bluuebunny/crossref_metadata_2025_split huggingface dataset:
Traits of positive and negative discrimination of the Copts in medieval Egypt as described by the “History of the Patriarchs of Alexandria”
Authors: Ivanova Anastasia M. 
Published: November 2019

Abstract
In the course of the Middle Ages, the Copts experienced a variety of drastic changes in the attitude of Muslim rulers towards them, from confidence to disgrace. The latter included not only the increasingly rigorous tax policies, but also social and domestic constraints.
Bicalutamide-associated hallucinations in a metastatic prostate cancer patient: A case report
Authors: Turkkan Gorkem , Dogan Caner , Tek Burak 
Published: November 2019

Introduction Bicalutamide is widely used in the treatment of prostate cancer. Among its side effects, central nervous system disorders are relatively rare, and the information about bicalutamide-associated hallucinations is limited. Case report We report an uncommon case of a patient with metastatic prostate cancer, who had hallucinations due to the use of bicalutamide. Management and outcome The patient accepted to receive only hormonal therapy (bicalutamide and leuprolide acetate). But he developed hallucinations due to bicalutamide use. His hallucinations disappeared after discontinuation of bicalutamide. A good response was obtained with the use of luteinizing hormone-releasing hormone agonist monotherapy. Discussion The pathophysiology of bicalutamide-induced hallucinations is unclear. We hypothesize that antiandrogens can indirectly cause hallucinations through changes in plasma testosterone and cerebral reelin expression. Additionally, luteinizing hormone-releasing hormone agonist monotherapy is a good option in metastatic prostate cancer patients who have intolerable side effects due to the use of antiandrogens.
Social work interventions with survivors of acts of political violence
Authors: Schiff Miriam , Lesser Lior , Levine Tova , Savo Yaeliy , Dashti Tzlil , Rosenne Hadas 
Published: November 2019

Summary Social workers and students in a large teaching hospital explored the characteristics of psychosocial interventions during acts of political violence. The associations between hospital length of stay, Acute Stress Reaction, and the characteristics of the implemented psychosocial interventions were also examined. One hundred and forty patients (61.4% males) treated during the so-called stabbing intifada/uprising in the years 2014–2015 in Israel in one large hospital were included. Data collection was based on clinical data mining. Findings The most frequent patient interventions were trauma-focused, while the most frequent family interventions were needs assessment and support-system building. Most of the interventions with the family (but not with the patient) were associated with longer hospital stays. Greater severity of Acute Stress Reaction was associated with greater use of trauma-focused interventions with the patient (but not with the family). Applications The findings suggest that social workers hold implicit trauma-focused intervention theories that should be written up in order to develop practice-based intervention models in the context of political violence.
Tropomyosin 1 Genetically Constrains in Vitro Megakaryopoiesis
Authors: Thom Christopher , Jobaliya Chintan , Lorenz Kimberly , Maguire Jean Ann , Gagne Alyssa , Gadue Paul , French Deborah L , Voight Benjamin F 
Published: November 2019

