bluuebunny/crossref_metadata_2025 huggingface dataset:
Detachment Waves and Self-Oscillation in a Belt-Drive System Incorporating Tensile Cords
Authors: Wu Yingdan , Varenberg Michael , Leamy Michael J.
Published: April 2020

Recent experimental studies have shown that tension transition via detachment waves (rather than via sliding, as commonly accepted) occurs at the belt–pulley interface for systems using simple homogeneous or textured flat belts operating under slow speeds. This raises the question of whether or not such detachment waves are universal—e.g., will they persist in systems incorporating belts with composite cross sections, such as those used in commercial applications? Herein, we experimentally explore the behavior of a belt-drive system incorporating a composite belt with tensile cords, with and without a patterned contact surface, and document the persistence of detachment waves. This then leads to a re-evaluation of the Firbank model of belt shear. We also explore the effect of tensile cords on (i) the amplitude and frequency of the observed detachment waves, (ii) the ensuing oscillations of the pulley, (iii) the evolution of belt shear strain, and (iv) the frictional losses of the system. We find that the detachment frequency increases and the pulley rotates steadier with inclusion of tensile cords. The corded belt undergoes shear deformation starting from the entry point due to a speed differential between the pulley envelope and the tension members, which is consistent with the classical Firbank shear model. However, the Firbank model cannot predict the rapid relaxation of the shear traction via detachment waves at the exit region. Additionally, accounting for shear and detachment events, we find that frictional losses in the belt-drive system decrease with inclusion of tensile cords.
Modeling, Analysis, and Control of SLIP Running on Dynamic Platforms
Authors: Iqbal Amir , Mao Zhu , Gu Yan
Published: April 2020

The complex dynamic behaviors of legged locomotion on stationary terrain have been extensively analyzed using a simplified dynamic model called the spring-loaded inverted pendulum (SLIP) model. However, legged locomotion on dynamic platforms has not been thoroughly investigated even by using a simplified dynamic model such as SLIP. In this paper, we present the modeling, analysis, and control of a SLIP model running on dynamic platforms. Three types of dynamic platforms are considered: (a) a sinusoidally excited rigid-body platform; (b) a spring-supported rigid-body platform; and (c) an Euler–Bernoulli beam. These platforms capture some important domains of real-world locomotion terrain (e.g., harmonically excited platforms, suspended floors, and bridges). The interaction force model and the equations of motion of the SLIP-platform systems are derived. Numerical simulations of SLIP running on the three types of dynamic platforms reveal that the platform movement can destabilize the SLIP even when the initial conditions of the SLIP motion are within the domain of attraction of its motion on flat, stationary platforms. A simple control strategy that can sustain the forward motion of a SLIP on dynamic platforms is then synthesized. The effectiveness of the proposed control strategy in sustaining SLIP motion on dynamic platforms is validated through simulations.
A New Index of Static Actuation Force Sensitivity of Mechanisms Based on Unified Forward Jacobian Matrix
Authors: Wang Xu , Guo Weizhong , Han Youcheng
Published: April 2020

This paper proposes a novel performance index, which is called static actuation force sensitivity (SAFS), to investigate the response of the actuation forces when the amplitude of the suffered load of the end-effector has a change. Smaller SAFS can protect the actuations, and the load is mainly suffered by the structural constraints. This work starts with the construction of the unified forward Jacobian matrix of both serial and parallel mechanisms by screw theory. Then, with the forward Jacobian matrix, the inverse static equation is established. SAFS is thus introduced by the “partial differential” operation on the inverse static equation. SAFS is only related to the position of the whole mechanism and the direction of the suffered load, but not related to the detailed value of the amplitude of the load and the detailed value of the actuation forces; thus, SAFS can reveal the essence of static force capacities of the mechanisms. The example mechanism (namely, the 3revolute-prismatic-spherical (RPS) parallel mechanism) is used to illustrate the distribution of SAFS both over the workspace and at a certain pose. The analysis method of SAFS and the proposed index are expected to be applied to the pose optimization in the motion planning of the mechanisms to protect the actuations.
A Hybrid Contact Implementation Framework for Finite Element Analysis and Topology Optimization of Machine Tools
Authors: Yuksel Esra , Erturk Ahmet Semih , Budak Erhan
Published: April 2020

Machine tool contacts must be represented accurately for reliable prediction of machine behavior. In structural optimization problems, contact constraints are represented as an additional minimization problem based on computational contact mechanics theory. An accurate contact constraint representation is challenging for structural optimization problems: (i) “No penetration” rule dictated by Hertz-Signorini-Moreau (HSM) conditions at contacts is satisfied by varying the contact stiffness during a finite element (FE) solution without control of a user which causes increased contact stiffness “erroneously” to avoid penetration of contacting node pairs in an FE solution; and (ii) the reliability of solutions varies according to the chosen computational contact method. This paper is devoted to the topology optimization of machine tools with contact constraints. A hybrid approach is followed that combines the computational contact problem framework and an obtained stable contact stiffness function (analytically or experimentally). According to the proposed method, the existing optimization problem in FE literature is restated in a reliable form for machine tool applications. To avoid the existing computational challenges and reliability problems, contact forces are directly mapped onto an FE model used in the restated topology optimization problem with the help of proposed method. In this study, the existing and the proposed methods for contact are investigated by means of the solid isotropic material with penalization model (SIMP) algorithm for topology optimization. The effectiveness of the proposed method is demonstrated by comparing the experimental measurements on a prototype machine tool manufactured according to the optimization solutions of the proposed method and those of a conventional machine tool.
An Undergraduate Elective Course That Introduces Topics of Diversity, Equity, and Inclusion into Discussions of Science
Authors: Reese Amy J.
Published: April 2020

In this
Science, Ethics, and Society
elective undergraduate course at the St. Louis College of Pharmacy, students consider topics that scientists face continuously, including human and animal subjects, science denial, treatment of scientists, who owns and funds science, personalized medicine and genetics, health disparities, and scientific integrity, all through lenses of inclusion and equity. Students read primary and secondary literature pertaining to each day’s topic, upload reflections to a course management system, and engage in structured dialogue in a facilitated classroom environment. Overarching themes address how women and men and their scientific work have been treated or received differently, as well as particular challenges faced by people of color, members of the LGBTQIA+ community, and those with disabilities. This course helps students see how the culture of science has been created and sustained, how it has not encouraged equal participation, and how it could be shaped differently. Student responses to the course recognize that this approach to the scientific material is valuable and that it does not appear elsewhere in their curriculum.
First-Day Info Sheets: A Tool to Prompt Semester-Long Inclusive Teaching
Authors: Killpack Tess L. , Melón Laverne C.
Published: April 2020

What faculty do and say on the first day of class is crucial to establishing and maintaining an inclusive learning environment for the duration of the semester. First-day information sheets (“info sheets”) are commonly used by instructors. By making simple modifications to this tool, we can gather more information about the goals and experiences of our students, the lives of our students outside of our classroom, and how our students’ lives may impact their engagement with the course material and course structure. We can also use this information to actively highlight to students that their full selves (names, pronouns, background) belong in our biology classroom. We provide a set of prompts and suggested steps, rooted in the scholarly literature, to encourage and facilitate faculty use of info-sheets as a valuable tool to inform semester-long inclusive teaching efforts.
Reaching a Large Urban Undergraduate Population through Microbial Ecology Course-Based Research Experiences
Authors: Parks Samantha , Joyner Jessica Lee , Nusnbaum Matthew
Published: April 2020

Traditional postsecondary education is making progress on embracing the diversity of student backgrounds and experiences while preparing them for the demands of STEM careers. Course-based undergraduate research experiences (CUREs) are effective tools to concurrently achieve many student and faculty goals: facilitating training of students, building career competencies, generating publishable research results and enabling research experiences where students apply their knowledge and interest. Georgia State University is not unique with a high student demand for research experiences and mentors that is greater than traditional research faculty labs can accommodate. Georgia State University is, however, unique in that it is a demographically diverse campus which serves minority and non-traditional students (i.e., second career and veterans) and is also rapidly growing. Therefore, to enhance the microbiology curriculum and facilitate authentic research experiences for the growing number of biology majors, a cluster of course-based research experiences in microbial ecology was developed. A former research lab space was converted to a collaborative teaching lab to serve the growth in course offerings, as well as to accommodate multiple microbial ecology research projects occurring in the same space. The courses offered appeal to students, build on the strengths of faculty experiences, and facilitate collaboration amongst students and with the greater Atlanta community. To ensure that our CUREs are accessible to the diverse students in our department, we addressed a variety of logistical and curricular challenges. Solutions to such challenges align with the goals of the university to offer research and signature experiences to ensure students are included and trained in STEM skills.
Impact of the PDFs on the Z and W lineshapes at LHC
Authors: Bertacchi Valerio , Bianchini Lorenzo , Manca Elisabetta , Rolandi Gigi , Chowdhury Suvankar Roy
Published: April 2020

The parton distribution functions (PDFs) of the proton play a role in determining the lineshape of Z and W bosons produced at the LHC. In particular, the mode of the gauge boson virtuality is shifted with respect to the pole due to the dependence of the partonic luminosity on the boson virtuality. The knowledge of this shift contributes to the systematic uncertainty for a direct measurement of the boson mass. A detailed study of the shift and of its systematic uncertainty due to the limited knowledge of the PDFs is obtained using a tree-level model of Z and W boson production in proton-proton collisions at $$\sqrt{s}=13~\hbox {TeV}$$s=13TeV. A Monte Carlo simulation is further used to validate the tree-level model and study the dependence of the shift on the transverse momentum of the gauge bosons. The tree-level calculation is found to provide a good description of the shift. The systematic uncertainty on the lineshape due to the PDFs is estimated to be below one MeV in the phase-space relevant for a future high-precision mass measurement of the gauge boson masses at the LHC.
Multiscale Patterning from Competing Interactions and Length Scales
Authors: Bishop A.R.
Published: April 2020

We live in a research era marked by impressive new tools powering the scientific method to accelerate the discovery, prediction, and control of increasingly complex systems. In common with many disciplines and societal challenges and opportunities, materials and condensed matter sciences are beneficiaries. The volume and fidelity of experimental, computational, and visualization data available, and tools to rapidly interpret them, are remarkable. Conceptual frameworks, including multiscale, multiphysics modeling of this complexity, are fueled by the data and, in turn, guide directions for future experimental and computational strategies. In this spirit, I discuss the importance of competing interactions, length scales, and constraints as pervasive sources of spatiotemporal complexity. I use representative examples drawn from materials and condensed matter, including the important role of elasticity in some technologically important quantum materials.
Basal Ganglia Circuits for Action Specification
Authors: Park Junchol , Coddington Luke T. , Dudman Joshua T.
Published: April 2020

