bluuebunny/crossref_metadata_2025_split huggingface dataset:
Application of thromboelastography in comparing coagulation difference of rivaroxaban and enoxaparin for thromboprophylaxis after total hip arthroplasty
Authors: Bai Chao-wen , Ruan Ru-xin , Pan Sheng , Huang Chao-ran , Zhang Xing-chen , Pang Yong , Zheng Xin , Guo Kai-jin 
Published: September 2021

Purpose: The purpose of this study was to compare the coagulation difference in patients with either rivaroxaban or enoxaparin as thromboprophylaxis after total hip arthroplasty (THA) regarding thromboelastography (TEG) and routine coagulation tests. Patients and methods: Two hundred and twenty-eight patients undergoing primary THA were recruited in this study. They were divided into two groups according to a computer-generated random sequence. Patients in the rivaroxaban group received 10 mg of rivaroxaban orally once daily. Patients in the enoxaparin group received 4000 AxaIU (0.4 mL) of enoxaparin subcutaneously once daily. Rivaroxaban and enoxaparin were started 6–8 h after surgery. The administration of the anticoagulant prophylaxis was lasted for a minimum of 14 days. TEG and routine coagulation tests were performed on the day before the operation and 1 day and 7 days after the operation. Results: No difference was observed in the incidence of deep vein thrombosis (DVT) or pulmonary embolism (PE) between the two groups. There was no significant difference with regard to prothrombin time (PT), activated partial thromboplastin time (PTT), international normalized ratio (INR), and thrombin time (TT) between the two groups. However, while considering TEG, R time of the rivaroxaban group was significantly higher than that of the enoxaparin group ( p = 0.003), whereas the maximum amplitude (MA) ( p = 0.036) value and coagulation index (CI) ( p = 0.002) value were significantly lower than those of the enoxaparin group. Conclusion: With regard to TEG analysis, there was coagulation difference in patients with rivaroxaban and those with enoxaparin as thromboprophylaxis after THA. Under recommended dose of rivaroxaban and enoxaparin, patients undergoing THA were in hypercoagulability on 7days postoperative.
Biomechanical Comparison of UCL Repair Using Suspensory Fixation Versus UCL Reconstruction
Authors: Mead R. Nelson , Nelson Trevor J. , Limpisvasti Orr , ElAttrache Neal S. , Metzger Melodie F. 
Published: September 2021

Background: Medial ulnar collateral ligament (mUCL) repair is growing in popularity as a treatment for younger athletes with mUCL tears. One of the most recent techniques utilizes a collagen-coated suture tape to augment the repair. The most popular repair technique uses a screw for proximal fixation in the humerus. We present an alternative technique that uses suspensory fixation in the proximal humerus. Purpose: To biomechanically compare elbow valgus stability and load to failure of a novel alternative repair technique with suspensory fixation to an mUCL reconstruction. Study Design: Controlled laboratory study. Methods: Eighteen fresh-frozen cadaveric elbows were dissected to expose the mUCL. Medial elbow stability was tested with the mUCL in an intact, deficient—either repaired or reconstructed—state. The repair technique used a suspensory fixation with suture augmentation, and the docking technique was used on all reconstructions. A 3-N·m valgus torque was applied to the elbow, and valgus rotation of the ulna was recorded via motion tracking cameras as the elbow was cycled through a full range of motion. After kinematic testing, specimens were loaded to failure at 70° of elbow flexion. Results: Both ulnar collateral ligament reconstruction and repair restored valgus stability to levels that were not statistically different from intact at all angles of flexion. There was no significant difference in the ultimate torque to failure between repaired and reconstructed mUCLs. Conclusion: There was no significant difference in the valgus strength between the mUCL repair with suspensory fixation and the mUCL reconstruction. Clinical Relevance: Suspensory fixation is an alternative method for proximal fixation in the mUCL without compromising the strength of the construct.
GDP/GTP exchange factor MADD drives activation and recruitment of secretory Rab GTPases to Weibel-Palade bodies
Authors: Kat Marije , Bürgisser Petra E. , Janssen Hans , De Cuyper Iris M. , Conte Ianina L. , Hume Alistair N. , Carter Tom , Voorberg Jan , Margadant Coert , Bierings Ruben 
Published: September 2021

