin , Tatalick Laurie , Walkey Carl , Swanson Ryan 
Published: November 2021

Abstract
NL-201 is a potent, selective, and long-acting computationally designed alpha-independent agonist of the IL-2 and IL-15 receptors that is being developed as an immunotherapy for cancer. NL-201 binds to the beta and gamma subunits, selectively stimulating dose-dependent expansion and tumor infiltration of cytotoxic CD8+ T cells and natural killer (NK) cells, thereby enhancing the immune response to the tumor. Absence of binding to the IL-2 alpha subunit reduces the undesirable effects of traditional IL-2 therapies, such as vascular leak syndrome and expansion of immunosuppressive regulatory T cells. In this abstract, we demonstrate that NL-201, alone or in combination, demonstrates robust antitumor activity in preclinical models of non-Hodgkin lymphoma (NHL).
We have previously demonstrated that NL-201 has marked antitumor activity in multiple syngeneic tumor models, including the A20 lymphoma model. These observations in lymphoma have been extended to explore the effects of NL-201 in combination with anti-mPD-1 checkpoint inhibitor therapy in vivo. In this model, NL-201 and anti-mPD-1 demonstrated tumor growth inhibition and increased median survival (21 days each vs 17 days as observed in control) when given alone. In combination, NL-201 and anti-mPD-1 resulted in increased antitumor activity and significant prolongation of survival (&gt;51 days). We have also demonstrated that NL-201 does not directly induce signaling or cell death in B cell−derived NHL, suggesting that the observed antitumor activity is due to activation of non-malignant host immune cells.
Additional in vitro and in vivo NHL models are being tested to enhance understanding of the interaction between NL-201 and other approved therapies within the hematopoietic tumor microenvironment. These data will be used to design future clinical trials of NL-201 in novel regimens to treat hematological malignancies.

Disclosures
Huard: Neoleukin Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Patents & Royalties. Tatalick: Neoleukin Therapeutics, Inc.: Consultancy, Current equity holder in publicly-traded company, Other: Independent paid nonclinical consultant for Neoleukin. Walkey: Neoleukin Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Swanson: Neoleukin Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties.