bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bone Marrow Multiparametric Magnetic Resonance Imaging with Texture Analysis for Follow-up of Advanced Stage Myelofibrosis after Transplantation
Authors: Gambella Massimiliano , Zaottini Federico , Bregante Stefania , Picasso Riccardo , Barabino Emanuele , Martinoli Carlo , Angelucci Emanuele 
Published: February 2021

Introduction
Hematopoietic cell transplantation (HCT) is a potentially curative treatment in myelofibrosis (MF). Nevertheless, in at least one-third of patients, a reliable parameter for disease response is lacking due to the absence of a molecular marker (in triple-negative MF) or the suboptimal sensitivity for CALR and MPL monitoring with routinely used PCR methods. Trephine biopsy provides a limited histological description, as it does not represent the fibrosis and/or blast eradication status of the entire bone marrow.
The aim of this study is to identify magnetic resonance imaging (MRI) biomarkers that reflect response to transplant and may serve as predictors of transplant efficacy.
Methods
We report the case of a 45-year-old man diagnosed with triple-negative MF who was eligible for HCT following progression after a previous procedure. A pre-transplant trephine biopsy showed grade III fibrosis, according to the WHO 2016 classification. CD34+ cells were found to comprise 10%-15% of cells. He underwent MRI 8 days before bone marrow transplantation from a haploidentical donor. A second, comparative MRI was performed 6 months after HCT; concurrent chimerism was estimated through Short Tandem Repeats (STRs) analysis. A multiparametric protocol was applied, including intravoxel incoherent motion (IVIM) diffusion-weighted imaging, Dixon GRE with fat fraction calculation, and Turbo Spin Echo T1 and STIR sequences. MRI examination was performed on a 3 Tesla MRI machine and included lumbar segments L4 and L5, pelvis, sacral bone, and coccyx. A phased-array surface coil was applied to optimize signal-to-noise ratio. Finally, radiomics and texture analysis were performed on ADC sequences using specific image software post-analysis (Slicer 3D v.4.10.2).
Results
The selected MRI parameters showed substantial modifications between the first and second exams. T1 and STIR sequences demonstrated a decrease in bone marrow fibrosis (Figure 1). ADC values increased at pre-specified target points (iliac crest, pre-transplant: 0.762, post-transplant: 0.901; femur, pre-transplant: 0.77, post-transplant: 0.808). Moreover, among 300 features analyzed (Figure 2), 20 presented changes potentially related with bone marrow restoration. Concomitant STRs analysis showed a full donor chimerism status.
Conclusions
To the best of our knowledge, this is the first case of functional, textural analysis-based MRI employed in transplanted MF. Multiparametric MRI data, including anatomical and functional sequences (particularly IVIM with texture analysis of ADC values and Dixon with fat fraction calculation) may represent valuable biomarkers for accurate detection of bone marrow engraftment and chimerism.

Disclosures
No relevant conflicts of interest to declare.
Construction of a Novel CD34+ Hematopoietic Stem Cell Derived Xenograft Model of Human Hyperleukocytic Acute Myeloid Leukemia
Authors: Jin Yanxia , Chen Yanling , Zheng Yujia , Zhou Fuling 
Published: February 2021