Behavior is readily classified into patterns of movements with inferred common goals—actions. Goals may be discrete; movements are continuous. Through the careful study of isolated movements in laboratory settings, or via introspection, it has become clear that animals can exhibit exquisite graded specification to their movements. Moreover, graded control can be as fundamental to success as the selection of which action to perform under many naturalistic scenarios: a predator adjusting its speed to intercept moving prey, or a tool-user exerting the perfect amount of force to complete a delicate task. The basal ganglia are a collection of nuclei in vertebrates that extend from the forebrain (telencephalon) to the midbrain (mesencephalon), constituting a major descending extrapyramidal pathway for control over midbrain and brainstem premotor structures. Here we discuss how this pathway contributes to the continuous specification of movements that endows our voluntary actions with vigor and grace.
Korean Nonprofit/Non-Government Sector Research: A Literature Review and Analysis
Authors: Kim Sung-Ju , Jung Jin-Kyung
Published: April 2020

Discourses on the nonprofit sector and civil society have elevated awareness of the significant growth of the sector’s roles and responsibilities since the early 1990s in South Korea (hereafter simply Korea). The nonprofit sector has played significant roles in promoting economic progress and democracy in Korea. Based on extensive empirical research and government statistics, this article presents the nature of the Korean nonprofit sector from various angles, including terminology, history, legal frames, size and dimensions, financial resources, changes in philanthropy and volunteer cultures, and social economic perspectives. In addition, the authors discuss contemporary issues for the nonprofit sector based on changes in the social environment.

In discussing the magnitude of the Korean nonprofit sector, this article makes three arguments. First, we confirm that the Korean nonprofit sector has rapidly grown in multidimensional aspects as the legal systems for the nonprofits have developed in Korea since World War II. The growth has been accelerated by strong government supports and initiatives. Second, we argue that lack of conceptual frameworks to identify the nonprofit sector and lack of a centralized administration system have hindered fully catching up on the nature of the nonprofit sector in Korea. Multiple legal frameworks and excessively complicated governing systems for the nonprofit sector have inhibited understanding the size and dimensions of the Korean nonprofit sector. This article further diagnoses the financial structures and the contemporary issues for the Korean nonprofit sector, discussing key suggestions for developing it.
Secondary school subjects and gendered STEM enrollment in higher education in Germany, Ireland, and Scotland
Authors: Jacob Marita , Iannelli Cristina , Duta Adriana , Smyth Emer
Published: April 2020

This article examines the extent to which science, technology, engineering, and mathematics (STEM) subject choice in upper secondary education explains gender differences in STEM enrollment in higher education. We adopt a cross-country approach using Germany, Ireland, and Scotland as three case studies. These countries differ in terms of both the degree of subject choice offered in upper secondary education and the relevance for higher education admission of having studied specific school subjects. Using datasets of young people from all three countries, our results indicate a stronger mediation of school subjects for Scotland than in Germany and Ireland and a remarkable gender gap in STEM enrollment in all three countries. We conclude that females studying science subjects within upper secondary education appears to be a necessary but not a sufficient condition to ensure gender equality in progression to STEM fields.
Robust super-twisting sliding mode controller with state observer for position tracking of ionic polymer–metal composite actuators
Authors: Kolahi Mohammad Reza Salehi , Moeinkhah Hossein
Published: April 2020

To date, a novel class of smart materials, known as ionic polymer–metal composites, have been intensively studied because of their huge potential applications in robotics, microelectromechanical systems, biomedical devices, and artificial muscles. The position tracking control of the ionic polymer–metal composite actuators is one of the challenging tasks due to the highly nonlinear, uncertain, and unmodeled dynamics. These inaccurate and unmodeled dynamics cause the unwanted disturbances which reduce the control performance. Therefore, a robust feedback controller for position tracking of the ionic polymer–metal composite actuators is necessary. To address this issue, this article presents a super-twisting sliding mode controller combined with integral-chain differentiator as state observer. The main advantage of the proposed method is its potential to estimate the states of the system continuously. As a result, the controller not only eliminates the parameter uncertainties and external disturbance but also it can overcome the chattering problem. The results confirm the feasibility and efficiency of the proposed method both in simulation and experiment.
Salvage Reconstructive Surgery During Nivolumab Therapy for a Patient With Hypopharyngeal Cancer
Authors: Tsushima Nayuta , Shinozaki Takeshi , Fujisawa Takao , Tomioka Toshifumi , Okano Wataru , Ikeda Masakazu , Tahara Makoto , Higashino Takuya , Hayashi Ryuichi
Published: April 2020

Objectives:

Nivolumab, a fully IgG4-programmed death-1 inhibitor antibody, led to improved overall survival compared with single-agent therapy in patients with platinum-refractory recurrent head and neck cancers. In general, nivolumab is used in inoperable patients. To the best of our knowledge, there have been no reports of salvage surgery during nivolumab therapy for patients with head and neck cancer. We report the case of a woman treated with salvage reconstructive surgery during nivolumab therapy.

Method:

Case report and literature review.