Abstractvon Willebrand factor (VWF) is an essential hemostatic protein that is synthesized and secreted by endothelial cells and stored in Weibel-Palade bodies (WPBs). The secretory Rab GTPases Rab27A, Rab3B, and Rab3D have been linked with WPB trafficking and secretion. How these Rabs are activated and recruited to WPBs remains elusive. In this study, we identified MAP kinase-activating death domain (MADD) as the guanine nucleotide exchange factor for Rab27A and both Rab3 isoforms in primary human endothelial cells. Rab activity assays revealed a reduction in Rab27A, Rab3B, and Rab3D activation upon MADD silencing. Rab activation, but not binding, was dependent on the differentially expressed in normal and neoplastic cells (DENN) domain of MADD, indicating the potential existence of 2 Rab interaction modules. Furthermore, immunofluorescent analysis showed that Rab27A, Rab3B, and Rab3D recruitment to WPBs was dramatically decreased upon MADD knockdown, revealing that MADD drives Rab membrane targeting. Artificial mistargeting of MADD using a TOMM70 tag abolished Rab27A localization to WPB membranes in a DENN domain–dependent manner, indicating that normal MADD localization in the cytosol is crucial. Activation of Rab3B and Rab3D was reduced upon Rab27A silencing, suggesting that activation of these Rabs is enhanced through previous activation of Rab27A by MADD. MADD silencing did not affect WPB morphology, but it did reduce VWF intracellular content. Furthermore, MADD-depleted cells exhibited decreased histamine-evoked VWF release, similar to Rab27A-depleted cells. In conclusion, MADD acts as a master regulator of VWF secretion by coordinating the activation and membrane targeting of secretory Rabs to WPBs.
Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML
Authors: Menghrajani Kamal , Gomez-Arteaga Alexandra , Madero-Marroquin Rafael , Zhang Mei-Jie , Bo-Subait Khalid , Sanchez Jonathan , Wang Hai-Lin , Aljurf Mahmoud , Assal Amer , Bacher Vera Ulrike , Badawy Sherif M. , Bejanyan Nelli , Bhatt Vijaya Raj , Bredeson Christopher , Byrne Michael , Castillo Paul , Cerny Jan , Chhabra Saurabh , Ciurea Stefan Octavian , DeFilipp Zachariah , Farhadfar Nosha , Gadalla Shahinaz , Gale Robert Peter , Ganguly Siddhartha , Gowda Lohith , Grunwald Michael R. , Hashmi Shahrukh , Hildebrandt Gerhard , Kanakry Christopher G. , Kansagra Ankit , Khimani Farhad , Krem Maxwell , Lazarus Hillard , Liu Hongtao , Martino Rodrigo , Michelis Fotios V. , Nathan Sunita , Nishihori Taiga , Olsson Richard , Reshef Ran , Rizzieri David , Rowe Jacob M. , Savani Bipin N. , Seo Sachiko , Sharma Akshay , Solh Melhem , Ustun Celalettin , Verdonck Leo F. , Hourigan Christopher , Sandmaier Brenda , Litzow Mark , Kebriaei Partow , Weisdorf Daniel , Zhang Yanming , Tallman Martin S. , Saber Wael 
Published: September 2021

Abstract
Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P &lt; .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P &lt; .001), as was overall survival (HR, 1.32; P &lt; .001, and HR, 1.45; P &lt; .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.
Successful treatment and integrated genomic analysis of an infant with FIP1L1-RARA fusion–associated myeloid neoplasm
Authors: Miltiadous Oriana , Petrova-Drus Kseniya , Kaicker Shipra , Mathew Susan , Kluk Michael , Geyer Julia T. , Rodriguez-Sanchez Irene , Bouvier Nancy , Inghirami Giorgio , Stieglitz Elliot , Khedoudja Nafa , Benayed Ryma , Richardson Michelle , Anderson Wade , Benhamida Jamal , You Daoqi , Londono Dory , Kung Andrew L. , Prockop Susan E. , Roshal Mikhail , Zhang Yanming , Shukla Neerav 
Published: September 2021