Platelet size and count are heritable, quantifiable outcomes of hematopoiesis. A better understanding of genetic mechanisms that regulate hematopoiesis could yield insights into blood disorders and augment clinical translational efforts to generate platelets in vitro. For example, induced pluripotent stem cell-derived blood cells could someday ameliorate adverse effects and increase transfusable platelet supplies. However, these methods remain inefficient.
Genome wide association studies (GWAS) have linked hundreds of DNA loci with altered human platelet traits, but little is known about how these GWAS loci mechanistically impact hematopoiesis, megakaryocyte or platelet biology. Using publicly available genome-wide association and epigenetic data sets, we applied a machine-learning framework to identify epigenetic features enriched at established platelet trait association sites. From these results, we derived a quantitative prediction model that identified hematopoiesis-, megakaryocyte-, and platelet-relevant genomic loci and related genes more accurately than any prior computational method. In addition to specifying exact genetic variants known to regulate platelet traits and function, our model highlighted several novel variants in established platelet trait variation GWAS loci that were predicted to disrupt key transcription factor binding sites.
Among loci nominated by our statistical model was a variant (rs11071720) that alters Tropomyosin 1 (TPM1) gene expression. TPM1 regulates cytoskeletal biology in many cell types, and cytoskeletal functions critically impact hematopoiesis and terminal blood cell biology. We used CRISPR/Cas9-mediated genome editing to create TPM1-knockout human induced pluripotent stem cells. TPM1KO cells were healthy and showed normal developmental progression through primitive streak, mesoderm, and early primitive hematopoietic differentiation programs. Unexpectedly, TPM1KO cells demonstrated enhanced formation of hemogenic endothelium and hematopoietic progenitor cells, increasing total megakaryocyte yield by more than 2-fold. TPM1KO megakaryocytes demonstrated normal morphology, gene expression patterns and functional responses to platelet agonists.
Our findings help explain human genetics associations and identify a novel strategy to enhance in vitro hematopoiesis. More broadly, our now-validated machine learning-based approach might specify additional functional loci underlying hematopoiesis, megakaryopoiesis, or thrombopoiesis.

Disclosures
No relevant conflicts of interest to declare.
Interim Serum Soluble Interleukin-2 Receptor Levels Are Strongly Associated with Prognosis in Newly Diagnosis DLBCL Patients
Authors: Okamoto Haruya , Miyashita Akihiro , Nagata Hiroaki , Tsutsumi Yasuhiko , Kamitsuji Yuri , Kobayashi Yutaka , Uoshima Nobuhiko 
Published: November 2019

<Background> Serum soluble interleukin-2 receptor (sIL2R) levels are often measured to evaluate the state of lymphoma. The serum sIL2R level at diagnosis has been reported to be correlated with the prognosis of diffuse large B cell lymphoma (DLBCL) patients treated with the R-CHOP regimen. However, it is unclear whether interim sIL2R levels are associated with prognosis in DLBCL. Here, we analyzed the prognostic impact of interim serum sIL2R levels in DLBCL.
<Patients and Methods> We retrospectively examined data for DLBCL patients who started receiving chemotherapy at the Japanese Red Cross Society Kyoto Daini Hospital between January 2012 and December 2018. All of the patients received R-CHOP-like regimens (rituximab plus pirarubicin or adriamycin, cyclophosphamide, vincristine, and prednisolone). The interim sIL2R level (I-IL2R) was defined as the value measured after the third chemotherapy cycle. I-IL2R levels of >700 U/ml were regarded as positive. The primary endpoints of this study were progression-free survival (PFS) and overall survival (OS). The unadjusted probabilities of PFS and OS were estimated using the Kaplan-Meier method. The log-rank test and multivariate Cox regression analysis were used to assess the prognostic value of each clinical variable.
<Results> In total, 102 patients were enrolled. The patients' median age was 73.5 years (range, 35-88), 58 patients (56.9%) were male, and 52 (51.0%) had poor revised International Prognostic Index scores. The median follow-up time was 25.2 months (range, 3.7-88.6). Twenty-three patients (22.5%) were I-IL2R-positive (>700 U/ml). Univariate analysis revealed that I-IL2R-positivity was associated with a poor prognosis. The 3-y PFS rates of the I-IL2R-negative (<700 U/ml) and I- IL2R-positive (>700 U/ml) patients were 60.4% (95% confidence interval [95%CI], 46.2-71.9) and 37.5% (95%CI, 15.7-59.4; p<0.001, log-rank test), respectively, and their 3-y OS rates were 82.2% (95%CI, 69.7-89.9) and 37.4% (95%CI, 13.8-61.4; p<0.001, log-rank test), respectively. Multivariate analysis confirmed that the I-IL2R level is independently associated with prognosis.
<Conclusion> The I-IL2R level of >700 U/ml patients had poor prognosis. The I-IL2R level can be used to predict the outcomes of DLBCL patients. IL2R levels should be measured during chemotherapy, and I-IL2R-positive patients could be targeted with high-dose or novel therapies. As this study was based on a retrospective analysis and involved a small cohort and a limited follow-up period, further studies are needed to confirm the prognostic impact of I-IL2R.
Figure