Results:

The patient underwent nivolumab therapy for recurrent primary and neck disease after induction chemotherapy, followed by concurrent chemoradiation therapy. The neck disease shrunk, whereas the primary disease temporarily shrunk but later progressed again. Recurrent primary disease led to a narrowing of her airway, and she required airway management. We performed total pharyngolaryngectomy with free jejunal reconstruction, and her quality of life improved. The surgery was performed without complications and the postoperative course was uneventful. She was discharged postoperative day 18 with oral intake function and a safer airway.

Conclusion:

As far as we know, this is the first report of salvage surgery during nivolumab therapy for patients with head and neck cancer. The salvage reconstructive surgery in this case proceeded uneventfully.
Developing EFL students’ pragmatic competence: The case of compliment responses
Authors: Alsuhaibani Zainab
Published: April 2020

This study investigated the effect of consciousness-raising instruction and corpus-based instruction on EFL (English as a foreign language) students’ development of compliment responses. It employed a quasi-experimental design with 136 EFL university students divided between three groups: control, consciousness-raising, and corpus groups. A discourse completion test (DCT) was used as a pre- and post-test with all the groups to investigate any significant differences between them. Further, a questionnaire with open-ended questions was used to explore students’ perceptions of pragmatic instruction of compliment responses. The results showed the effectiveness of pragmatic instruction of compliment responses through both consciousness-raising instruction and corpus- based instruction. More specifically, significant differences were found between consciousness-raising group and the corpus group on one hand, and the control group on the other. No significant differences were found between the consciousness-raising group and the corpus group. The results also revealed that the students value the importance of pragmatic instruction indicating that it was important, necessary, useful, and enjoyable at the same time. The article ends with some pedagogical recommendations for pragmatic instruction.
Early Myeloablative Allogeneic Stem Cell Transplantation during High-Dose Cytarabin Induced Cytopenia in Patients with Refractory or Relapsed Myeloid Leukemias.
Authors: Graef Thorsten T. , Neumann Frank F. , Fenk Roland R. , Kondakci Mustafa M. , Ruf Lailani L. , Steidl Ulrich U. , Haas Rainer R. , Kobbe Guido G.
Published: April 2020

Allogeneic stem cell transplantation is the most effective therapy for myeloid leukemias. Still, especially patients with refractory disease, unfavourable cytogenetics or blast transformation of a myeloproliferative disorder (mpd) have a poor prognosis as a result of a high rate of treatment related mortality and relapse with conventional conditioning regimens. Recently, Kolb et al. have introduced a sequential protocol utilizing early TBI-based non-myeloablative transplantation following conventional induction therapy in high-risk patients.

In this study, in dependence to Kolb, we have treated 21 patients (median age 51 years, range 17–63, 4 female, 17 male) with advanced leukemias according to an intensified sequential high-dose protocol. Diagnoses were AML (primary refractory 2, relapsed 5), MDS (refractory 7, untreated 1) and blast transformation of a MPD (refractory 6, untreated 0). The median blast count at induction was 22% (range 1–90) and 9 patients (43 %) had unfavourable cytogenetics. Induction therapy consisted of fludarabine, high-dose cytarabine with or without idarubicine, amsacrine or topotecan. ATG, high-dose melphalan with or without high-dose thiotepa was used for conditioning while patients were still cytopenic from the preceeding induction therapy. Following transplantation of a median of 6.1x10E6 CD34+ cells/kg (range 0.85–12.0) from related (6) or unrelated (15) donors, the median time to a wbc>1000/μl and plt>20000/μl was 15 days (range 10–24) and 17 days (range 8–30), respectively. No toxic death was observed during the first 30 days and 95% of patients achieved CR by day 28, 100% by day 50. Twelve patients (57%) developed aGvHD (12I-II°, 0III-IV°) and 7 patients (33%) at risk have developed chronic GvHD (5 limited, 2 extensive) so far. After a median time of 181 days (range 3 – 596 days) fifteen patients (72%) are alive and all are in complete remission. Six patients died, one of infection (5%), two of a combination of a chronic GvHD and infections (9%), two of disease progression (9%) and one patient from a second malignancy (SCLC).

We conclude that early sequential transplantation during induction therapy induced cytopenia using high-dose melphalan and thiotepa based conditioning is feasible and highly effective in patients with advanced myeloid leukemias and poor prognosis. Although these early results are promising, a longer follow up and comparison with standard regimens are required.
Results of a Phase II Trial Testing Interferon Alpha 2b and Cytarabine in Children with Chronic Myelogenous Leukemia.
Authors: Millot Frédéric , Guilhot Joelle , Nelken Brigitte , Lamagnère Jean-Pierre , Leblanc Thierry , Leverger Guy , Notz Anne , Plantaz Dominique , Bernard Frédéric , Bordigoni Pierre , Yacouben Karima , Behar Catherine , Thyss Antoine , Guy Cornu , Duchène Sylvain , Guilhot François
Published: April 2020