Acute myeloid leukemia (AML) is an abnormal clonal proliferative disease of hematopoietic progenitors in the bone marrow, which is the most common malignant disease in the blood system. Hyperleukocytic leukemia (HLL) is one of the high-risk types and commonly defined as peripheral blood leukocyte counts exceeding 50-100×109/l. The patients with hyperleukocytic acute myeloid leukemia (HL-AML) usually suffer from poor prognosis due to low responsiveness to initial chemotherapeutic agents, so these patients have higher mortality with life-threatening complication than those without hyperleukocytosis. However, there is no available patient derived xenograft model (PDX) in HL-AML, especially the CD34+ hematopoietic stem cell derived xenograft model of human HL-AML.
In this study, firstly, the primary HL-AML cells were collected and separated from the patients who underwent leukapheresis by using Fresenius COM.TEC machine, and the CD34+ hematopoietic stem cells were isolated from primary HL-AML cells using magnetic beads. Then, the NOD-SCID-IL2rγnull (B-NSG) mice were treated with 1.5 Gy χ-ray for total body irradiation at day 0, and intravenously injected with isolated 1.5 × 107 HLL cells or 1.5 × 106 CD34+ cells mixed with G-CSF within 24 h of irradiation. After inoculation, the blood smear, bone marrow smear, immunophenotyping and histopathology were used to test whether the model was successfully constructed.
For construction of hematopoietic stem cell derived xenograft model in HL-AML, at day 9, the immunophenotypes of hCD45+ and hCD34+ cells were found and had higher ratios in CD34+ group than HLL group in peripheral blood, which suggested the model was successfully established. The body weight of mice in CD34+ group were decreased faster than the HLL group due to severe tumor load and the leukocyte counts were increased higher than the correspondent HLL group after cell inoculation. In CD34+ group, the blood routine examination had changed, especially the WBC counts and PLT counts. On the 25th day, leukemic cells were found by the blood smears analysis and detected by flow cytometry, and which were more obviously found in bone marrow, and the immunophenotypes ratio of hCD45+ and hCD34+ were increased in CD34+ group. A lot of CD34+ cells were infiltrated into bone marrow, liver and spleen tissues on the 25th day that detected by histopathological analysis, which indicated that the more obviously model construction using hematopoietic stem cell derived leukemic cell.
In a conclusion, we successfully constructed a novel CD34+ hematopoietic stem cells derived animal model of human hyperleukocytic AML, which is available for mechanism research and drug treatment.

Disclosures
No relevant conflicts of interest to declare.
Novel 2 Marker Sandwich Immunoassay for the Detection of Precursor- and Mature Granulocyte-Derived Exosomes in Peripheral Blood: A Preliminary Case Study
Authors: Chong Esther G , Nguyen Anthony Loc , Mitsuhash Masato , Cao Huynh 
Published: February 2021

Introduction:
In order to assess hematopoietic precursor cells, bone marrow biopsies are routinely conducted, which is painful for the patient and is not applicable for frequent testing. However, precursor, maturating, and matured cells are known to produce exosomes, which are released into peripheral blood. By analyzing these exosomes in plasma, bone marrow condition may be assessed noninvasively.
Myeloid precursor cells express different surface markers than when they have matured. It is reasonable to speculate that these markers would be incorporated into exosomes. In this study, we developed a novel sandwich enzyme-linked immunosorbent assay (ELISA) by using a combination of monoclonal antibodies against 2 different leukocyte antigens, to account for the number of exosomes in plasma.
Methods
In 6 patients undergoing chemotherapy, venous blood was drawn at regular intervals before, during, and after respective chemotherapies was given. Various clones of monoclonal antibodies against CD11b, CD33, CD34, CD35, CD81, and CD117 were obtained, and antibodies were biotinylated by EZ link Sulfo-NHS-LC-Biotin. Anti-brain antibodies were switched with anti-leukocyte antibodies, and exosome activity was trended.
Results
CD11b+ and CD 117+ plates showed small changes during chemotherapy (within +/- 50% of the initial value), while plasma WBC count showed a dramatic decrease during chemotherapy.
In the recovery phase of WBC after chemotherapy, CD11b+ and CD16+showed a greater than 2-fold increase, with the up-trend taking place earlier than its plasma WBC counterparts. CD 117+ CD33+ also showed an up-trend, but was slower than their CD11b+ and CD16+ counterpart.
Finally, each exosome value was divided by other markers to calculate the ratio, and compared between pre and post chemotherapy blood. In half of the cases, there was not a difference, versus an almost double premature/mature ratio in post-chemotherapy blood in the other half of patients.
Conclusion
From data collected from pre-chemotherapy studies, the lack of correlation between ELISA data compared to plasma WBC data, indicates that plasma exosome analysis might not be suitable for the monitoring of acute bone marrow suppression.
Additionally, in the recovery phase, surface markers correlation with WBC was present in only some of the markers, indicating that the assay sensitivity is dependent on the marker combinations.
Overall, both myeloid precursor- and mature granulocyte-derived exosomes were increased during the recovery from chemotherapy in 3 out of 5 patients, and exosome profiles were different after chemotherapy in 2 out of 5 patients.