Disclosures
No relevant conflicts of interest to declare.
Endothelial JAK3 Expression Enhances Pro-Hematopoietic Angiocrine Function of Sinusoidal Endothelial Cells
Authors: Barcia Durán José Gabriel 
Published: November 2019

Unlike Jak1, Jak2, and Tyk2, Jak3 is the only member of the Jak family of secondary messengers that signals exclusively by binding the common gamma chain of interleukin receptors IL2, IL4, IL7, IL9, IL15, and IL21. Jak3-null mice display defective T and NK cell development, which results in a mild SCID phenotype. Still, functional Jak3 expression outside the hematopoietic system remains unreported. Our data show that Jak3 is expressed in endothelial cells across hematopoietic and non-hematopoietic organs, with heightened expression in the bone marrow and spleen. Increased arterial zonation in the bone marrow of Jak3-null mice further suggests that Jak3 is a marker of sinusoidal endothelium, which is confirmed by fluorescent microscopy staining and single-cell RNA-sequencing. We also show that the Jak3-null niche is deleterious for the maintenance of long-term repopulating hematopoietic stem and progenitor cells (LT-HSCs) and that Jak3-overexpressing endothelial cells have increased potential to expand LT-HSCs in vitro. In addition, we identify the soluble factors downstream of Jak3 that provide endothelial cells with this functional advantage and show their localization to the bone marrow sinusoids in vivo. Our work serves to identify a novel function for a non-promiscuous tyrosine kinase in the bone marrow vascular niche and further characterize the hematopoietic stem cell niche of sinusoidal endothelium.

Disclosures
No relevant conflicts of interest to declare.
ETH-155008, a Novel Selective Dual Inhibitor of FLT3 and CDK4/6 in Preclinical Treatment of Acute Myeloid Leukemia
Authors: Liu Changnian , Liu Bin , Xu Chunping , Zhang Pan , Li Bin , Ji Bin , Zhang Bin , Liu Qingjun , Zhang James , Yu Chengzhi 
Published: November 2019

Fms-like tyrosine kinase 3 (FLT3) is part of a family of receptor tyrosine kinases (RTKs), and a molecular therapeutic target of acute myeloid leukemia (AML). There are three FTL3 inhibitors, midostaurin, gilteritinib, and quizartinib have been approved for clinical treatment of AML. We have evaluated the inhibition of cell proliferation in vitro and antitumor activity in vivo of ETH-155008, a novel triple inhibitor of FLT3, Pim-3 and CDK4/6. ETH-155008 was found to have a strong inhibitory activity against key target enzymes (FLT3 IC50 at 0.5nM; Flt3 -Itd IC50 at 0.6 nM; CDK4/D1 IC50 at 0.8nM, CDK6/D1 IC50 at 1.4nM), which were more potent than the tested positive controls gilteritinib, quizartinib, and AMG-925. ETH-155008 showed to have highly potent antiproliferative activities against cultured human acute myeloid leukemia cells (MV4-11 and Molm-13) with IC50 at 4.1nM and 12 nM, respectively, and showed remarkable antitumor efficacy in vivo.
The in vivo antitumor activity of ETH-155008 was evaluated and compared with midostaurin and gilteritinib in the treatment of the two models with mutant forms in TKD and gatekeeper region, namely BaF3 FLT3-ITD-F691L and BaF3 FLT3-ITD-D835Y, respectively. Treatment with ETH-155008 (40 mg/kg/daily x 18, oral) significantly delayed tumor growth and resulted in a smaller mean tumor size (tumor growth inhibition (TGI) of 86% (p<0.001 compared with the control group) in the BaF3 FLT3-ITD-F691L model, and cured all of the tumor-bearing mice in the BaF3 FLT3-ITD-D835Y model. The antitumor activity of ETH-155008 was comparable to gilteritinib, but much better than midostaurin, the latter showed only mild antitumor activity with ~25% of TGI in the two FLT3 mutant models. We also tested the therapeutic efficacy of ETH-155008 in the human AML xenograft model MV4-11, ETH-155008 cured all of the tumor-bearing mice (mean tumor size at time of treatment 126 mm3), at a dose of 40mg/kg/daily for 14 days, that showed very little toxicity (only 2% body weight loss) which were well below the maximum tolerated dose.
ETH-155008 represents a novel dual inhibitor that may yet fulfill the promise of effective AML therapy through dual targeting of FLT3 and CDK4/6. These preclinical results supported the safety and efficacy observed in the preclinical studies and worthy of further clinical evaluation.

