115 results on '"Alexander MacDonald"'
Search Results
2. Safety, tolerability, and pharmacokinetics of Aurora kinase B inhibitor AZD2811: a phase 1 dose-finding study in patients with advanced solid tumours
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Melissa L. Johnson, Judy S. Wang, Gerald Falchook, Carol Greenlees, Suzanne Jones, Donald Strickland, Giulia Fabbri, Caroline Kennedy, J. Elizabeth Pease, Liz Sainsbury, Alexander MacDonald, Stein Schalkwijk, Philip Szekeres, Jan Cosaert, and Howard Burris
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Cancer Research ,Oncology - Abstract
Background AZD2811 is a potent, selective Aurora kinase B inhibitor. We report the dose-escalation phase of a first-in-human study assessing nanoparticle-encapsulated AZD2811 in advanced solid tumours. Methods AZD2811 was administered in 12 dose-escalation cohorts (2-h intravenous infusion; 15‒600 mg; 21-/28-day cycles) with granulocyte colony-stimulating factor (G-CSF) at higher doses. The primary objective was determining safety and maximum tolerated/recommended phase 2 dose (RP2D). Results Fifty-one patients received AZD2811. Drug exposure was sustained for several days post-dose. The most common AZD2811-related adverse events (AEs) were fatigue (27.3%) at ≤200 mg/cycle and neutropenia (37.9%) at ≥400 mg/cycle. Five patients had dose-limiting toxicities: grade (G)4 decreased neutrophil count (n = 1, 200 mg; Days 1, 4; 28-day cycle); G4 decreased neutrophil count and G3 stomatitis (n = 1 each, both 400 mg; Day 1; 21-day cycle); G3 febrile neutropenia and G3 fatigue (n = 1 each, both 600 mg; Day 1; 21-day cycle +G-CSF). RP2D was 500 mg; Day 1; 21-day cycle with G-CSF on Day 8. Neutropenia/neutrophil count decrease were on-target AEs. Best overall responses were partial response (n = 1, 2.0%) and stable disease (n = 23, 45.1%). Conclusions At RP2D, AZD2811 was tolerable with G-CSF support. Neutropenia was a pharmacodynamic biomarker. Clinical trial registration NCT02579226.
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- 2023
3. Development of a specialist ileoanal pouch surgery pathway: a multidisciplinary patient-centred approach
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Valerio Celentano, Henna Rafique, Melanie Jerome, Yu Jin Lee, Christos Kontovounisious, Oliver Warren, Alexander MacDonald, Mahmood Wahed, Sarah Mills, and Paris Tekkis
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Hepatology ,Gastroenterology - Abstract
BackgroundRestorative proctocolectomy with ileal pouch–anal anastomosis (IPAA) is the gold standard procedure for ulcerative colitis refractory to medical treatment, as an alternative to permanent end ileostomy. Gaining experience in pouch surgery is difficult as the procedure is performed infrequently. This study presents an institutional initiative to promote standardisation of multidisciplinary care in IPAA surgery.MethodsA dedicated pathway for patients who had an IPAA or are considering IPAA surgery was developed among colorectal surgeons, gastroenterologists, paediatric colorectal surgeons, inflammatory bowel disease (IBD) nurses, dietitians, stoma nurses, trainees in colorectal surgery. Pathway items were discussed and finalised via emails and videoconferences.The pathway included triaging of patients referred for IPAA surgery, preoperative IBD multidisciplinary team discussion and management plan for surgery, surgical review prior to surgery, peer to peer counselling, surgical technique, postoperative short-term and long-term follow-up, audit, research and training in IPAA surgery.ResultsA multidisciplinary preoperative pathway was developed and a stepwise approach to minimally invasive ileoanal pouch surgery was formalised. A dedicated one-stop ileoanal pouch clinic was established integrating endoscopy and imaging on the same day of the consultation with the surgical and gastroenterology team. The clinic reviewed 72 patients over 24 months, and during the same time 36 patients underwent IPAA surgery at our institution.ConclusionsWe have described our initial experience in establishing a specialist IPAA surgery pathway and have proposed outcome measures that we hope will support a subspecialty IPAA service.
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- 2022
4. Social Interpersonal Relationship Attitudes Toward Cisgender and Transgender Peers Among Cisgender Heterosexual University Students in Taiwan
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Te-Sheng Chang, Chakree Kerdsomboon, and Alexander MacDonald Haynes
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Cultural Studies ,Gender Studies - Published
- 2023
5. Keep it Real: Investigating Driver-Cyclist Interaction in Real-World Traffic
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Ammar Al-Taie, Yasmeen Abdrabou, Shaun Alexander Macdonald, Frank Pollick, and Stephen Anthony Brewster
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- 2023
6. Sex and hypertensive organ damage: stroke
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Jesse Dawson and Alexander MacDonald
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Stroke is a common cause of death and disability in both men and women. Differences in the incidence, presenting features and outcome after stroke have been reported between men and women. The global lifetime risk of stroke of approximately 25% is similar in men and women, although in women, the first cardiovascular event is more likely to be stroke than in men. Concerningly, there are reports of underuse of some treatments in women, although these differences may be diminishing over time. In addition, there are specific clinical challenges that can arise in women with stroke, such as stroke in people taking hormonal therapy, and stroke during pregnancy and stroke in the post-partum period. This review will cover these areas highlighting important differences and areas for future research. We found there are important differences in incidence of stroke, which differ by age. Further, there is concerning evidence that some treatments such as intravenous thrombolysis are underused in women. While there may be some differences in the relative effectiveness of treatments such as antiplatelet therapy and blood pressure reduction between men and women, for most aspects of stroke care, benefit is clear in both men and women and the emphasis must be on more equitable access. There is limited evidence to inform decision making during pregnancy and the post-partum period, but guidelines now exist and further research is needed in these areas.
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- 2023
7. Conducting and Mitigating Portable Thermal Imaging Attacks on User Authentication using AI-driven Methods
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Shaun Alexander Macdonald, Norah Mohsen T Alotaibi, Md Shafiqul Islam, and Mohamed Khamis
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- 2023
8. SARS-CoV-2 Aptasensors Based on Electrochemical Impedance Spectroscopy and Low-Cost Gold Electrode Substrates
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Perrine Lasserre, Banushan Balansethupathy, Vincent J. Vezza, Adrian Butterworth, Alexander Macdonald, Ewen O. Blair, Liam McAteer, Stuart Hannah, Andrew C. Ward, Paul A. Hoskisson, Alistair Longmuir, Steven Setford, Eoghan C. W. Farmer, Michael E. Murphy, Harriet Flynn, and Damion K. Corrigan
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SARS-CoV-2 ,Dielectric Spectroscopy ,Spike Glycoprotein, Coronavirus ,COVID-19 ,Humans ,RNA, Viral ,QD ,Electrodes ,Sensitivity and Specificity ,Article ,Analytical Chemistry - Abstract
SARS-CoV-2 diagnostic practices broadly involve either quantitative polymerase chain reaction (qPCR)-based nucleic amplification of viral sequences or antigen-based tests such as lateral flow assays (LFAs). Reverse transcriptase-qPCR can detect viral RNA and is the gold standard for sensitivity. However, the technique is time-consuming and requires expensive laboratory infrastructure and trained staff. LFAs are lower in cost and near real time, and because they are antigen-based, they have the potential to provide a more accurate indication of a disease state. However, LFAs are reported to have low real-world sensitivity and in most cases are only qualitative. Here, an antigen-based electrochemical aptamer sensor is presented, which has the potential to address some of these shortfalls. An aptamer, raised to the SARS-CoV-2 spike protein, was immobilized on a low-cost gold-coated polyester substrate adapted from the blood glucose testing industry. Clinically relevant detection levels for SARS-CoV-2 are achieved in a simple, label-free measurement format using sample incubation times as short as 15 min on nasopharyngeal swab samples. This assay can readily be optimized for mass manufacture and is compatible with a low-cost meter.
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- 2022
9. A comparative study of university students’ ‘English as medium of instruction’ experiences in international faculty-led classrooms in Taiwan and Thailand
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Te-Sheng Chang, Alexander MacDonald Haynes, Jittinun Boonsathirakul, and Chakree Kerdsomboon
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Education - Published
- 2022
10. The Impact of Thermal Cues on Affective Responses to Emotionally Resonant Vibrations
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Shaun Alexander Macdonald, Stephen Brewster, and Frank Pollick
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- 2022
11. Venus Exploration in the New Human Spaceflight Age
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Alexander Macdonald, Kirby Runyon, Ralph L. McNutt, Paul K. Byrne, and Noam R. Izenberg
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020301 aerospace & aeronautics ,Engineering ,Spacecraft ,biology ,business.industry ,Human spaceflight ,Aerospace Engineering ,Venus ,02 engineering and technology ,Mars Exploration Program ,biology.organism_classification ,Exploration of Mars ,01 natural sciences ,Observations and explorations of Venus ,Astrobiology ,Planetary science ,0203 mechanical engineering ,Planet ,0103 physical sciences ,business ,010303 astronomy & astrophysics - Abstract
An often-overlooked aspect of human missions to Mars is that the optimal path to the Red Planet could include a flyby of Venus. As part of so-called opposition missions, a crewed spacecraft would, after departing Earth, approach Venus en route to Mars. Such Venus flybys would offer unique opportunities to practice deep-space human operations during phases of flight for which a direct return to Earth would be a viable abort option. Indeed, crewed flyby missions to Venus provide a basis for longer-duration human spaceflight activities before committing to longer-duration and lower-launch-cadence missions solely to Mars. During Venus flybys, astronauts bound for Mars could carry out opportunistic “human-in-the-loop” scientific activities, such as controlling an aerial platform or directing in situ sampling by a landed spacecraft for much lower cost than a dedicated crewed mission to Venus. An independent crewed Venus flyby could also serve as a useful systems demonstration mission prior to a first human mission to Mars. With a renewed focus on landing humans on Mars in the 2030s and the formidable challenges still ahead for safe and successful long-duration human spaceflight, the time to consider incorporating Venus on the path to Mars is now.
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- 2021
12. Contributors
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Kate Anderson, Rahul D. Barmanray, Alison Beauchamp, Dario Boschiero, Sharon L. Brennan-Olsen, Cathleen Colón-Emeric, Natanael Perez Cordero, Selma Cvijetic, Andrea L. Darling, Larry Dian, Rachel L. Duckham, Gustavo Duque, Joshua N. Farr, Jack Feehan, Sadanand Fulzele, Ali Ghasem-Zadeh, Jennifer C. Gilman, Ebrahim Bani Hassan, William D. Hill, Eisuke Hiruma, Yushu Huang, Jasminka Z. Ilich, Mahdi Imani, David Karasik, Japneet Kaur, Owen J. Kelly, Iryna Khrystoforova, Peter Lee, Sean X. Leng, Yukang Li, Ching-Ti Liu, Brian Alexander MacDonald, Fatemeh Malekipour, Hossein Mokhtarzadeh, Ahmed M. Negm, Jordan O’Connor, Alexandra Papaioannou, Naaz Parmar, Patricia V. Schoenlein, Kenneth Ladd Seldeen, Neema Sharda, Charikleia Stefanaki, Bruce Robert Troen, Debra L. Waters, and Christopher J. Yates