Abstract
FIP1L1-RARA–a ssociated neoplasm is a very rare and aggressive disease, with only 3 previously reported cases in the literature. Here, we describe a 9-month-old boy who presented with a FIP1L1-RARA fusion–associated myelodysplastic/myeloproliferative neoplasm-like overlap syndrome, with similarities and distinct features to both acute promyelocytic leukemia and juvenile myelomonocytic leukemia. Using a combined approach of chemotherapy, differentiating agents, and allogeneic hematopoietic stem cell transplant (allo-HCT), this patient remains in remission 20 months after allo-HCT. To our knowledge, this is only the second published pediatric case involving this condition and the only case with a favorable long-term outcome. Given the aggressive disease described in the previously published case report, as well as the successful treatment course described, the combinatorial use of chemotherapy, differentiation therapy, and allo-HCT for treatment of FIP1L1-RARA fusion–associated myeloid neoplasms should be considered.
Daratumumab for immune thrombotic thrombocytopenic purpura
Authors: van den Berg Jana , Kremer Hovinga Johanna A. , Pfleger Claudia , Hegemann Inga , Stehle Gregor , Holbro Andreas , Studt Jan-Dirk 
Published: September 2021

Abstract
Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy. It is caused by a severe ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs, 13) deficiency due to circulating autoantibodies, and is associated with significant morbidity and mortality. Current treatment options include plasma exchange, immunosuppression, and caplacizumab. When remission is achieved, the risk of relapse is high, especially in patients with persistent ADAMTS13 deficiency. We report the eradication of persistent ADAMTS13 inhibitory autoantibodies and restoration of normal ADAMTS13 activity using the anti-CD38 antibody daratumumab in two patients with iTTP. One patient had a frequently relapsing course, and the other a treatment-refractory first episode. There were no relevant adverse drug reactions.
Tissue-resident macrophages promote early dissemination of multiple myeloma via IL-6 and TNFα
Authors: Akhmetzyanova Ilseyar , Aaron Tonya , Galbo Phillip , Tikhonova Anastasia , Dolgalev Igor , Tanaka Masato , Aifantis Iannis , Zheng Deyou , Zang Xingxing , Fooksman David 
Published: September 2021

Abstract
Multiple myeloma (MM) is a plasma cell malignancy characterized by the presence of multiple foci in the skeleton. These distinct tumor foci represent cycles of tumor growth and dissemination that seed new clusters and drive disease progression. By using an intratibial Vk*MYC murine myeloma model, we found that CD169+ radiation-resistant tissue-resident macrophages (MPs) were critical for early dissemination of myeloma and disease progression. Depletion of these MPs had no effect on tumor proliferation, but it did reduce egress of myeloma from bone marrow (BM) and its spread to other bones. Depletion of MPs as a single therapy and in combination with BM transplantation improved overall survival. Dissemination of myeloma was correlated with an increased inflammatory signature in BM MPs. It was also correlated with the production of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) by tumor-associated MPs. Exogenous intravenous IL-6 and TNFα can trigger myeloma intravasation in the BM by increasing vascular permeability in the BM and by enhancing the motility of myeloma cells by reducing the adhesion of CD138. Moreover, mice that lacked IL-6 had defects in disseminating myeloma similar to those in MP-depleted recipients. Mice that were deficient in TNFα or TNFα receptor (TNFR) had defects in disseminating MM, and engraftment was also impaired. These effects on dissemination of myeloma required production of cytokines in the radiation-resistant compartment that contained these radiation-resistant BM MPs. Taken together, we propose that egress of myeloma cells from BM is regulated by localized inflammation in foci, driven in part by CD169+ MPs.
Pre-selection against a lethal recessive allele in breeding schemes with optimum-contribution selection or truncation selection
Authors: Hjortø Line , Henryon Mark , Liu Huiming , Berg Peer , Thomasen Jørn Rind , Sørensen Anders Christian 
Published: September 2021

Abstract
Background
We tested the hypothesis that breeding schemes with a pre-selection step, in which carriers of a lethal recessive allele (LRA) were culled, and with optimum-contribution selection (OCS) reduce the frequency of a LRA, control rate of inbreeding, and realise as much genetic gain as breeding schemes without a pre-selection step.