Disclosures
Liu: Euthare LLC: Other: founder. Zhang:shengke therapeutics: Other: cofounder. Yu:shengke Therapeutics: Other: co-founder.
Combination of BCL-2 Inhibition and Triptolide Causes Synthetic Lethality in Acute Myeloid Leukemia through Preventing Reciprocal Resistance
Authors: Xu Bing , Shi Yuanfei , Liu Long , Carter Bing Z 
Published: November 2019

BCL-2 inhibition exerts effective pro-apoptotic activities in acute myeloid leukemia (AML) but clinical efficacy as a monotherapy was limited in part due to the treatment-induced MCL-1 increase. Triptolide (TPL) exhibits anti-tumor activities in part by upregulating pro-apoptotic BCL-2 proteins and decreasing MCL-1 expression in various malignant cells. We hypothesized that combined BCL-2 inhibition and TPL exert synergistic anti-leukemia activities and prevent the resistance to BCL-2 inhibition in AML. We here report that TPL combined with BCL-2 inhibitor ABT-199 synergistically induced apoptosis in leukemic cells regardless of p53 status through activating the intrinsic mitochondrial apoptotic pathway in vitro. Although ABT-199 or TPL alone inhibited AML growth in vivo, the combination therapy demonstrated a significantly stronger anti-leukemic effect. Mechanistically, TPL significantly upregulated BH3 only proteins including PUMA, NOXA, BID and BIM and decreased MCL-1 but upregulated BCL-2 expression in both p53 wild type and p53 mutant AML cell lines, while the combination decreased both BCL-2 and MCL-1 and further increased BH3 only BCL-2 proteins. MCL-1 and BCL-2 increases associated with respective ABT-199 and TPL treatment and resistance were also observed in vivo. Significantly downregulating MCL-1 and elevating BH3 only proteins by TPL could not only potentially block MCL-1-mediated resistance but also enhance anti-leukemic efficacy of ABT-199. Conversely, BCL-2 inhibition counteracted the potential resistance of TPL mediated by upregulation of BCL-2. The combination further amplified the effect, which likely contributed to the synthetic lethality. This mutual blockade of potential resistance provides a rational basis for the promising clinical application of TPL and BCL-2 inhibition in AML independent of p53 status.

Disclosures
Carter: Amgen: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding.
SF3B1/DNMT3A Double Mutations Are Associated with Better Prognosis Than DNMT3A Mutation Alone in Myeloid Neopasms
Authors: Song Jinming , Hussaini Mohammad , Moscinski Lynn C. , Zhang Ling , Zhang Xiaohui , Shao Haipeng , Zhang Hailing 
Published: November 2019