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- 2022
13. Frailty: The end of the osteosarcopenia continuum?
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Kenneth Ladd Seldeen, Brian Alexander MacDonald, and Bruce Robert Troen
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- 2022
14. On-chip recapitulation of clinical bone-marrow toxicities and patient-specific pathophysiology
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Petar Pop-Damkov, Rhiannon David, Arianna Rech, Lucy R. O’Sullivan, Susan Marquez, Brooke A. Furlong, Douglas Ferguson, Kasiani C. Myers, Amanda Jiang, Liliana Moreira Teixeira, Oren Levy, Youngjae Choe, Özge Vargel Bölükbaşı, David B. Chou, Richard M. Novak, Olga K. Weinberg, Carl D. Novina, Robert P. Hasserjian, Lorna Ewart, Yuka Milton, Cailin E. Joyce, Viktoras Frismantas, Elizabeth Calamari, Sasan Jalili-Firoozinezhad, Rachelle Prantil-Baun, Donald E. Ingber, Alexander MacDonald, Akiko Shimamura, and Carlos F. Ng
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0301 basic medicine ,Stromal cell ,business.industry ,Cell growth ,Cellular differentiation ,Mesenchymal stem cell ,Biomedical Engineering ,CD34 ,Medicine (miscellaneous) ,Bioengineering ,Article ,Computer Science Applications ,Blood cell ,03 medical and health sciences ,Haematopoiesis ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Cancer research ,Medicine ,Bone marrow ,business ,030217 neurology & neurosurgery ,Biotechnology - Abstract
The inaccessibility of living bone marrow (BM) hampers the study of its pathophysiology under myelotoxic stress induced by drugs, radiation or genetic mutations. Here, we show that a vascularized human BM-on-a-chip (BM chip) supports the differentiation and maturation of multiple blood cell lineages over 4 weeks while improving CD34+ cell maintenance, and that it recapitulates aspects of BM injury, including myeloerythroid toxicity after clinically relevant exposures to chemotherapeutic drugs and ionizing radiation, as well as BM recovery after drug-induced myelosuppression. The chip comprises a fluidic channel filled with a fibrin gel in which CD34+ cells and BM-derived stromal cells are co-cultured, a parallel channel lined by human vascular endothelium and perfused with culture medium, and a porous membrane separating the two channels. We also show that BM chips containing cells from patients with the rare genetic disorder Shwachman–Diamond syndrome reproduced key haematopoietic defects and led to the discovery of a neutrophil maturation abnormality. As an in vitro model of haematopoietic dysfunction, the BM chip may serve as a human-specific alternative to animal testing for the study of BM pathophysiology. A vascularized human bone-marrow-on-a-chip improves the maintenance of patient-derived CD34+ cells, and recapitulates clinically relevant aspects of bone marrow injury as well as key haematopoietic defects of patients with a rare genetic disorder.
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- 2020
15. User Preferences for Calming Affective Haptic Stimuli in Social Settings
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Frank E. Pollick, Euan Freeman, Shaun Alexander Macdonald, and Stephen Brewster
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Computer science ,Affective haptics ,Social anxiety ,Thematic analysis ,Coding (social sciences) ,Haptic technology ,Personalization ,Cognitive psychology - Abstract
This paper presents a survey informing a user-first approach to designing calming affective haptic stimuli by eliciting user preferences in different social scenarios. Prior affective haptics research presented users with stimuli and recorded emotional responses. By contrast this work focuses on the sensations users wish to experience and how these can be simulated using haptics. The survey (n=81) investigated which users preferences in four social situations to reduce social anxiety. Using thematic analysis of responses we created a coding scheme of stimuli derived from real-world experiences to emulate with affective haptics. By cross-referencing these categories with affective haptics research, we provide recommendations to designers about which calming stimuli users wish to experience socially and how they can be implemented.
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- 2021
16. A SARS-CoV-2 aptasensor based on electrochemical impedance spectroscopy and low-cost gold electrode substrates
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Eoghan C. W. Farmer, Stuart Hannah, Steven Setford, Michael E. Murphy, Alexander MacDonald, Ewen O. Blair, Harriet Flynn, Andrew C. Ward, Paul A. Hoskisson, Adrian Butterworth, Banushan Balansethupathy, Alistair Longmuir, Damion K. Corrigan, Perrine Lasserre, Liam McAteer, and Vincent Vezza
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Reproducibility ,Materials science ,medicine.diagnostic_test ,Aptamer ,Electrode ,medicine ,Glucose test ,Nanotechnology ,Sensitivity (control systems) ,Biosensor ,Dielectric spectroscopy ,Point of care - Abstract
SARS-CoV-2 diagnostic practices broadly involve either qPCR based nucleic amplification or lateral flow assays (LFAs). qPCR based techniques suffer from the disadvantage of requiring thermal cycling (difficult to implement for low-cost field use) leading to limitation on sample to answer time, the potential to amplify viral RNA sequences after a person is no longer infectious and being reagent intense. LFA performance is restricted by qualitative or semi-quantitative readouts, limits on sensitivity and poor reproducibility. Electrochemical biosensors, and particularly glucose test strips, present an appealing platform for development of biosensing solutions for SARS-CoV-2 as they can be multiplexed and implemented at very low cost at point of use with high sensitivity and quantitative digital readout. This work reports the successful raising of an Opti-mer sequence for the spike protein of SARS-CoV-2 and then development of an impedimetric biosensor which utilises thin film gold sensors on low-cost laminate substrates from home blood glucose monitoring. Clinically relevant detection levels for SARS-CoV-2 are achieved in a simple, label-free measurement format using sample incubation times of 15 minutes. The biosensor developed here is compatible with mass manufacture, is sensitive and low-cost CE marked readout instruments already exist. These findings pave the way to a low cost and mass manufacturable test with the potential to overcome the limitations associated with current technologies.
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- 2021
17. Chloride channel inhibition improves neuromuscular function under conditions mimicking neuromuscular disorders
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Ole Bækgaard Nielsen, Osk Halldorsdottir, Martin Broch-Lips, William Alexander Macdonald, and Thomas Holm Pedersen
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0301 basic medicine ,medicine.medical_specialty ,Physiology ,neuromuscular transmission disorders ,Neuromuscular transmission ,Neuromuscular Junction ,030204 cardiovascular system & hematology ,Synaptic Transmission ,Membrane Potentials ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Chloride Channels ,ClC-1 Cl channels ,Internal medicine ,muscle contractions ,medicine ,Extracellular ,Animals ,Membrane potential ,Chemistry ,Skeletal muscle ,medicine.disease ,Acetylcholinesterase ,Myasthenia gravis ,Neostigmine ,Rats ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Chloride channel ,medicine.drug - Abstract
Aim: The skeletal muscle Cl− channels, the ClC-1 channels, stabilize the resting membrane potential and dampen muscle fibre excitability. This study explored whether ClC-1 inhibition can recover nerve-stimulated force in isolated muscle under conditions of compromised neuromuscular transmission akin to disorders of myasthenia gravis and Lambert–Eaton syndrome. Methods: Nerve-muscle preparations were isolated from rats. Preparations were exposed to pre-or post-synaptic inhibitors (ω-agatoxin, elevated extracellular Mg2+, α-bungarotoxin or tubocurarine). The potential of ClC-1 inhibition (9-AC or reduced extracellular Cl−) to recover nerve-stimulated force under these conditions was assessed. Results: ClC-1 inhibition recovered force in both slow-twitch soleus and fast-twitch EDL muscles exposed to 0.2 µmol/L tubocurarine or 3.5 mmol/L Mg2+. Similarly, ClC-1 inhibition recovered force in soleus muscles exposed to α-bungarotoxin or ω-agatoxin. Moreover, the concentrations of tubocurarine and Mg2+ required for reducing force to 50% rose from 0.14 ± 0.02 µmol/L and 4.2 ± 0.2 mmol/L in control muscles to 0.45 ± 0.03 µmol/L and 4.7 ± 0.3 mmol/L in muscles with 9-AC respectively (P + channels (4-AP) relieve symptoms in myasthenia gravis and Lambert–Eaton syndrome, respectively. Neostigmine and 9-AC additively increased the tubocurarine concentration required to reduce nerve-stimulated force to 50% (0.56 ± 0.05 µmol/L with 9-AC and neostigmine) and, similarly, 4-AP and 9-AC additively increased the Mg2+ concentration required to reduce nerve-stimulated force to 50% (6.5 ± 0.2 mmol/L with 9-AC and 4-AP). Conclusion: This study shows that ClC-1 inhibition can improve neuromuscular function in pharmacological models of compromised neuromuscular transmission.