Before the Imatinib era, a prospective phase II trial was conducted in 2000 to assess the efficacy and the tolerance a combination of interferon alpha 2b (IFN) and cytarabine in children and adolescents with chronic myelogenous leukemia in first chronic phase without a suitable HLA-identical donor. Children received daily IFN (5 million units/m2) and subcutaneous cytarabine (20 mg/m2) for monthly course of 10 days. Between September 2000 and March 2003, 14 children (10 males, 4 females) median age 12 years (range 2–16.5) were recruited from 12 french centres. Patients (pts) were evaluated for time to, rate of hematologic and cytogenetic responses, toxicity and progression free survival. The median duration of follow-up is 13 months (range 2–32 mo). Eight pts achieved a complete hematologic response after a median time of treatment of 3 months (range 0–4 mo) including a pt enrolled in complete hematologic response after 1 month of therapy with hydroxyurea. Three pts were not evaluable for the cytogenetic response (early discontinuation for toxicity, no achievement of complete hematologic response within 3 months of treatment, progression). The best cytogenetic response by 12 months was: major response in 7 pts including complete cytogenetic response in 2 pts, minor response in 3 pts and failure in 1 pt. The median time to major cytogenetic response was 7 months (range 3–12 mo). Thirteen pts discontinued treatment protocol with a median time of 11 months for the following reasons: absence of complete hematologic response at 3 months (2 pts), loss of hematologic response (2 pts), absence of major cytogenetic response at 12 months (1 pt ), loss of major cytogenetic response (2pts), progression (3 pts), adverse event (1pt), other (2 pts). Probability of progression free survival at 18 months was 66% (95% CI, 34–98%). No treatment-related death occurred. The most frequently reported drug-related events were fever, mucositis, neutropenia and thrombocytopenia. Grade 3 and 4 non hematologic toxicity (fever and mucositis) was observed in 4 pts and grade 3 and 4 hematologic toxicity (anemia, neutropenia and thrombocytopenia) in 7 pts. The median total dose of IFN and cytarabine administered was 3.7 million units/m2 /day (range 2.3–5.1) and 20 mg/m2 /day (range 11–23). The median duration of IFN therapy was 11 months (range1–117 mo). The median number of courses of cytarabine was 7 (range 1–37). The combination of IFN and cytarabine is a well tolerated therapy providing hematologic and cytogenetic responses in children and adolescents with CML. Rates of hematologic and cytogenetic responses compare favourably with results observed in adults. Results should be compared to these of imatinib in children and adolescents.
A Rapid and Sustained Increase in Neutrophil Elastase Levels Correlates Temporally with Decreased Coagulation Factor Activity during E.coli-Sepsis in Baboons.
Authors: Samis John A. , Stewart Kenneth A. , Taylor Fletcher B. , Nesheim Michael E.
Published: April 2020

Infection is the most common pathology resulting in disseminated intravascular coagulation (DIC) in humans. Disturbances of the cell interactions between neutrophils and endothelial cells are an integral part of the pathophysiology of E.coli-sepsis. Although neutrophil elastase (NE) is required for the destruction of gram negative bacteria, dysregulated NE activity towards coagulation factors may contribute to the coagulopathies that accompany infections if its activity is not properly regulated by alpha-1-protease inhibitor (A1PI). The temporal relationships between these variables were studied in plasma samples from three baboons before and after infusion of either two sublethal doses (2.50x106 cfu/kg and 1.10x108 cfu/kg) or a lethal dose (6.50x108 cfu/kg) of E.coli. In comparison to pre-infusion levels, the A1PI/NE complex levels increased by up to 17-fold after 2hrs and remained 6-fold above baseline after 53hrs as the amount of E.coli was increased. In contrast, the A1PI activity and specific activity both decreased by up to 30% during the 2–6hrs following the lethal dose of E.coli. Large transient decreases, of between 60–96%, in the factor V and VIII activity and fibrinogen levels occurred only during the 2–6hrs following infusion of the lethal dose. In addition, there was a 70–80% decrease in the factor II, VII, IX, and X clotting activity after 6–24hrs as the dose of E.coli was increased. In conclusion, there is a temporal association between the changes in A1PI activity, the appearance of the A1PI/NE complex, and the decrease of coagulation factor activity during E.coli-sepsis in baboons. Further, the sustained elevation of the A1PI/NE complexes beyond 48hrs, even after sublethal challenge with E.coli, indicates that a persistent increase in the neutrophil activity occurs as part of the inflammatory response to bacterial infection in this animal model. This study demonstrates that the neutrophil/endothelial interaction continues far beyond the first margination stage into the second ischemia/reperfusion stage during E.coli-sepsis. The results raise the possibility that clotting factor degradation/inactivation by NE as well as consumption via the coagulation cascade occurs following infusion of sublethal and lethal doses of E.coli.
At 90 Micrograms Per Kilogram, Recombinant Factor VIIa Partially Corrects Abnormal Hemostatic Function in Blood from Factor IX Deficient Patients.
Authors: Carr Marcus E. , Martin Erika J. , Kuhn Janice G. , Nolte Melinda
Published: April 2020