Background: DNMT3A and SF3B1 are two of the most commonly mutated genes in myeloid neoplasms. DNMT3A mutations have been found to be associated poor prognosis in acute myeloid leukemia (AML), while SF3B1 mutations have been reported to be associated with favorable prognosis in myelodysplastic syndrome (MDS). Studies exploring the clinical significance of DNMT3A and SF3B1 co-mutation are limited and conflicting. Furthermore, the previous studies did not control for the presence of other co-mutated genes, which could be confounding factors.
Materials and Methods: 4390 in-house patients with confirmed or suspected myeloid neoplasms were tested by Next Generation Sequencing (NGS) (up to 54 gene panel). From these, we identified 68 patients with only DNMT3A mutation, 61 patients with only SF3B1 mutation, and 23 patients with only SF3B1/DNMT3A co-mutation, for a total of 152 patients. Patient demographics, diagnosis, cytogenetic abnormalities, and overall survival time were collated and analyzed.
Results: Patients with SF3B1 mutation alone or SF3B1/DNMT3A double mutations were found to be significantly older (median age of 76 and 75, respectively) than patients with isolated DNMT3A mutation (median age of 66, p values = 0.00016 and 0.00174 respectively). Patients with SF3B1/DNMT3A double mutations or isolated SF3B1 mutations occurred more commonly in MDS. They occurred less frequently in acute myeloid leukemia (AML) (1.63% and 21.74% respectively) than isolated DNMT3A mutation (41.76%, p values < 0.00001 and p = 0.00529 respectively). Patients with double mutations demonstrated increased ring sideroblasts (100%) at a rate similar to patients with isolated SF3B1 mutation (92.16%), which are unsurprisingly higher than patents with DNMT3A mutation alone (8%, p value < 0.000001). The patients with SF3B1 mutation alone or SF3B1/DNMT3A co-mutation were less likely to have poor cytogenetics and more likely to have intermediate cytogenetics than patients with DNMT3A mutation alone. Finally, patients with sole SF3B1 mutation or SF3B1/DNMT3A co-mutation showed significantly longer median survival time (26.60 months and 19.93 months respectively) and better overall survival curve (Figure 1) than patients with DNMT3A mutation alone (8.32 months, p value = 0.001 and 0.01078 respectively), for all the patients in this study as well as for patients with only myelodysplastic syndrome.
Conclusion: Patients with SF3B1/DNMT3A double mutations showed a prognosis similar to patients with isolated SF3B1 mutation and better clinical outcomes than patients with isolated DNMT3A mutation. This suggests that the favorable prognosis of SF3B1 mutation in MDS or AML patients is not abrogated by the concurrent presence of a DNMT3A mutation.
Figure 1

Disclosures
No relevant conflicts of interest to declare.
Predictive Significance of Selected Gene Mutations Identified Using Next Generation Sequencing in Relapsed and Refractory Chronic Lymphocytic Leukemia Patients Treated with Ibrutinib
Authors: Machnicki Marcin M , Górniak Patryk , Pepek Monika , Szymczyk Agnieszka , Iskierka-Jażdżewska Elżbieta , Steckiewicz Pawel , Bluszcz Aleksandra , Rydzanicz Malgorzata , Hus Marek , Ploski Rafal , Juszczynski Przemyslaw , Stoklosa Tomasz , Jamroziak Krzysztof , Pula Bartosz 
Published: November 2019