Methods
We used stochastic simulation to estimate true genetic gain realised at a 0.01 rate of true inbreeding (ΔFtrue) by breeding schemes that combined one of four pre-selection strategies with one of three selection strategies. The four pre-selection strategies were: (1) no carriers culled, (2) male carriers culled, (3) female carriers culled, and (4) all carriers culled. Carrier-status was known prior to selection. The three selection strategies were: (1) OCS in which $$\Delta {\text{F}}_{{{\text{true}}}}$$

Δ

F
true

was predicted and controlled using pedigree relationships (POCS), (2) OCS in which $$\Delta {\text{F}}_{{{\text{true}}}}$$

Δ

F
true

was predicted and controlled using genomic relationships (GOCS), and (3) truncation selection of parents. All combinations of pre-selection strategies and selection strategies were tested for three starting frequencies of the LRA (0.05, 0.10, and 0.15) and two linkage statuses with the locus that has the LRA being on a chromosome with or without loci affecting the breeding goal trait. The breeding schemes were simulated for 10 discrete generations (t = 1, …, 10). In all breeding schemes, ΔFtrue was calibrated to be 0.01 per generation in generations t = 4, …, 10. Each breeding scheme was replicated 100 times.

Results
We found no significant difference in true genetic gain from generations t = 4, …, 10 between breeding schemes with or without pre-selection within selection strategy. POCS and GOCS schemes realised similar true genetic gains from generations t = 4, …, 10. POCS and GOCS schemes realised 12% more true genetic gain from generations t = 4, …, 10 than truncation selection schemes.

Conclusions
We advocate for OCS schemes with pre-selection against the LRA that cause animal suffering and high costs. At LRA frequencies of 0.10 or lower, OCS schemes in which male carriers are culled reduce the frequency of LRA, control rate of inbreeding, and realise no significant reduction in true genetic gain compared to OCS schemes without pre-selection against LRA.
MDMX is essential for the regulation of p53 protein levels in the absence of a functional MDM2 C-terminal tail
Authors: Sanford Jack D. , Yang Jing , Han Jing , Tollini Laura A. , Jin Aiwen , Zhang Yanping 
Published: September 2021

Abstract
Background
MDM2 is an E3 ubiquitin ligase that is able to ubiquitinate p53, targeting it for proteasomal degradation. Its homologue MDMX does not have innate E3 activity, but is able to dimerize with MDM2. Although mouse models have demonstrated both MDM2 and MDMX are individually essential for p53 regulation, the significance of MDM2-MDMX heterodimerization is only partially understood and sometimes controversial. MDM2C462A mice, where the C462A mutation abolishes MDM2 E3 ligase activity as well as its ability to dimerize with MDMX, die during embryogenesis. In contrast, the MDM2Y487A mice, where the Y487A mutation at MDM2 C-terminus significantly reduces its E3 ligase activity without disrupting MDM2-MDMX binding, survive normally even though p53 is expressed to high levels. This indicates that the MDM2-MDMX heterodimerization plays a critical role in the regulation of p53. However, it remains unclear whether MDMX is essential for the regulation of p53 protein levels in the context of an endogenous MDM2 C-terminal tail mutation.

Results
Here, we studied the significance of MDM2-MDMX binding in an MDM2 E3 ligase deficient context using the MDM2Y487A mouse embryonic fibroblast (MEF) cells. Surprisingly, down-regulation of MDMX in MDM2Y487A MEFs resulted in a significant increase of p53 protein levels. Conversely, ectopic overexpression of MDMX reduced p53 protein levels in MDM2Y487A MEFs. Mutations of the RING domain of MDMX prevented MDMX-MDM2 binding, and ablated MDMX-mediated suppression of p53 protein expression. Additionally, DNA damage treatment and nuclear sequestration of MDMX inhibited MDMX activity to suppress p53 protein expression.

Conclusions
These results suggest that MDMX plays a key role in suppressing p53 protein expression in the absence of normal MDM2 E3 ligase activity. We found that the ability of MDMX to suppress p53 levels requires MDM2 binding and its cytoplasmic localization, and this ability is abrogated by DNA damage. Hence, MDMX is essential for the regulation of p53 protein levels in the context of an MDM2 C-terminal mutation that disrupts its E3 ligase activity but not MDMX binding. Our study is the first to examine the role of MDMX in the regulation of p53 in the context of endogenous MDM2 C-terminal mutant MEF cells.
Patterns of reproductive isolation in a haplodiploid mite, Amphitetranychus viennensis: prezygotic isolation, hybrid inviability and hybrid sterility
Authors: Sato Yukie , Fujiwara Satoshi , Egas Martijn , Matsuda Tomoko , Gotoh Tetsuo 
Published: September 2021