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- 2021
18. Enhancing student creativity through an interdisciplinary, project-oriented problem-based learning undergraduate curriculum
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Te-Sheng Chang, Hung-Che Wang, Alexander MacDonald Haynes, Mei-Mei Song, Shih-Yao Lai, and Shang-Hsien Hsieh
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Education - Published
- 2022
19. Population pharmacokinetic and exposure-response analyses to support fixed dosing of tezepelumab in patients with severe asthma
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Åsa Hellqvist, Yuying Gao, Alexander Macdonald, Karin Bowen, Yanan Zheng, Ye Guan, Lu Liu, Lubna Abuqayyas, and Gene L. Colice
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medicine.medical_specialty ,education.field_of_study ,Pharmacokinetics ,business.industry ,Internal medicine ,Severe asthma ,Population ,medicine ,In patient ,Dosing ,business ,education ,Exposure response - Published
- 2021
20. A phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies
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Ian W. Flinn, Andre Goy, Kathleen A. Burke, Raquel Izumi, Barrett Nuttall, Amelia Raymond, Brandon Willis, Julie M. Vose, J. Elizabeth Pease, Dan Stetson, Brian Dougherty, David Cunningham, Tracy Clevenger, Jean Cheung, Lin Tao, Christopher P. Fox, Anusha Vallurupalli, Elizabeth A. Harrington, Buyue Yang, Stein Schalkwijk, Melanie M. Frigault, Grzegorz S. Nowakowski, Alexander MacDonald, John G. Gribben, Ahmed Hamdy, Mark Roschewski, Larissa S. Carnevalli, and Graham P. Collins
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Cancer Research ,Morpholines ,mTORC1 ,Refractory ,Pharmacokinetics ,medicine ,Bruton's tyrosine kinase ,Humans ,Protein Kinase Inhibitors ,B cell ,B-Lymphocytes ,biology ,business.industry ,Hematology ,medicine.disease ,Lymphoma ,medicine.anatomical_structure ,Pyrimidines ,Oncology ,Pharmacodynamics ,Pyrazines ,Benzamides ,biology.protein ,Cancer research ,Acalabrutinib ,Neoplasm Recurrence, Local ,business - Abstract
In a phase 1b study of acalabrutinib (a covalent Bruton tyrosine kinase (BTK) inhibitor) in combination with vistusertib (a dual mTORC1/2 inhibitor) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), multiple ascending doses of the combination as intermittent or continuous schedules of vistusertib were evaluated. The overall response rate was 12% (3/25). The pharmacodynamic (PD) profile for acalabrutinib showed that BTK occupancy in all patients was >95%. In contrast, PD analysis for vistusertib showed variable inhibition of phosphorylated 4EBP1 (p4EBP1) without modulation of AKT phosphorylation (pAKT). The pharmacokinetic (PK)/PD relationship of vistusertib was direct for TORC1 inhibition (p4EBP1) but did not correlate with TORC2 inhibition (pAKT). Cell-of-origin subtyping or next-generation sequencing did not identify a subset of DLBCL patients with clinical benefit; however, circulating tumor DNA dynamics correlated with radiographic response. These data suggest that vistusertib does not modulate targets sufficiently to add to the clinical activity of acalabrutinib monotherapy. Clinicaltrials.gov identifier: NCT03205046.
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- 2021
21. Intussusception in 2 Children With Severe Acute Respiratory Syndrome Coronavirus-2 Infection
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Jonathan Bretherton, Elizabeth Eyre, Mathew Jobson, Alexander MacDonald, Xiaoxia Lu, Tariq Mehmood, Amulya Kumar Saxena, Adelene Wong, Lorna Pakkiri, Susan Wallace, Furong Zhang, Gary Wong, Jianbo Shao, and Heidi Makrinioti
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2019-20 coronavirus outbreak ,Pediatrics ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,medicine.medical_treatment ,General Medicine ,Enema ,medicine.disease ,medicine.disease_cause ,digestive system diseases ,03 medical and health sciences ,0302 clinical medicine ,Infectious Diseases ,030225 pediatrics ,Intussusception (medical disorder) ,Pediatrics, Perinatology and Child Health ,Medicine ,Pediatrics, Perinatology, and Child Health ,030212 general & internal medicine ,Respiratory system ,business ,Coronavirus Infections ,Coronavirus - Abstract
We note that intussusception was likely associated with severe acute respiratory syndrome coronavirus-2 infection in 2 infants in Wuhan and London. The intussusception was reduced by enemas in Wuhan; the outcome was fatal. The intussusception was not reduced by enemas in London and required surgery; the outcome was favorable.