Reports of the potential clinical utility of recombinant Factor VIIa (rFVIIa, NovoSeven®, NovoNordisk) in a variety of bleeding disorders have raised the possibility that this agent may have broad spectrum hemostatic properties. We have previously demonstrated that rFVIIa produces dose dependent correction of hemostatic status in patients with Factor VIII deficiency and/or Factor VIII inhibitor. In this study we measured the dose dependent effects of rFVIIa on Platelet Contractile Force (PCF), Clot Elastic Modulus (CEM) and Thrombin Generation Time (TGT) (Hemodyne® Analyzer, Hemodyne, Inc.) in patients with factor IX deficiency. Results were compared to those seen with recombinant factor IX (BeneFIX® [GI, Wyeth]) and factor nine concentrate (Mononine® [Aventis-Behring]). Blood from three patients with factor IX deficiency was collected via aseptic venipuncture into evacuated tubes containing 3.2% sodium citrate. The samples were spiked with increasing amounts of each hemostatic agent so as to yield levels ranging from 25 to 200% of the recommended dose. At baseline, each of the factor IX deficient patients had prolonged TGT, decreased PCF and decreased CEM. Despite the fact that each patient had less than 1% of normal factor IX activity, there was significant variability between the patients in their baseline values. TGT for the three patients varied from 587 to 1200 seconds. Baseline PCF ranged from 0.9 to 1.4 Kdynes, while CEM varied from 1.6 to 5.4 Kdynes/cm2. Normal TGT, PCF and CEM values for asymptomatic controls (mean ± SD, n=25) were 392±100 seconds, 7.8±1.3 Kdynes and 18.8±5.6 Kdynes/cm2 respectively. At the 100% of recommended dose, each of the factor IX agents produced shortening of the TGT, and increases in PCF and CEM. The degree of normalization of these parameters did not appear to depend on the baseline values. The patient with the worst baseline parameters completely normalized his values at 100% doses of BeneFIX® and Mononine®. The patient with the best baseline values also normalized his parameters with BeneFIX® but not with Mononine®. The patient with intermediate baseline abnormalities improved all parameters with both factor IX products but appeared to respond better to BeneFIX® at the 100% dose level. The response to NovoSeven®, at 100% of the dose recommended for treatment of factor VIII inhibitor patients, was detectable but clearly inferior to the response to the factor IX agents. These results indicate significant variability in hemostatic status between factor IX deficient patients both at baseline and in response to factor replacement. While rFVIIa has activity in these patients, the dose previously shown to correct TGT in factor VIII deficient patients may not be appropriate for factor IX deficient patients.
Estrogen Replacement Therapy (ERT) Is Not Associated with an Increased Risk of Leukemia.
Authors: Ross Julie A. , Sinner Penny J. , Blair Cindy K. , Cerhan James R. , Folsom Aaron R.
Published: April 2020

Recent studies have reported an increased risk of breast, endometrial, ovarian, and gall bladder cancer associated with ERT. One proposed mechanism by which ERT increases risk is through the binding of estrogen to receptors at the tissue site. Estrogen receptors are also present on certain hematopoietic cells as well as on myeloid leukemia cells. Further, downregulation of the estrogen receptor through DNA methylation has been associated with increased acute myeloid leukemia (AML) survival. We evaluated whether ERT is associated with an increased risk of leukemia, particularly AML, in the Iowa Women’s Health Study. A cohort of 37,172 post-menopausal Iowa women ages 55 to 69 years with no history of prior cancer was linked annually to the population-based state cancer registry through 2001. In addition to other self-reported cancer risk factors, participants were asked about current and former use of ERT in 1986 and on four subsequent follow-up questionnaires. A total of 201 cases of leukemia were identified over 16 years of follow-up including 64 AMLs and 87 chronic lymphocytic leukemias (CLLs). Compared to never users of ERT at study baseline, current [multivariate relative risk (RR), 1.09; 95% Confidence Interval (CI) 0.70–1.72) and former users (RR=0.81, 95% CI=0.58–1.14) were at no increased risk of developing leukemia. For AML, current users also had no increased risk (RR=0.86, 95% CI=0.39–1.92) and there was a suggestion that former users had a slight decreased risk (RR=0.68, 95% CI=0.38–1.22). For CLL, all results were around unity. Duration of ERT or time-dependent use had no appreciable effect on the RRs. We conclude that ERT use is unlikely to be a risk factor for leukemia, including AML. Supported by NCI R01 CA39741.
Effect of Age on Prognosis in Childhood Acute Myeloid Leukemia.
Authors: Razzouk Bassem I. , Estey Elihu , Pounds Stanley B. , Lensing Shelly , Pierce Sherry , Brandt Mark , Rubnitz Jeffrey E. , Ribeiro Raul C. , Rytting Michael , Pui Ching-Hon , Kantarjian Hagop M. , Jeha Sima C.
Published: April 2020

Age affects the treatment outcome in adults with acute myeloid leukemia (AML) but its effect in pediatric AML is less certain. We reviewed outcome in 423 patients, 21 years of age or younger, who were treated for newly diagnosed AML (excluding acute promyelocytic leukemia) at St. Jude Children’s Research Hospital (n=288) or M.D. Anderson Cancer Center (n=135) between 1983–2002. Patients were divided into those treated between 1983–1989 and 1990–2002. During these two time periods, distinct sets of protocols were used in both institutions, with higher intensity treatment used in the more recent era. After accounting for the effects of cytogenetics, Down syndrome (favorable), increased WBC (unfavorable), FAB type M7 (unfavorable) and early treatment era (unfavorable), every additional year of age conveyed a 4.4 % increase in the risk of death and a 3.3% increase in the risk of any adverse event (death, failure to achieve complete remission, or relapse), with p< 0.001 for the effect of age on survival or event-free survival (EFS). When patients were divided into those above or below the median age (10 years), there was a significant interaction between age and treatment era (p=.05), with patients below 10 having better EFS when treated in the recent era. For patients below 10, the relative risk of an event was 1.6 folds higher in the early treatment era than in the recent era ( p=.016). For patients 10 and older, the improvement in EFS according to treatment era was not significant. Treatment site did not influence the EFS or survival, and the effects of age were similar at both sites. These results suggest that age is an independent prognostic factor in childhood AML with younger children benefiting from more intensive treatment than their older counterparts.
Rapid and Quantitative Detection of Mutations of the FLT3 Gene in AML.
Authors: Gilkes Amanda F. , Walsh Valerie , Sweeney Marion C. , Austin Steven J. , Gale Rosemary E. , Mills Kenneth I.
Published: April 2020

