bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-Effectiveness Analyses of FDA-Approved Drugs for Cancer Indications, 2015-2017
Authors: Oren Ohad 
Published: October 2019

Abstract
Background:
In addition to a drug's anti-tumor efficacy and tissue toxicity, it is now apparent that affordability is a pivotal factor determining the net therapeutic value of an anti-cancer compound. Cost-Effectiveness Analyses (CEA) are therefore key to appreciating the overall balance between the clinical and economical repercussions of a pharmaceutical agent. We aimed to investigate the cost-effectiveness data of newly approved drugs in cancer care.
Methods:
The FDA website was reviewed for all drugs approved for any cancer indication between the years 2015-2017. A systematic search of Pubmed and Google Scholar was conducted for Cost-Effectiveness Analyses (CEA) of each of these medications. Average Wholesale Prices were collected from Uptodate.com.
Results:
30 drugs were approved for cancer indications in 2015-2017. Each of the approved drugs had an average of 1.27 CEA studies (range 0-6). 4 of the 38 (10.5%) available CEAs were done before approval of an index drug. 18 (60%) of the approved medications had an available published CEA at the time of our search (March, 2018). Partition survival modelling (31.5%) and Markov modelling (26.3%) were the most common methods of analysis. 47.3% (18/38) of the CEAs were thought to reflect a favorable ICER per the analysis's investigators. The nature of the malignancy (solid versus hematologic) did not distinguish between the mean number of a drug's CEAs (1.25; 1.2) but drugs for solid cancer indications were less likely to be associated with a favorable CE assessment compared with hematological cancers (47.8% versus 58.3%). "Expensive" drugs (defined as monthly cost greater than 8,618 dollars) had a lower mean number of CEA studies than "less expensive" drugs (1.09 versus 1.36) and were less likely to be associated with a favorable cost-effectiveness profile (27.2% versus 73.6%). 47.3% (18/38) of the economic evaluations were published as conference proceeding/abstract, 36.8% (14/38) were in the form of a full-text article, and the remainder as journal letters or conference posters (6/38; 15.7%).
Conclusion:
Insufficient data on the cost-effectiveness profile of novel anti-cancer medications jeopardises our ability to determine their real value. Although these drugs are being routinely used in a large-scale fashion, gaps persist as to their financial harm relative to the associated (potential) clinical benefit. Our study shows that recently-approved anti-cancer drugs have a very small number of CEAs to back their clinical-societal merit. Paradoxically, more costly drugs have fewer CEAs compared with cheaper drugs. Also of note, the majority of the analyses followed the approval of the drug, were published in a non full-text format, and were associated with non-sustainable ICER values. We argue that publication of rigorous, peer-reviewed CEAs should be a mandatory pre-approval step for academia/industry and serve as a pre-requisite to the routine distribution and usage of new cancer-directed medications.

Disclosures
No relevant conflicts of interest to declare.
The Appropriateness of Testing PF4/Heparin Antibody in Patients Suspected of Heparin-Induced Thrombocytopenia
Authors: Jindal Vishal , Singh Aditi , Siddiqui Ahmad Daniyal , Leb Laszlo 
Published: October 2019

Abstract
Heparin Induced thrombocytopenia (HIT) is an adverse reaction to the administration of heparin due to activation of platelet by the IgG antibody-PF4/heparin immune complex. Since the clinical outcome is uncertain as it could be associated with significant morbidity and sometimes death, an early diagnosis and appropriate treatment is necessary. The 4Ts pretest clinical scoring system and testing for all anti PF4/heparin antibody can markedly improve the diagnosis and prompt adequate treatment. Our study was undertaken to evaluate the appropriateness of ordering the PF4-ELISA test reviewing retrospectively the use of 4Ts scoring system in a tertiary institution. We examined a database of 118 patients who had the PF4-ELISA and we calculated retrospectively their 4Ts scores. A total of 107 patients were evaluated; 95 patients (88.79%) had negative PF4-ELISA assay and 12 patients tested positive (11.21%). Only one patient tested weakly positive in the low probability group (negative predictive value 98%). In the intermediate group, six patients were strongly positive (OD >1.0). In this latter group further confirmatory testing (SRA) could have been done. We also evaluated the setting where the tests were performed and found that the majority patients (63.55%) were tested in the ICU where thrombocytopenia is multifactorial. We conclude that the large majority of patients were not appropriately evaluated prior to testing which incurred unnecessary expense and patient distress. For the proper identification of patients suspected of HIT who should undergo PF4/heparin antibody testing, further education of the ordering physicians is recommended.