Abstract
Background
Evolution of reproductive isolation is an important process, generating biodiversity and driving speciation. To better understand this process, it is necessary to investigate factors underlying reproductive isolation through various approaches but also in various taxa. Previous studies, mainly focusing on diploid animals, supported the prevalent view that reproductive barriers evolve gradually as a by-product of genetic changes accumulated by natural selection by showing a positive relationship between the degree of reproductive isolation and genetic distance. Haplodiploid animals are expected to generate additional insight into speciation, but few studies investigated the prevalent view in haplodiploid animals. In this study, we investigate whether the relationship also holds in a haplodiploid spider mite, Amphitetranychus viennensis (Zacher).

Results
We sampled seven populations of the mite in the Palaearctic region, measured their genetic distance (mtDNA) and carried out cross experiments with all combinations. We analyzed how lack of fertilization rate (as measure of prezygotic isolation) as well as hybrid inviability and hybrid sterility (as measures of postzygotic isolation) varies with genetic distance. We found that the degree of reproductive isolation varies among cross combinations, and that all three measures of reproductive isolation have a positive relationship with genetic distance. Based on the mtDNA marker, lack of fertilization rate, hybrid female inviability and hybrid female sterility were estimated to be nearly complete (99.0–99.9% barrier) at genetic distances of 0.475–0.657, 0.150–0.209 and 0.145–0.210, respectively. Besides, we found asymmetries in reproductive isolation.

Conclusions
The prevalent view on the evolution of reproductive barriers is supported in the haplodiploid spider mite we studied here. According to the estimated minimum genetic distance for total reproductive isolation in parent population crosses in this study and previous work, a genetic distance of 0.15–0.21 in mtDNA (COI) appears required for speciation in spider mites. Variations and asymmetries in the degree of reproductive isolation highlight the importance of reinforcement of prezygotic reproductive isolation through incompatibility and the importance of cytonuclear interactions for reproductive isolation in haplodiploid spider mites.
SCReadCounts: estimation of cell-level SNVs expression from scRNA-seq data
Authors: Prashant N. M. , Alomran Nawaf , Chen Yu , Liu Hongyu , Bousounis Pavlos , Movassagh Mercedeh , Edwards Nathan , Horvath Anelia 
Published: September 2021

Abstract
Background
Recent studies have demonstrated the utility of scRNA-seq SNVs to distinguish tumor from normal cells, characterize intra-tumoral heterogeneity, and define mutation-associated expression signatures. In addition to cancer studies, SNVs from single cells have been useful in studies of transcriptional burst kinetics, allelic expression, chromosome X inactivation, ploidy estimations, and haplotype inference.

Results
To aid these types of studies, we have developed a tool, SCReadCounts, for cell-level tabulation of the sequencing read counts bearing SNV reference and variant alleles from barcoded scRNA-seq alignments. Provided genomic loci and expected alleles, SCReadCounts generates cell-SNV matrices with the absolute variant- and reference-harboring read counts, as well as cell-SNV matrices of expressed Variant Allele Fraction (VAFRNA) suitable for a variety of downstream applications. We demonstrate three different SCReadCounts applications on 59,884 cells from seven neuroblastoma samples: (1) estimation of cell-level expression of known somatic mutations and RNA-editing sites, (2) estimation of cell- level allele expression of biallelic SNVs, and (3) a discovery mode assessment of the reference and each of the three alternative nucleotides at genomic positions of interest that does not require prior SNV information. For the later, we applied SCReadCounts on the coding regions of KRAS, where it identified known and novel somatic mutations in a low-to-moderate proportion of cells. The SCReadCounts read counts module is benchmarked against the analogous modules of GATK and Samtools. SCReadCounts is freely available (https://github.com/HorvathLab/NGS) as 64-bit self-contained binary distributions for Linux and MacOS, in addition to Python source.

Conclusions
SCReadCounts supplies a fast and efficient solution for estimation of cell-level SNV expression from scRNA-seq data. SCReadCounts enables distinguishing cells with monoallelic reference expression from those with no gene expression and is applicable to assess SNVs present in only a small proportion of the cells, such as somatic mutations in cancer.