Ibrutinib, a selective inhibitor of the Bruton's kinase (BTK), is characterized by high efficacy in the therapy of treatment-naïve and relapsed and refractory chronic lymphocytic leukemia patients (RR-CLL). Numerous clinical trials and "real-world evidence" confirmed its clinical efficacy also in high-risk patients, including those with TP53 aberrations. Predictive factors to ibrutinib therapy present at time of treatment initiation are not well recognized, therefore we aimed at analyzing the potential significance of mutational status of selected 22 genes in the disease outcome. For this purpose, targeted sequencing of approx. 2 Mb of exonic regions was carried out in 45 RR-CLL patients using custom-made gene panel and sequencing on Illumina MiSeq FGx platform (median 73x mean coverage, range 21.23-149x). Median patient age was 65 years, 28 (62.2%) patients were male and 25 (55.5%) patients had Rai 3-4 stage at ibrutinib initiation. Mean observation time was 34.5 (±19.9 SD) months, while ibrutinib was administered for the mean time of 33.8 (±20.8 SD) months. Median progression-free survival (PFS) and overall survival (OS) was not reached. The 36-month estimated rate of PFS and OS was 79.1% and 68.2%, respectively. The overall response rate (ORR) was noted in 23 patients (51.1%). Complete remission was noted in one (2.2%) patient, while partial remission and partial remission with lymphocytosis was noted in 16 (35.6%) and 6 (13.3%) patients, respectively. Twenty (44.4%) patients had stable disease, whereas progression following ibrutinib initiation was noted in 2 (4.5%) cases. The highest rate of pathogenic gene mutations was observed in TP53 (n=18; 40.0%), NOTCH1 (n=13; 28.8%), SF3B1 (n=11; 24.4%), ATM (n=7; 15.6%), MED12 (n=6, 13.3%), CHD2 (n=5; 11.1%), XPO1 (n=5; 11.1%), NFKBIE (n=5; 11.1%), BIRC3 (n=4; 8.9%), SPEN (n=4; 8.9%), POT1 (n=4; 8.9%), EGR2 (n=3; 6.7%), RPS15 (n=3; 6.7%). Single cases of mutation in ZMYM3, PIM2, PIM3, BRAF, RB1, TNFAIP3 were detected. No mutations in MYD88, BTK or BCL2 were detected. Univariate survival analysis revealed that none of the analyzed mutations had predictive significance in the analyzed group. Interestingly, ibrutinib treatment was characterized by stable PFS and OS despite the low ORR levels with a significant number of patients achieving disease stability.

Disclosures
Juszczynski: Selvita S.A.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jamroziak:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.
Bile Acids Induce Platelet Activation Leading to Degranulation and a Prothrombotic Phenotype
Authors: Zobel Joachim , Strini Tanja , Tischitz Martin , Pohl Sina , Greimel Theresa , Jahnel Jörg , Schlagenhauf Axel 
Published: November 2019

Background: Previous articles have identified the farnesoid X receptor (FXR) as an integral part in the formation of coated platelets. Coated platelets are preactivated platelets featuring degranulation, increased fibrinogen binding, and increased serine protease activity leading to fibrin generation. Furthermore, phosphatidylserine exposure is increased and integrin α2bβIII is inhibited - leading to a prothrombotic phenotype despite decreased platelet aggregation. We hypothesize that bile acids, as natural ligands of FXR, lead to a change of platelet phenotype and therefore play a pivotal role in the formation of coated platelets, especially in presence of cholestasis.
Methods: Based on previous findings, we incubated human washed platelets of healthy adult volunteers with the synthetic FXR ligand GW4064 in various concentrations (0, 10, 20, 50, 100µM) and used flow cytometry to detect a shift in p-selectin expression, PAC-1 binding and annexin-V-binding. Moreover, we used different concentrations (0, 100, 200, 400, 600µM) of three bile acids (ursodeoxycholic acid, UDCA; chenodeoxycholic acid, CDCA; glycochenodeoxycholic acid, GCDCA) to see if natural FXR ligands induce an effect on the platelet phenotype.
Results: We observed a dose dependent shift in annexin-V-binding when treating washed platelets with GW4064 as well as CDCA and GCDCA. Similarly, GW4064 led to increased p-selectin expression while increased PAC-1-binding was only detected at the highest concentration. In contrast, CDCA and GCDCA showed merely slight changes in p-selectin expression whereas PAC-1-binding seemed to be unaffected. However, none of these effects were seen when using UDCA.
Conclusion: We conclude that pretreatment of washed platelets with CDCA and GCDCA initiate a dose-dependent shift towards a prothrombotic platelet phenotype. Therefore, we assume that increased levels of certain bile acids drive thrombosis in patients with cholestatic liver injury. Furthermore, a recent mouse model study suggested that platelet derived growth factor β (PDGFβ), a component of α-granula, drives liver fibrosis. Hence, in addition to their prothrombotic effects, coated platelets might exacerbate liver fibrosis.

Disclosures
No relevant conflicts of interest to declare.