Disclosures
No relevant conflicts of interest to declare.
Mitochondria Clearance Mechanisms Via Interaction with Macrophages in Erythropoiesis
Authors: Yang Chong , Suda Toshio , Lin Xiaoxuan , Endo Mitsuhiro 
Published: October 2019

Abstract
Adult erythropoiesis involves a series of well-coordinated events resulting in the production of mature red blood cells. One of such events is the mitochondria clearance, which is known to occur cell-autonomously via autophagy-dependent mechanisms. Interestingly, we identified a sequential changes in the transcriptional pattern during terminal erythroid differentiation based on the expression of several macroautophagy (e.g. Atg3, Atg5, Atg7 and Atg10) and non-canonical mitophagy (e.g. Pink1, Park2, Bnip3l/Nix, P62 and Ulk1) genes. Hence we hypothesize that the progressive reduction in mitochondria during terminal erythroid differentiation is directed by distinct transcriptionally-regulated programs. Notably, we revealed a gradual reduction of the expression of lysosome related genes (e.g. Lamp1, CD63, and Atp6v) and lysosomal activities from early to late stages of terminal differentiation. On the other hand, P62-Pink1-Parkin mediated ubiquitin proteasome degradation of mitochondria proteins seems to be more prominent during late stage erythropoiesis. Hence our data suggest that mitochondria clearance is predominantly mediated by canonical autophagy during early stages of terminal differentiation, whereas non-canonical mitophagy pathway seem to play a more predominant role to regulate late stages erythroid maturation.
Next, we discovered mitochondria transfer activities from erythroblasts to their niche. In the context of erythropoiesis, macrophages are known to interact closely with erythroblasts to provide a specialized niche for erythroid precursors to proliferate, differentiate and enucleate. We showed defective erythropoiesis after macrophage depletion in the bone marrow. Subsequently, we identified a tendency for early erythroblasts to associate with macrophages and isolated those erythroblasts from mito-dendra2 mice with trackable mitochondria to establish a murine primary cell co-culture system. Then we report mitochondria transfer activities in the erythroid niche via different modes including direct uptake, micro-vesicle transfer and tunnelling nanotubes (TNT). Interestingly, interchangeable structures between micro-vesicles and TNTs have been observed, suggesting an interplay between cytoskeleton and membrane lipid molecules in the mitochondria transfer mechanisms. Furthermore, mitochondria transfer activities have also been observed in the co-culture of mito-dendra2 erythroid cells with a macrophage cell line, RAW cells, and are significantly enhanced by the activation of the RAW cells via Tfe3 activation.
In summary, our findings may provide insight into the mitochondria clearance machineries that mediates erythroid maturation to fulfil the clinical demand for large scale transfusable blood cell production in vitro.

Disclosures
No relevant conflicts of interest to declare.
The Incidence of Post-Thrombotic Syndrome after the Treatment of Upper Extremity Deep Vein Thrombosis with Oral Rivaroxaban
Authors: Lobastov Kirill , Barinov Victor , Schastlivtsev Iliya , Laberko Leonid , Rodoman Grigory , Zhuravlev Sergey , Boyarintsev Valeriy 
Published: October 2019