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- 2020
22. Phase I study of orally administered 14Carbon-isotope labelled-vistusertib (AZD2014), a dual TORC1/2 kinase inhibitor, to assess the absorption, metabolism, excretion, and pharmacokinetics in patients with advanced solid malignancies
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Tinnu Sarvotham, Julie Charlton, Graeme Scarfe, Wolfram Brugger, Alexander MacDonald, Dominic Magirr, and Emma Dean
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0301 basic medicine ,Pharmacology ,Cancer Research ,Saliva ,business.industry ,Urine ,Toxicology ,medicine.disease ,Bioavailability ,Excretion ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Pharmacokinetics ,030220 oncology & carcinogenesis ,Medicine ,Pharmacology (medical) ,business ,Adverse effect ,Stomatitis ,ADME - Abstract
Vistusertib is an orally bioavailable dual target of rapamycin complex (TORC) 1/2 kinase inhibitor currently under clinical investigation in various solid tumour and haematological malignancy settings. The pharmacokinetic, metabolic and excretion profiles of 14Carbon-isotope (14C)-labelled vistusertib were characterised in this open-label phase I patient study. Four patients with advanced solid malignancies received a single oral solution dose of 14C-labelled vistusertib. Blood, urine, faeces, and saliva samples were collected at various time points during the 8-day in-patient period of the study. Safety and preliminary efficacy were also assessed. 14C-labelled vistusertib was rapidly absorbed following administration (time to maximum concentration (Tmax) 90% of radioactivity was recovered with the majority recovered as metabolites in faeces (on average 80% vs. 12% recovered in urine). The majority of circulating radioactivity (~ 78%) is unchanged vistusertib. Various morpholine-ring oxidation metabolites and an N-methylamide circulate at low concentrations [each
- Published
- 2019
23. Target engagement and cellular fate of otelixizumab: a repeat dose escalation study of an anti‐CD3ε mAb in new‐onset type 1 diabetes mellitus patients
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Ruth M Barnard, David Inman, Kevin R. Page, Bart Keymeulen, Quentin Leirens, Alexander MacDonald, Antonella Napolitano, Kim Brown, David Lanham, Jonathan Bullman, Minesh Patel, André van Maurik, Enrica Mezzalana, Caroline O. S. Savage, Georgios Vlasakakis, Stefano Zamuner, Pathology/molecular and cellular medicine, Diabetes Pathology & Therapy, and Diabetes Clinic
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Adult ,Male ,Adolescent ,CD3 Complex ,type 1 diabetes ,T-Lymphocytes ,Receptors, Antigen, T-Cell ,Pharmacology ,Antibodies, Monoclonal, Humanized ,030226 pharmacology & pharmacy ,Otelixizumab ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,medicine ,immunoinflammation ,Humans ,Pharmacology (medical) ,Molecular Targeted Therapy ,030212 general & internal medicine ,Dosing ,Infusions, Intravenous ,PK/PD models ,Type 1 diabetes ,Dose-Response Relationship, Drug ,target engagement ,business.industry ,T-cell receptor ,PK/PD ,Original Articles ,medicine.disease ,Clinical trial ,Diabetes Mellitus, Type 1 ,Treatment Outcome ,Pharmacodynamics ,Female ,dose–response ,business ,medicine.drug - Abstract
Aims This paper describes the pharmacological findings from a study where otelixizumab, an anti-CD3ɛ mAb, was dosed in new onset Type 1 diabetes mellitus (NOT1DM) patients. This is the first time that the full dose-response of an anti-CD3ɛ mAb has been investigated in the clinic. The data have been validated using a previously developed pharmacokinetic/pharmacodynamic (PK/PD) model of otelixizumab to simulate the interplay between drug administration, CD3ɛ target engagement and downmodulation. Methods Patients were randomized to control or active treatment with otelixizumab (1:4), administered via infusion over 6 days, in a dose-ascending study consisted of three cohorts (n = 10 per cohort) at doses of 9, 18 or 27 mg respectively. The study allowed quantification of otelixizumab PK, CD3ɛ target engagement and its pharmacodynamic effect (CD3e/TCR modulation on circulating T lymphocytes). Results Otelixizumab concentrations increased and averaged to 364.09 (54.3), 1625.55 (72.5) and 2781.35 (28.0) ng ml-1 (Geom.mean, %CV) at the 9, 18 and 27 mg dose respectively. CD3ɛ target engagement was found to be rapid (within the first 30 min), leading to a receptor occupancy of ~60% within 6 h of dosing in all three doses. A dose-response relationship was observed with the two highest doses achieving a ~90% target engagement and consequential CD3ɛ/TCR downmodulation by Day 6. Conclusions Data from this study revealed maximum target engagement and CD3ɛ/TCR modulation is achieved at doses of 18, 27 mg of otelixizumab. These findings can be useful in guiding dose selection in clinical trials with anti-CD3ɛ mAbs.
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- 2019
24. A Comparison of Trace Gas Trends in Urban Areas Collected via Whole Air Sampling during the COVID-19 Pandemic
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Elena Press, Melissa Yang, John Carlson, Donald R. Blake, Morgan Schachterle, Joseph Palmo, Dominick Ryan, Brent Love, Walker Demel, Gloria Weitz, Gabriela Vidad, Emily Schaller, Joseph Bennett, Katey Dong, Barry Lefer, Patrick R. Sullivan, An Li, Scarlet Passer, Joel Been, Ryan Stauffer, Maya Zimmerman, Graham Trolley, James Flynn, Kendra Herweck, Raphael M. Kudela, McKenna Price-Patak, Jessica Kasamoto, Alexander MacDonald, Barbara Chisholm, Alex Jarnot, Mackenzie Conkling, Nathan Pappalardo, Sergio Alvarez, MacKenzie Warner, Amanda Rodell, Andreas Beyersdorf, Paola Granados, Barbara Barletta, Amelia Hurst, Jordan Zachmann, Everett Rzeszowski, Jacob Schenthal, Roya Bahreini, Ariana Deegan, J. Bausell, Jack Kaye, Hal Maring, David Moore, Travis Griggs, Dar A. Roberts, Simone Meinardi, Tatiana Jimenez, and Nicole Taylor
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Air sampling ,Coronavirus disease 2019 (COVID-19) ,Industrial production ,Pandemic ,Environmental engineering ,Environmental science ,Trace gas - Abstract
COVID-19’s impact on society and our daily habits has been unprecedented. With a decrease in vehicular traffic and industrial production, a decrease in local emissions was expected to occur. In ord...