Disclosures
Mitsuhash: NanoSomiX:Current Employment.
Covid-19 Disease Is Not Associated with Venous Thromboembolism in a Cohort of Patients in Jeddah, Saudi Arabia
Authors: Kamel Fatemah , Magadmi Rania , Alqutub Sulafa , Badawi Maha A. , Al-Sayes Fatin , Badawi Mazen , Madani Tariq , Adam Soheir 
Published: February 2021

Background: Coronavirus disease 2019 (COVID-19) caused by acute respiratory syndrome coronavirus 2 (SARS2), is associated with significant morbidity and mortality. The aim of this study is to characterize risk factors and clinical features of COVID-19 disease in an adult cohort in Jeddah, Saudi Arabia.
Methods: A retrospective case control study was conducted at King Abdulaziz University hospital (KAUH) in Jeddah, Saudi Arabia. Clinical and demographic data on patients presenting at KAUH with concern for COVID-19 disease between March 18 and May 18, 2020 were collected and analyzed.
Results: Electronic medical records on 297 patients presenting at KAUH were reviewed. Of these, 175 (59%) tested positive for COVID-19 by polymerase chain reaction (PCR) and 122 (41%) tested negative. COVID-19 positive patients were more likely to be males (OR=1.59; 95% CI=1.22-2.07), and non-health care workers (OR=1.53; 95% CI=1.13-2.08). Hypertension (10%), diabetes (10%), and two or more concurrent co-morbid conditions (54.4%), were more prevalent among COVID-19 positive patients. Patients presenting with fever, cough, and loss of sense of taste or smell were more likely to test positive for COVID-19 (p=0.001, 0.008, 0.008, respectively. Radiological evidence of pneumonia was associated with confirmed COVID-19 disease. Dyspnea, cough and gastrointestinal symptoms were not associated with risk of COVID-19 at presentation. On admission, white blood cells, neutrophils, lymphocytes, eosinophils, basophils, and platelets were significantly lower among COVID-19 positive patients compared to controls. Surprisingly, D-dimer levels were lower among COVID-19 positive patients. Furthermore, only two patients developed thrombosis; one with pulmonary embolism and one with coronary artery thrombosis.
Conclusion: Male gender, hypertension and diabetes were associated with risk of COVID-19 disease in this study population. D-dimer levels were not elevated in COVID-19 patients, and venous thromboembolism was not prevalent in cases, compared to controls. This is in contrast to previous reports on the association of COVID-19 disease with venous thromboembolism in other populations. Thus, individual and environmental risk factors may play an important role in the pathophysiology of thrombosis in COVID-19 disease.

Disclosures
No relevant conflicts of interest to declare.
Optical Mapping Uncovers Multiple Novel Genomic Structural Variants in Patient Leukemias
Authors: Finlay Darren , Murad Rabi , Hong Karl , Lee Joyce , Pang Andy , Lai Chi-Yu , Burian Carol , Mason James R. , Hastie Alex , Yin Jun , Vuori Kristiina 
Published: February 2021

Leukemias are a diverse collection of hematopoietic cancers with limited chemotherapeutic treatment options. Patients unsuitable or unable for bone marrow transplantation have a dismal prognosis. Although previous studies have shown that there are only a limited number of potential driver mutations (3-8) per leukemia, there is an extensive heterogeneity of subtypes of disease. Using optical mapping with the Saphyr genome imaging system we confirm what other laboratories have found; that leukemias have additionally approximately 30-70 genomic structural variants per patient. This suggests that these SVs could ascribe the observed heterogeneity and could be responsible for individual pathogenesis of disease. Furthermore, we show that of many these SVs involve genes with functions associated with cellular processes relevant to cancer. Whilst known SVs, such asBCR-ABLtranslocations, are readily detected, multiple novel variants are also uncovered by Saphyr. Here we demonstrate the utility of this technique to uncover potential driver SV events and provide examples of such, some of which are associated with sensitivity and resistance to chemotherapeutics, including the standard of care drug Idarubicin (Idamycin). Finally, optical genome mapping shows 100% concordance with extant cytogenetic analyses, yet with a more streamlined methodology, a greater resolution, and higher sensitivity of detection.
Figure

Disclosures
Hong: Bionano Genomics:Current Employment.Lee:Bionano Genomics, San Diego:Current Employment.Pang:Bionano Genomics:Current Employment.Lai:Bionano Genomics:Current Employment.Hastie:Bionano Genomics:Current Employment.Vuori:Bionano Genomics:Membership on an entity's Board of Directors or advisory committees.
Molecular coevolution of coagulation factor VIII and von Willebrand factor
Authors: Zakas Philip M. , Coyle Christopher W. , Brehm Anja , Bayer Marion , Solecka-Witulska Barbara , Radford Caelan E. , Brown Christine , Nesbitt Kate , Dwyer Courtney , Kannicht Christoph , Spencer H. Trent , Gaucher Eric A. , Doering Christopher B. , Lillicrap David 
Published: February 2021