Abstract
Aim: To assess oral rivaroxaban's efficacy and safety in the treatment of upper extremity deep vein thrombosis (UEDVT).
Methods: This was a prospective observational study involving patients with their first UEDVT episodes confirmed by duplex ultrasound (DUS) without symptoms of pulmonary embolism (PE). All patients initially received low-molecular-weight heparin for 1 to 2 days and were then switched to oral rivaroxaban (15 mg bid) for three weeks and then to 20 mg qid for up to three months. Patients who had already undergone interventional UEDVT treatment were excluded. Patients were followed up with clinical examination and DUS for six months. The endpoints of the study were symptomatic PE, recurrent UEDVT, major, clinically relevant non-major and minor bleeding, recanalization of the affected veins, recognized as a blood flow with DUS, post-thrombotic syndrome (PTS) incidence of the affected limb assessed by modified Villata score by Czihal.
Results: A total of 30 patients (13 men and 17 women) aged 28-78 years (mean age 52.4 ± 17.3) were included in the study. Some (16.7%) of them had undergone physical exertion which triggered the UEDVT. In 13.3%, there was a pacemaker previously implanted through the affected limb. Also, patients had from 0 to 5 individual risk factors for venous thromboembolism (mean 1.9±1.6). The subclavian vein, predominantly on the right side (60%), was involved in the thrombotic process in all cases. The mean duration of symptoms before diagnosis was 1.8±1.7 days.
All 30 patients were followed for six months. There were no episodes of symptomatic PE and/or recurrent UEDVT during the period of anticoagulation (0-3 months) and after stop of treatment (3-6 months). No episodes of major bleeding were observed. Clinically relevant non-major bleeding occurred in 2 patients (6.7%: 95% confidence interval [CI]: 1.9-21.4%) caused by uterine bleeding and large skin hemorrhage. Minor bleeding was observed in two patients (6.7%: 95% CI: 1.9-21.4%) caused by nasal and gingival bleeding. Thus, cumulative bleeding incidence was 13.4% (95% CI: 5.4-29.8%). Recanalization of upper extremity deep veins was observed in all affected limbs at three months and persist up to six months. The signs of upper limbs PTS (≥5 modified Villalta score) were found in four patients (13.4 %; 95% CI: 5.4-29.8%), and the mean score was 2.1±1.9.
Conclusion: Treatment of UEDVT with oral rivaroxaban seems to be effective, safe, and associated with the low incidence of upper limb PTS.

Disclosures
Lobastov: Bayer: Honoraria, Speakers Bureau; Servier: Honoraria, Speakers Bureau. Barinov:Bayer: Honoraria, Speakers Bureau; Servier: Honoraria, Speakers Bureau. Schastlivtsev:Bayer: Honoraria, Speakers Bureau; Servier: Honoraria, Speakers Bureau.
Long-Term Results of Non- Fludarabine Versus Fludarabine-Based Conditioning Regimens in Severe Aplastic Anemia Patients
Authors: Aladag Elifcan , Demiroglu Haluk , Ciftciler Rafiye , Buyukasik Yahya , Sayinalp Nilgun , Aksu Salih , Haznedaroglu Ibrahim Celalettin , Ozcebe Osman , Chao Nelson J. , Goker Hakan 
Published: October 2019

Abstract
BACKGROUND AND OBJECTIVE: Allogenic hematopoietic cell transplantation (AHSCT) is the best therapeutic modality capable of correcting the hematologic manifestations of severe aplastic anemia (SAA), here in this study we have compared the results of well-tolerated fludarabine-based conditioning regimens for SAA patients who are heavily transfused undergoing AHSCT.
DESIGN AND SETTINGS: This is a retrospective study consist of 25 patients diagnosed with SAA who underwent AHSCT between February 2002 and March 2015 at the Bone Marrow Transplantation Unit of Hacettepe University. All patients gave written informed consent for the procedure.
PATIENTS AND METHODS: We analyzed the outcome of 25 SAA patients who had undergone AHSCT between 2002 and 2015. the median age at transplantation was 27(16-55) years. Patients received transplants from an HLA-identical sibling (n=24) and mismatched allogeneic related HSCT (n=1). Hematopoietic Stem Cells (HSC) were collected from the donors via apheresis. Eight patients underwent standard CY 50 mg/kg plus ATG-FreseniusR 5-10 mg/kg as conditioning fort he transplantation procedure and 13 patients conditioned with CY(50 mg/kg for 2 days) plus fludarabine 25 mg/m2 for 5 days and ATG-FreseniusR 5-10 mg/kg as AHSCT conditioning and received GvHD (Graft-vs-Host Disease) prophylaxis was standard CsA 3 mg/kg IV inf. plus Methotrexate(MTX) 10mg/m2 on day 1,and MTX 5 mg/m2 on days 3.,6. and 11.
RESULTS: The median follow-up period for all the survivors was 117 months [minimum 3 and maximum 159 months]. The 5-year overall survival (os) for patients who did or did not receive fludarabine-based preparative regimens for the allograft was 93%, and 87%, respectively. However, there were no statistically significant differences in os rates between these two groups (P=0,58). Median neutrophil engraftment time was 11 days and median platelet engraftment time was 13 days. Primary graft failure occurred in 1 patients (4%) who received fludarabine-based conditioning regimens.
CONCLUSION: Fludarabine-Based (Flu-CY-ATG) conditioning is a safe and viable option when compared to the standard CY-ATG conditioning in heavily-transfused SAA patients who undergo Allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Disclosures
No relevant conflicts of interest to declare.
Identification of a Whole Blood Signature for Venous Thromboembolism
Authors: Hogan Marie , Zhou Hua , Lhakhang Tenzin , Barrett Tessa Jo , O'Reilly Deirdre , Smilowitz Nathaniel , Heguy Adriana , Maldonado Thomas , Tsirigos Aristotelis , Berger Jeffrey 
Published: October 2019