- Published
- 2021
25. NASA Student Airborne Research Program (SARP) Whole Air Sampling across the United States during the COVID-19 Pandemic
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Melissa Yang, Donald Blake, Alex Jarnot, Simone Meinardi, Gloria Weitz, Brent Love, Barbara Barletta, Barbara Chisholm, James Flynn, Sergio Alvarez, Travis Griggs, Maya Zimmerman, Jordan Zachmann, MacKenzie Warner, Gabriela Vidad, Graham Trolley, Jacob Schenthal, Morgan Schachterle, Everett Rzeszowski, Dominick Ryan, Amanda Rodell, McKenna Price-Patak, Elena Press, Scarlet Passer, Nathan Pappalardo, Joseph Palmo, David Moore, An Li, Jessica Kasamoto, Tatiana Jimenez, Amelia Hurst, Kendra Herweck, Paola Granados, Katey Dong, Walker Demel, Ariana Deegan, Mackenzie Conkling, John Carlson, Joel Been, Nicole Taylor, Patrick Sullivan, Alexander MacDonald, Jesse Bausell, Dar Roberts, Raphael Kudela, Andreas Beyersdorf, Roya Bahreini, Barry Lefer, Jack Kaye, Hal Maring, Ryan Stauffer, Joseph Bennett, and Emily Schaller
- Published
- 2021
26. An electrochemical SARS-CoV-2 biosensor inspired by glucose test strip manufacturing processes
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Eoghan C. W. Farmer, Ewen O. Blair, Vincent Vezza, Alexander MacDonald, Paul A. Hoskisson, Alistair Longmuir, Michael E. Murphy, Stuart Hannah, Damion K. Corrigan, Steven Setford, Christopher Rinaldi, Andrew C. Ward, Adrian Butterworth, and Perrine Lasserre
- Subjects
2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,02 engineering and technology ,Biosensing Techniques ,010402 general chemistry ,01 natural sciences ,Catalysis ,COVID-19 Testing ,Limit of Detection ,TA164 ,Materials Chemistry ,medicine ,Glucose test ,Humans ,QD ,Electrodes ,ACE2 enzyme ,Fluorocarbons ,medicine.diagnostic_test ,SARS-CoV-2 ,Metals and Alloys ,Diagnostic test ,COVID-19 ,General Chemistry ,Electrochemical Techniques ,021001 nanoscience & nanotechnology ,Enzymes, Immobilized ,0104 chemical sciences ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Spike Glycoprotein, Coronavirus ,Ceramics and Composites ,Biochemical engineering ,Angiotensin-Converting Enzyme 2 ,Gold ,0210 nano-technology ,Biosensor - Abstract
Accurate and rapid diagnostic tests are critical to reducing the impact of SARS-CoV-2. This study presents early, but promising measurements of SARS-CoV-2 using the ACE2 enzyme as the recognition element to achieve clinically relevant detection. The test provides a scalable route to sensitive, specific, rapid and low cost mass testing.
- Published
- 2021
27. Contextual Textualism: How Legislative History Can Restrain Judges, Revitalize Congress, and Restore the Conservative Legal Movement
- Author
-
Alexander MacDonald
- Subjects
Statute ,Power (social and political) ,Law ,Political science ,Legislative history ,Policy objectives ,Context (language use) ,Federal policy - Abstract
In recent decades, Congress has steadily ceded power to the federal judiciary. The judiciary, not Congress, is often left to make important choices about federal policy, in part because Congress leaves it with too little guidance about its policy objectives. The problem has been exacerbated by textualism, which disregards extra-textual clues about Congress's intent. This paper argues that Congress can ameliorate the problem by adopting a Legislative History Act. The Act would direct judges to interpret statutes according to Congress's intent, as expressed in specified legislative-history materials. That direction would give textualist judges a textual hook to consider a much broader range of materials than they consider today. They would have more context for interpreting statutes, and would thus more often adopt interpretations in line with Congress's policy goals.
- Published
- 2021
28. An uncomplicated electrochemical sensor combining a perfluorocarbon SAM and ACE2 as the bio-recognition element to sensitively and specifically detect SARS-CoV-2 in complex samples
- Author
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Steven Setford, Christopher Rinaldi, Alexander MacDonald, Michael E. Murphy, Andrew C. Ward, Adrian Butterworth, Vincent Vezza, Alistair Longmuir, Ewen O. Blair, Damion K. Corrigan, Paul A. Hoskisson, Stuart Hannah, and Perrine Lasserre
- Subjects
Detection limit ,education.field_of_study ,Chromatography ,Chemistry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Population ,Spike Protein ,Virus ,Electrochemical gas sensor ,law.invention ,Test strips ,law ,Recombinant DNA ,education - Abstract
Emerging in late 2019, the SARS-CoV-2 virus has had a devastating health and economic effects around the world forcing governments to enact restrictions on day to day life, resulting in severe economic and social disruption. The virus has stimulated new research in the fields of drug development, vaccinology and diagnostic testing. Here we present the basis for a simple, mass manufacturable saliva based electrochemical assay for the SARS-CoV-2 virus acheived through adsorption of the Angiotsnsin Converting Enzyme 2 (ACE2) into thiolated amphiphobic prefluoro monolayer assemled on a gold sensor surface. Following sensor preparation, it is possible to measure specific binding of recombinant spike protein and discriminate positive and negative samples of inactivated SARS-CoV-2 following 30 minutes incubation under ambient conditions. Representative calculations of limits of detection are made for recombinant spike protein (1.68 ng/ml) and inactivated virus (37.8 dC/mL). The assay as presented ultimately shows discrimination between positive and negative inactivated SARS-CoV-2 samples originating from clinical molecular standards kit intended for clinical and biomedical assay validation, and which is designed to mimic clinical samples through presence of cells and proteins in the sample medium. The simple design of the label free measurement and the selection of reagents involved means the assay has clear potential for transfer onto mass producible units such as screen-printed electrodes similar to glucose-format test strips, to enable widespread, low cost and rapid testing for SARS-CoV-2 in the general population
- Published
- 2020
29. Eliciting Emotion with Vibrotactile Stimuli Evocative of Real-World Sensations
- Author
-
Shaun Alexander Macdonald, Stephen Brewster, and Frank E. Pollick
- Subjects
Vibrotactile stimulus ,medicine.medical_specialty ,Computer science ,Sensation ,medicine ,Audiology ,Association (psychology) ,Affective response - Abstract
This paper describes a novel category of affective vibrotactile stimuli which evoke real-world sensations and details a study into emotional responses to them. The affective properties of short and abstract vibrotactile waveforms have previously been studied and shown to have a narrow emotional range. By contrast this paper investigated emotional responses to longer waveforms and to emotionally resonant vibrotactile stimuli, stimuli which are evocative of real-world sensations such as animal purring or running water. Two studies were conducted. The first recorded emotional responses to Tactons with a duration of 20 seconds. The second investigated emotional responses to novel emotionally resonant stimuli. Stimuli that users found more emotionally resonant were more pleasant, particularly if they had prior emotional connections to the sensation represented. Results suggest that future designers could use emotional resonance to expand the affective response range of vibrotactile cues by utilising stimuli with which users bear an emotional association.