AbstractAncestral sequence reconstruction provides a unique platform for investigating the molecular evolution of single gene products and recently has shown success in engineering advanced biological therapeutics. To date, the coevolution of proteins within complexes and protein–protein interactions is mostly investigated in silico via proteomics and/or within single-celled systems. Herein, ancestral sequence reconstruction is used to investigate the molecular evolution of 2 proteins linked not only by stabilizing association in circulation but also by their independent roles within the primary and secondary hemostatic systems of mammals. Using sequence analysis and biochemical characterization of recombinant ancestral von Willebrand factor (VWF) and coagulation factor VIII (FVIII), we investigated the evolution of the essential macromolecular FVIII/VWF complex. Our data support the hypothesis that these coagulation proteins coevolved throughout mammalian diversification, maintaining strong binding affinities while modulating independent and distinct hemostatic activities in diverse lineages.
CiliarMove: new software for evaluating ciliary beat frequency helps find novel mutations by a Portuguese multidisciplinary team on primary ciliary dyskinesia
Authors: Sampaio Pedro , da Silva Mónica Ferro , Vale Inês , Roxo-Rosa Mónica , Pinto Andreia , Constant Carolina , Pereira Luisa , Quintão Carla M. , Lopes Susana S. 
Published: February 2021

Evaluation of ciliary beat frequency (CBF) performed by high-speed videomicroscopy analysis (HVMA) is one of the techniques required for the correct diagnosis of primary ciliary dyskinesia (PCD). Currently, due to lack of open-source software, this technique is widely performed by visually counting the ciliary beatings per a given time-window. Our aim was to generate open-source, fast and intuitive software for evaluating CBF, validated in Portuguese PCD patients and healthy volunteers.Nasal brushings collected from 17 adult healthy volunteers and 34 PCD-referred subjects were recorded using HVMA. Evaluation of CBF was compared by two different methodologies: the new semi-automated computer software CiliarMove and the manual observation method using slow-motion movies. Clinical history, nasal nitric oxide and transmission electron microscopy were performed for diagnosis of PCD in the patient group. Genetic analysis was performed in a subset (n=8) of suspected PCD patients.The correlation coefficient between the two methods was R2=0.9895. The interval of CBF values obtained from the healthy control group (n=17) was 6.18–9.17 Hz at 25°C. In the PCD-excluded group (n=16), CBF ranged from 6.84 to 10.93 Hz and in the PCD group (n=18), CBF ranged from 0 to 14.30 Hz.We offer an automated open-source programme named CiliarMove, validated by the manual observation method in a healthy volunteer control group, a PCD-excluded group and a PCD-confirmed group. In our hands, comparisons between CBF intervals alone could discern between healthy and PCD groups in 78% of the cases.
Effect of galcanezumab on severity and symptoms of migraine in phase 3 trials in patients with episodic or chronic migraine
Authors: Ament Michael , Day Kathleen , Stauffer Virginia L , Skljarevski Vladimir , Rettiganti Mallikarjuna , Pearlman Eric , Aurora Sheena K. 
Published: February 2021