The most common single mutation observed in approximately one-third of AML cases, is an activating mutation of the tyrosine kinase receptor FLT3. The presence of the mutation is associated with adverse prognosis in terms of increased risk of disease relapse. The majority of mutations (25–35% of AML patients) occur as an internal tandem duplication (ITD) within the juxtamembrane region. A further 3–7% of patients have a mutation within the tyrosine kinase domain (TKD) of FLT3. The type of mutation, and its population size, may have prognostic implications. We have used the Agilent 2100 Bioanalyser to assay PCR reactions for the ITD and the TKD mutations. The “chips” used within the Bioanalyser separate RNA or DNA through glass etched micro channels filled with gel matrix, nucleic acid is stained and laser detected. The PCR primers and protocol for the ITD analysis were as previously published (Kottaridis et al. Blood. 98, 2001), but within our laboratory the reactions were analysed on the Bioanalyser using a DNA 500 chip. We detected the presence of an ITD in 19.9% of the 291 AML samples, with percent of mutant RNA varying from 2.9% to 97.5% (median 27%) and with the size of the ITD varying from 15–212 bp (median 41 bp). A separate PCR reaction using primers flanking the TKD domain was used, in combination with an Eco RV or Hinf I (Smith et al, MTAL Workshop, 2003) digestion, to detect and quantitate the different mutations. Distinctive digestion and/or heteroduplex patterns were observed that identified D835, D835del, I836del or D839G mutation. TKD mutations were observed in 12.9% (10.1% D835 mutations, 1.4% I836del, 1.4% D839G) of samples examined, with the mutant RNA ranging from 1.0% to 52.8%. The D835/6 mutation rate was higher than previously reported and may be due to the efficiency and sensitivity of the 2100 Bioanalyser for the analysis of FLT3 mutations. This gave an overall FLT3 mutation rate in the AML population studied of approximately 32.8%; females had a higher overall incidence of 39.1% compared to 27.2% for males. The samples were derived from two NCI trials, AML 14 for patients over 60 years old and AML15 for younger patients. The rate of ITD mutations was 15.3% in AML14 patients compared to 27.5% in AML15, although the incidence of TKD mutations was similar (13.5% v 14.3%). The incidence of ITD mutations was over 45% in patients in the 30–40 year age group at diagnosis. A large percentage of these patients have also been gene expression profiled and the molecular effect of the FLT3 ITD mutations across the age groups has also been examined.
Loss of Heterozygosity in Childhood Acute Lymphoblastic Leukaemia Detected by Genome-Wide Microarray Single Nucleotide Polymorphism Analysis.
Authors: Hall Andrew G. , Bloodworth Lisa C. , Hogarth Linda A. , Bown Nick P. , Irving Julie A.
Published: April 2020

Loss of heterozygosity (LOH) is detectable in many forms of malignancy, including leukaemia, using techniques such as microsatellite analysis and comparative genomic hybridisation. However, these techniques are laborious and require the use of relatively large amounts of DNA if the whole genome is to be examined. Here we describe the use of oligonucleotide microarrays to characterise single nucleotide polymorphisms (SNPs) in lymphoblasts isolated from children with acute lymphoblastic leukaemia for the pan-genomic mapping of LOH with a resolution of 100–200kb. Results were compared with DNA obtained during remission and on relapse. Abnormalities were seen in 8 of 10 cases. The two cases with no abnormalities and one case which showed identical changes affecting whole chromosomes at relapse and presentation remain in remission 1–9 years following retreatment. The 7 cases which showed LOH not affecting entire chromosomes died following relapse, suggesting that partial LOH may be associated with a poor prognosis. In 4 cases LOH was only detectable at relapse suggesting that progressive LOH may be a cause of disease progression and/or drug resistance. This was supported by detailed analysis of one case in which LOH involving the glucocorticoid receptor (GR) was associated with mutation of the remaining allele. In cell line models the loss of a functional GR is associated with profound resistance to steroids. The most frequent abnormality detected in this series involved chromosome 9p. In each of the four cases where this was observed LOH included the INK4 locus. In three of the four cases INK4 loss was only observed at relapse (see figure), suggesting that this abnormality may be commonly associated with treatment failure, supporting previous reports that 9p abnormailities are associated with a poor prognosis. One case was reported as showing monosomy 20 as the sole cytogenetic aberration but LOH analysis identified 9p LOH and loss of 20q, with retention of heterozygocity for 20p. These findings strongly implicate unbalanced translocation der(9)t(9;20),-20 as described by Clark et al (Leukaemia, 2000, 14:241). Our observations demonstrate that SNP array analysis is a powerful new tool for the analysis of allelic imbalance and unbalanced translocations in leukaemic blasts.
Generation of Anti-Leukemia Reactive T-Cells by Costimulation with Established B-ALL Cell Lines Expressing Costimulatory Molecules.
Authors: Yan Ying , Steiherz Peter , Ruan Jianda , Chen Yibang , Abhyankar Sunil , Guan Xiuqin , Williams Casey , Belt Robert , McGuirk Joseph
Published: April 2020