Abstract
Venous thromboembolism (VTE), comprised of deep vein thrombosis and pulmonary embolism, is a common health problem both in the United States and worldwide, with significant associated morbidity and mortality. Despite multiple known genetic and situational risk factors, an estimated 30% of all events remain classified as idiopathic, demonstrating a significant knowledge gap in the pathophysiology VTE. While platelets are well established as an essential contributor to thrombus formation and there has been recent interest in the role of neutrophil extracellular traps, specific cell types and pathways involved in the pathogenesis of VTE remain uncertain. In this study, our primary aims were to define a unique transcriptional signature for VTE and to identify the types of cells and specific pathways involved in development of VTE.
Whole blood was collected in PAX gene tubes and RNA sequencing for coding mRNA was performed in an unbiased manner in 201 patients with prevalent VTE as well as 43 healthy controls. We used a bioinformatics approach to develop a unique signature for VTE by identifying differentially expressed genes, developing cell-type modules, and ascertaining pathways driving differentially expressed transcripts. We performed additional analyses on subgroups of patients with idiopathic VTE, patients with incident VTE, and VTE patients matched to healthy controls by age and sex. We went on to use machine learning methods to learn models that best differentiate VTE patients from healthy controls and validated it on a left out test set within our VTE population.
Genes specific to neutrophils, erythrocytes, and platelets, in that order, were most significantly upregulated in patients with VTE compared to healthy controls. Genes related to T-cells were downregulated. Pathway analysis revealed upregulated neutrophil activation and degranulation, erythrocyte differentiation and homeostasis, and platelet degranulation. A gene signature of 217 transcripts was outstanding at differentiating patients with VTE versus healthy controls (AUC 0.94). Following adjustment for age, sex, and race/ethnicity our genetic signature remained significantly robust at differentiating patients with VTE versus controls (AUC 0.83). Our expression signature remained stable across patients with idiopathic VTE (AUC 0.93), and in patients who went on to develop future VTE events (AUC 0.95).
In summary, we have demonstrated a whole blood transcriptional signature for prevalent and incident VTE. Genes related to neutrophils, erythrocytes, and platelets are upregulated in patients with VTE and genes related to T-cells were downregulated. These findings suggest an active role of cell types once thought to be passively entrapped within thrombus and provide new areas of study to establish the pathophysiology of VTE.

Disclosures
No relevant conflicts of interest to declare.
Piezo1-Sensitive Biomechanical Pulsation Stimulates Long-Term Hematopoietic Stem Cell Formation
Authors: Scapin Giorgia , Cillis Jennifer , Patch Taylor , Dharampuriya Priyanka R , Hagedorn Elliott J. , Lundin Vanessa , Tamplin Owen J , Andeson Heidi , Zon Leonard I. , Daley George Q. , Shah Dhvanit I 
Published: October 2019