- Published
- 2020
30. Vitamin D Insufficiency Reduces Grip Strength, Grip Endurance and Increases Frailty in Aged C57Bl/6J Mice
- Author
-
Reem Nagi Berman, Brian Alexander MacDonald, Kenneth L. Seldeen, Ramkumar Thiyagarajan, Bruce R. Troen, Manhui Pang, Ginger Lasky, Carleara Weiss, and Yonas Redae
- Subjects
0301 basic medicine ,cholecalciferol ,medicine.medical_specialty ,Bone density ,Parathyroid hormone ,Nutritional Status ,030209 endocrinology & metabolism ,lcsh:TX341-641 ,frailty ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Grip strength ,Mice ,0302 clinical medicine ,Internal medicine ,medicine ,Vitamin D and neurology ,Animals ,parathyroid hormone ,Treadmill ,Vitamin D ,body composition ,Nutrition and Dietetics ,Hand Strength ,business.industry ,aging ,bone density ,physical performance ,Physical Functional Performance ,Vitamin D Deficiency ,Mice, Inbred C57BL ,Disease Models, Animal ,25-OH vitamin D ,030104 developmental biology ,Endocrinology ,chemistry ,Dietary Supplements ,Lean body mass ,Physical Endurance ,Cholecalciferol ,business ,Anaerobic exercise ,lcsh:Nutrition. Foods and food supply ,Food Science - Abstract
Low 25-OH serum vitamin D (VitD) is pervasive in older adults and linked to functional decline and progression of frailty. We have previously shown that chronic VitD insufficiency in “middle-aged” mice results in impaired anaerobic exercise capacity, decreased lean mass, and increased adiposity. Here, we examine if VitD insufficiency results in similar deficits and greater frailty progression in old-aged (24 to 28 months of age) mice. Similar to what we report in younger mice, older mice exhibit a rapid and sustained response in serum 25-OH VitD levels to differential supplementation, including insufficient (125 IU/kg chow), sufficient (1000 IU/kg chow), and hypersufficient (8000 IU/kg chow) groups. During the 4-month time course, mice were assessed for body composition (DEXA), physical performance, and frailty using a Fried physical phenotype-based assessment tool. The 125 IU mice exhibited worse grip strength (p = 0.002) and inverted grip hang time (p = 0.003) at endpoint and the 8000 IU mice transiently displayed greater rotarod performance after 3 months (p = 0.012), yet other aspects including treadmill performance and gait speed were unaffected. However, 125 and 1000 IU mice exhibited greater frailty compared to baseline (p = 0.001 and p = 0.038, respectively), whereas 8000 IU mice did not (p = 0.341). These data indicate targeting higher serum 25-OH vitamin D levels may attenuate frailty progression during aging.
- Published
- 2020
31. A Randomized, Open-label, Presurgical, Window-of-Opportunity Study Comparing the Pharmacodynamic Effects of the Novel Oral SERD AZD9496 with Fulvestrant in Patients with Newly Diagnosed ER+ HER2- Primary Breast Cancer
- Author
-
Michele Moschetta, Abigail Evans, S. Henschen, Rachel Wuerstlein, Kwok-Leung Cheung, Teresa Klinowska, Ashutosh Kothari, A Jahan, Cliona C. Kirwan, Justin P.O. Lindemann, Myria Nikolaou, Diansong Zhou, Martine P. Roudier, John F.R. Robertson, Omar Mohamed, J Michael Dixon, Alexander MacDonald, Danielle Carroll, Nadia Harbeck, Peter Schmid, Rhiannon Maudsley, Richard Mather, Li Zhou, Peter A. Fasching, Tinnu Sarvotham, Gaia Schiavon, and Laura M. Kenny
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Cancer Research ,Newly diagnosed ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Window of opportunity ,Fulvestrant ,Manchester Cancer Research Centre ,business.industry ,ResearchInstitutes_Networks_Beacons/mcrc ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Pharmacodynamics ,Open label ,business ,Primary breast cancer ,medicine.drug - Abstract
Purpose:Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2− primary breast cancer awaiting curative intent surgery.Patients and Methods:Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5–14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety.Results:Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (−33.3%) and Ki-67 levels (−39.9%) from baseline, but was also not superior to fulvestrant (PR: −68.7%, P = 0.97; Ki-67: −75.4%, P = 0.98). No new safety findings were identified.Conclusions:This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.
- Published
- 2020
32. Human Assisted Science at Venus: Venus Exploration in the New Human Spaceflight Age
- Author
-
Ralph L. McNutt, Alexander Macdonald, Paul K. Byrne, Kirby Runyon, and Noam R. Izenberg
- Subjects
Engineering ,biology ,business.industry ,Human spaceflight ,FOS: Physical sciences ,Venus ,NASA Deep Space Network ,Mars Exploration Program ,Popular Physics (physics.pop-ph) ,Exploration of Mars ,biology.organism_classification ,Physics - Popular Physics ,Observations and explorations of Venus ,Astrobiology ,Planet ,business ,Astrophysics - Instrumentation and Methods for Astrophysics ,Scientific study ,Instrumentation and Methods for Astrophysics (astro-ph.IM) - Abstract
Some human mission trajectories to Mars include flybys of Venus. These flybys provide opportunities to practice deep space human operations, and offer numerous safe-return-to-Earth options, before committing to longer and lower-cadence Mars-only flights. Venus flybys, as part of dedicated missions to Mars, also enable human-in-the-loop scientific study of the second planet. The time to begin coordinating such Earth-to-Mars-via-Venus missions is now, A White Paper for the Planetary Science and Astrobiology Decadal Survey 2023-2032. 7 pages +cover page, 2 figures +cover image
- Published
- 2020
33. Citation Style is a Cruel Mistress: A Review of the 21st Edition of The Bluebook
- Author
-
Alexander MacDonald
- Subjects
Literature ,Style (visual arts) ,History ,business.industry ,Bluebook ,business ,Citation ,Legal writing - Published
- 2020
34. Shall We Proceed? Ebbs, Flows, and Futility in the Debate over Words of Authority
- Author
-
Alexander MacDonald
- Subjects
History ,Polymers and Plastics ,Political science ,media_common.quotation_subject ,ComputingMilieux_LEGALASPECTSOFCOMPUTING ,Context (language use) ,Ambiguity ,Business and International Management ,Industrial and Manufacturing Engineering ,Supreme court ,Law and economics ,media_common ,Legal writing - Abstract
This article discusses recent revisions to the Virginia Supreme Court's rules of practice to address potentially ambiguous uses of the word "shall." It also places those revisions in the context of a broader debate within the legal-writing community about words of authority. It argues that current calls to eliminate "shall" from legal documents are facile; the only way to eliminate ambiguity is to draft carefully and pay attention to context.