Activated B cells expressing the B7 family of molecules are efficient antigen presenting cells. However, most of B-lineage leukemia cells do not fullfill these criteria, having lost their immunostimulatory potential both in vivo and in vitro. We have established 3 human B-ALL(L3) cell-lines (BA-25, BA-78 and BA91) which in comparison with an established pre-B-ALL cell line (BA-127) and other patients-derived pre-B-ALL blast cells do express the costimulatory molecules CD80 and/or CD86, as well as other critical costimulatory molecules for T-cell stimulation such as: CD40, ICAM-I, LFA-3 and CD72. Flow cytometry analysis demonstrate that these B-ALL cells have an activated B-cell phenotype (CD19+, CD20+, CD22+, CD38+, CD71+, CD75+, DR+, HLA-class-I and HLA-class-II). Chromosomal translocations consistent with B-ALL (L3) were determined in BA-25 [t(2;28)(p12;q24)], BA-78 [t(8;14)(q24,q32)] and BA-91 [t(8;14) (q24,q32)]. No EBV DNA sequence was found in these B-ALL cell lines by Southern blot analysis with a probe for EBV genome. In mixted lymphocyte reaction (MLR) assay, Allogeneic T cells were stimulated by BA-25 and BA-91 cells at a B : T cells ratios of 1/30, 1/100, 1/300 and 1/1000. The BA-25 and BA-91 demonstrated 1-2 logs higher ccpm than the control pre-B-ALL cells (BA-127) which with no expression of B7 family molecules. The dose response curves for the B-cell mixture ratio display a linear pattern between 217-213 log2 ccpm. To determine T cell stimulation potential of the B-ALL cells, we co-cultured allogeneic PBMC with irradiated (3,000 Rad x-ray) BA-25 cells at 30:1 effector/stimulator ratio and achieved a 3–4 fold expansion of T cells after one round 7-day stimulation. Stimulation of allogeneic PBMC with BA-25 elicited proliferation of the T-cells and lysis of BA-25 as an target in a 4h Cr51 release assay, demonstrating BA-25 as an antigen presenting cell. Studies also show that the BA-25 cells could stimulate allo-cytolytic reactions by CTLs against other human leukemic target cells which lack these molecules and fail to stimulate T cell responses by themselves. Thus, BA-25 and other similar lines may prove useful for the provision of costimulatory signal needed to stimulate T-cell response against leukemias lacking these molecules.
Use of Plasma RNA for Real-Time Quantitative RT-PCR to Monitor Imatinib Therapy in Patients with Chronic Myeloid Leukemia.
Authors: Thomazy Vilmos A. , Kantarjian Hagop M. , Imam Maha , Davies Peter J. , Aguilar Christine , Jilani Iman , Cortes Jorge , Giles Francis J. , Albitar Maher
Published: April 2020

Monitoring minimal residual disease (MRD) in chronic myeloid leukemia after imatinib therapy can help in determining therapeutic strategy. Sensitive methods based on the detection of the BCR/ABL fusion gene or its fusion transcript by FISH or RT-PCR, respectively, are used to monitor residual leukemia in peripheral blood or bone marrow cells. While sensitive, these methods require an invasive procedure to obtain bone marrow. The patchy nature of the residual disease may cause some of the reported variation in detecting MRD. We hypothesized that plasma RNA level reflects total body disease and is unaffected by the tendency of some myeloid cells not to circulate. We measured the BCR/ABL fusion transcript by real-time quantitative RT-PCR using RNA isolated from blood plasma. We used a quantitative RT-PCR assay capable of measuring both the b2a2 and b3a2 BCR/ABL fusion transcripts by targeting exon 13 of BCR with the 5′ and exon 2 of ABL by the 3′ primer. RNA isolated from 10–30 μl of frozen plasma was subjected to real-time quantitative RT-PCR using the Taqman technology. Quantification was achieved by extrapolation from a standard curve generated from a ten-fold dilution series of a synthetic oligonucleotide corresponding to the (+) strand of the target sequence. To normalize the fusion mRNA levels we also measured β-actin mRNA from the same samples. Assays were run in duplicate. The results of plasma RT-PCR were correlated with results of conventional cytogenetic analysis, FISH, and quantitative RT-PCR of bone marrow suspension (“bone marrow PCR”). Plasma and bone marrow samples were obtained at 3, 6, 9, 12 and 15 months after imatinib therapy. Ninety-five plasma samples were analyzed. There was a strong positive correlation between the results of plasma RT-PCR vs. positive cytogenetics (n=95, p<0.00001), FISH (n=88, p<0.00001), and bone marrow RT-PCR (n=74, p<0.00001). At 12 months after imatinib therapy all but 2 of the 29 patients were in complete hematologic and cytogenetic remission (CR); one patient was in partial remission (PR) and one in hematologic, but not cytogenetic, remission. These two non-CR patients were positive by both bone marrow and plasma-based RT-PCR assay for the fusion transcript. Three of the four CR patients positive by both plasma and bone marrow PCR at 12 months progressed and converted to PR/minimal response at 15 months post-therapy. The level of plasma BCR/ABL fusion mRNA at 12 months was significantly higher (p=0.04) in these patients than in those who did not progress. Our results show that, by using 10–30 μl of plasma per assay, RT-PCR is at least as sensitive as cytogenetic or FISH analysis of bone marrow cells in monitoring MRD.