Abstract
The birth and development of hemat\opoietic stem cells (HSCs) remain a mystery. During fetal development, a subset of endothelial cells transitions to become HSCs in the aorta-gonad-mesonephros (AGM) region. Blood flow-mediated shear stress and activation of nitric oxide synthase (NOS) were demonstrated to stimulate the endothelial-to-HSC transition in the AGM. However, we showed that malbec (mlbbw306), a zebrafish mutant for cadherin 5, produces HSCs despite circulation arrest and the inhibition of NOS, suggesting that other biomechanical forces, mechanosensation pathways, or epigenetic mechanisms might regulate HSC formation and could have utility in developing HSCs. Using zebrafish, murine, and human models, we show that Piezo1-sensitive biomechanical stretching of hemogenic endothelial cells enhances Dnmt3b expression for long-term (LT)-HSC formation.
Our microangiography and time-lapse confocal imaging established that cdh5-MO embryos have a heartbeat and pulsation in blood vessels despite the absence of blood flow. We also employed light sheet and time-lapse confocal microscopy followed by Fourier transform analyses to establish that although pulsation is independent of blood flow in the AGM, it is concurrent with the endothelial-to-hematopoietic transition. To establish the functional link between pulsation and HSC formation, we developed a bioreactor simulating the pulsating blood vessel conditions. We found that the biomechanical stretching of hemogenic endothelial cells or the pharmacological activation of Piezo1 yields three times higher amounts of LT-HSC formation; which reconstitute to normal multi-lineage adult blood even upon serial transplantation. Our gene-silencing, time-lapse imaging, explant culture, and computational analyses further demonstrated that biomechanical stretching activates Piezo1; which enhances epigenetic regulator Dnmt3b expression to stimulate the endothelial-to-HSC transition.
Our results demonstrate how pulsation-mediated biomechanical forces stimulate cell-fate transitions and stem cell formation by activating mechanosensitive channels as well as epigenetic machinery. We present a model that addresses major challenges in HSC transplantation and cellular therapies for treating blood and bone marrow diseases. In addition, we report a scalable bioreactor with potential widespread use and a pharmacological target to develop and expand LT-HSCs.

Disclosures
No relevant conflicts of interest to declare.
ARRB1-Induced NOTCH1 Degradation Is Inhibited By Mir-223 in T-ALL
Authors: Zou Lin , Shu Yi , Wang Yi , Lv Wenqiong , Peng Danyi , Zhang Hang , Jiang Guangjie , Liu Shan , Chen Yanhua , Tang Shi , Fu Guo , Qi Xinkun , Liu Zhidai , Liu Haiyan , Yang Chao , Liu Fangjie , Yu Jie , Zhang Penghui , Qu Bin , Zhao Hui , He Tongchuan 
Published: October 2019

Abstract
Leukemia is the most common malignant tumor in children under 15 years old, which is divided into several subtypes, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL) and chronic myeloid leukemia (CML), based on the disease phases and effected cells. Each subtype has its specific molecular feature and key regulation factors. In our previous studies, we reported that β-arrestin1 (ARRB1), the pivotal scaffold protein to transduce various cellular signals, could bind with EZH2 to increase Bcr/Abl H4 acetylation level and thus promote CML progression (Brit J Cancer 2014, 111(3): 568-76). ARRB1 could enhance DNMT1 activity and PTEN methylation, decrease PTEN expression and promote self-renew of B-ALL leukemia initiating cells (LICs) (Cancer Lett 2015, 357(1): 170-8.). ARRB1 could increase P300 to bind with SP1 to hTERT promoter, and thus increase hTERT transcription/expression, telomerase activity, telomere length and cell senescence in B-ALL LICs (Cell Death Diff 2017, 8(4): e2756.). However, little is known in the T-ALL, which about 70% have the mutations of NOTCH1 gene. Here, we unveil ARRB1 could curb the progression of T-ALL cells in vitro and in vivo, while the expression of ARRB1 was suppressed by the aberrant increased miR-223. Mechanistically, ARRB1 could recruit DTX1, the E3 ubiquitin ligase, to promote the ubiquitination and degradation of NOTCH1 protein in T-ALL. Furthermore, Overexpression of ARRB1-derived miR-223 sponge BUTR was incompatible with cell proliferation and induces apoptosis in T-ALL cells. Collectively, our results for the first time revealed that ARRB1 acted as a tumor suppressor by promoting NOTCH1 degradation in T-ALL cells where miR-223 effectively antagonized ARRB1 functions. This provides that miR-223 may serve as a valid drug target for developing novel and efficacious T-ALL therapeutics.

Disclosures
No relevant conflicts of interest to declare.