AbstractBackgroundGalcanezumab, a humanized monoclonal antibody that binds calcitonin gene-related peptide, has demonstrated a significant reduction in monthly migraine headache days compared with placebo. Here, we analyze data from 3 randomized clinical trials (2 episodic trials [EVOLVE-1, EVOLVE-2] and 1 chronic trial [REGAIN]), to examine if galcanezumab also alleviates the severity and symptoms of migraine.MethodsThe episodic migraine trials were 6-month, double-blind studies in patients with episodic migraine (4–14 monthly migraine headache days). The chronic migraine trial was a 3-month, double-blind study in patients with chronic migraine (≥ 15 headache days per month, where ≥ 8 met criteria for migraine). Patients (18–65 years) were randomized to placebo or galcanezumab 120 mg with a 240-mg loading dose or 240 mg. Patients recorded headache characteristics, duration, severity, and presence of associated symptoms with each headache. The outcomes analyzed were changes from baseline in number of monthly migraine headache days with nausea and/or vomiting, photophobia and phonophobia, aura, and prodromal symptoms other than aura. Additional outcomes analyzed included the number of moderate-to-severe monthly migraine headache days, number of severe migraine headache days, and mean severity of remaining migraine headache days. Change from baseline in the proportion of days with nausea and/or vomiting and the proportion of days with photophobia and phonophobia among the remaining monthly migraine headache days were also analyzed.ResultsGalcanezumab was superior to placebo in reducing the frequency of migraine headache days with associated symptoms of migraine such as nausea and/or vomiting, photophobia and phonophobia, and prodromal symptoms. Galcanezumab reduced the frequency of migraine headache days with aura in the episodic migraine studies. There was a significant reduction in the proportion of remaining migraine headache days with nausea and/or vomiting for the episodic and chronic migraine studies, and with photophobia and phonophobia for the episodic migraine studies. Galcanezumab was superior to placebo in reducing the number of monthly moderate-to-severe migraine headache days and the overall and monthly severe migraine headache days.ConclusionsGalcanezumab reduces the frequency of migraine headache days and can alleviate potentially disabling non-pain symptoms on days when migraine is present in patients with episodic or chronic migraine.Trial registrationNCT,NCT02614183(EVOLVE-1), registered 25 November 2015; NCT,NCT02614196, (EVOLVE-2), registered 25 November 2015; NCT,NCT02614261(REGAIN), registered 25 November 2015.
Structure Investigations of Islands with Atomic-Scale Boron–Carbon Bilayers in Heavily Boron-Doped Diamond Single Crystal: Origin of Stepwise Tensile Stress
Authors: Polyakov S. N. , Denisov V. N. , Denisov V. V. , Zholudev S. I. , Lomov A. A. , Moskalenko V. A. , Molchanov S. P. , Martyushov S. Yu. , Terentiev S. A. , Blank V. D. 
Published: February 2021

AbstractThe detailed studies of the surface structure of synthetic boron-doped diamond single crystals using both conventional X-ray and synchrotron nano- and microbeam diffraction, as well as atomic force microscopy and micro-Raman spectroscopy, were carried out to clarify the recently discovered features in them. The arbitrary shaped islands towering above the (111) diamond surface are formed at the final stage of the crystal growth. Their lateral dimensions are from several to tens of microns and their height is from 0.5 to 3 μm. The highly nonequilibrium conditions of crystal growth enhance the boron solubility and, therefore, lead to an increase of the boron concentrations in the islands on the surface up to 1022 cm−3, eventually generating significant stresses in them. The stress in the islands is found to be the volumetric tensile stress. This conclusion is based on the stepwise shift of the diamond Raman peak toward lower frequencies from 1328 to 1300 cm−1 in various islands and on the observation of the shift of three low-intensity reflections at 2-theta Bragg angles of 41.468°, 41.940° and 42.413° in the X-ray diffractogram to the left relative to the (111) diamond reflection at 2theta = 43.93°. We believe that the origin of the stepwise tensile stress is a discrete change in the distances between boron–carbon layers with the step of 6.18 Å. This supposition explains also the stepwise (step of 5 cm−1) behavior of the diamond Raman peak shift. Two approaches based on the combined application of Raman scattering and X-ray diffraction data allowed determination of the values of stresses both in lateral and normal directions. The maximum tensile stress in the direction normal to the surface reaches 63.6 GPa, close to the fracture limit of diamond, equal to 90 GPa along the [111] crystallographic direction. The presented experimental results unambiguously confirm our previously proposed structural model of the boron-doped diamond containing two-dimensional boron–carbon nanosheets and bilayers.
A nanograting-based flexible and stretchable waveguide for tactile sensing
Authors: Peng Wang , Liao Qingxi , Song Han 
Published: February 2021

AbstractBased on the related characteristics of optical waveguide and flexible optical materials, a flexible and stretchable optical waveguide structure oriented to tactile perception is proposed. The sensing principle of optical waveguide is based on mechanical deformation caused by output light loss. It overcomes the shortcomings of traditional optical waveguide devices, which are unable to conform to irregular surface. The flexible and stretchable optical waveguide is fabricated with nanoreplica molding method, and it has been applied to the measurement of pressure and strain in the field of tactile sensing. The flexible and stretchable optical waveguide had a strain detection range of 0 to 12.5%, and the external force detection range is from 0 to 23 × 10–3 N.