- Published
- 2020
35. A Randomized, Open-label, Presurgical, Window-of-Opportunity Study Comparing the Pharmacodynamic Effects of the Novel Oral SERD AZD9496 with Fulvestrant in Patients with Newly Diagnosed ER
- Author
-
John F R, Robertson, Abigail, Evans, Stephan, Henschen, Cliona C, Kirwan, Ali, Jahan, Laura M, Kenny, J Michael, Dixon, Peter, Schmid, Ashutosh, Kothari, Omar, Mohamed, Peter A, Fasching, Kwok-Leung, Cheung, Rachel, Wuerstlein, Danielle, Carroll, Teresa, Klinowska, Justin P O, Lindemann, Alexander, MacDonald, Richard, Mather, Rhiannon, Maudsley, Michele, Moschetta, Myria, Nikolaou, Martine P, Roudier, Tinnu, Sarvotham, Gaia, Schiavon, Diansong, Zhou, Li, Zhou, and Nadia, Harbeck
- Subjects
Aged, 80 and over ,Indoles ,Estradiol ,Receptor, ErbB-2 ,Estrogen Receptor alpha ,Breast Neoplasms ,Middle Aged ,Cinnamates ,Biomarkers, Tumor ,Humans ,Female ,Receptors, Progesterone ,Fulvestrant ,Aged - Abstract
Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ERPatients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5-14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety.Forty-six women received treatment (AZD9496This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.
- Published
- 2019
36. Newly discovered variant of oesophageal atresia: 'Type Y'
- Author
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Dina Fouad, Nordeen Bouhadiba, Alexander Macdonald, and Iain Yardley
- Subjects
Male ,medicine.medical_specialty ,Paediatric surgery ,Unusual Presentation of More Common Disease/Injury ,medicine.diagnostic_test ,business.industry ,Fistula ,Infant, Newborn ,General Medicine ,New variant ,medicine.disease ,Surgery ,03 medical and health sciences ,0302 clinical medicine ,Bronchoscopy ,030220 oncology & carcinogenesis ,Atresia ,MULTIPLE VARIATIONS ,medicine ,Humans ,Female ,Incomplete fistula ,business ,Esophageal Atresia ,030217 neurology & neurosurgery - Abstract
Multiple variations of oesophageal atresia (OA) have been described. We present two cases of a new variant of OA (‘Type Y’) where the fistula enters the trachea in a Y-shaped configuration. Awareness of this is important. Bronchoscopy will reveal a single fistula opening and therefore there will initially be no suspicion of anatomical variation. It may be that only one bifurcation of the ‘Y’ fistula is patent which poses a risk of incomplete fistula closure.
- Published
- 2019
37. Getting a Second Wind: Reviving Natural Rights Clauses as a Means to Challenge Unjustified Occupational Licensing Regulations
- Author
-
Alexander C. Lemke and Alexander Macdonald
- Published
- 2021
38. Recent advances in biomedical, biosensor and clinical measurement devices for use in humans and the potential application of these technologies for the study of physiology and disease in wild animals
- Author
-
Alexander MacDonald, Lucy A. Hawkes, and Damion K. Corrigan
- Subjects
Cell engineering ,2019-20 coronavirus outbreak ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Physiology ,Animals, Wild ,Biosensing Techniques ,Disease ,General Biochemistry, Genetics and Molecular Biology ,Wearable Electronic Devices ,QH301 ,Human health ,Zoonoses ,Animals ,Humans ,Nanotechnology ,Cell Engineering ,Wearable technology ,Monitoring, Physiologic ,QL ,Zoonotic Infection ,Animal health ,Zika Virus Infection ,business.industry ,COVID-19 ,Articles ,Point-of-Care Testing ,RC0321 ,Synthetic Biology ,General Agricultural and Biological Sciences ,business ,Biomarkers - Abstract
The goal of achieving enhanced diagnosis and continuous monitoring of human health has led to a vibrant, dynamic and well-funded field of research in medical sensing and biosensor technologies. The field has many sub-disciplines which focus on different aspects of sensor science; engaging engineers, chemists, biochemists and clinicians, often in interdisciplinary teams. The trends which dominate include the efforts to develop effective point of care tests and implantable/wearable technologies for early diagnosis and continuous monitoring. This review will outline the current state of the art in a number of relevant fields, including device engineering, chemistry, nanoscience and biomolecular detection, and suggest how these advances might be employed to develop effective systems for measuring physiology, detecting infection and monitoring biomarker status in wild animals. Special consideration is also given to the emerging threat of antimicrobial resistance and in the light of the current SARS-CoV-2 outbreak, zoonotic infections. Both of these areas involve significant crossover between animal and human health and are therefore well placed to seed technological developments with applicability to both human and animal health and, more generally, the reviewed technologies have significant potential to find use in the measurement of physiology in wild animals.This article is part of the theme issue ‘Measuring physiology in free-living animals (Part II)’.
- Published
- 2021
39. Gamification of a To-Do List with Emotional Reinforcement
- Author
-
Stephen Brewster and Shaun Alexander Macdonald
- Subjects
T1 ,business.industry ,Field (Bourdieu) ,media_common.quotation_subject ,05 social sciences ,020207 software engineering ,02 engineering and technology ,Q1 ,Software ,Feeling ,0202 electrical engineering, electronic engineering, information engineering ,0501 psychology and cognitive sciences ,Meaning (existential) ,business ,Psychology ,Reinforcement ,050107 human factors ,media_common ,Cognitive psychology - Abstract
Gamification can change how and why people interact with software. A common approach is to use quantitative feedback to give users a feeling of progress or achievement. There are, however, other ways to provide users with motivation or meaning during normal computer interactions, such as using emotional reinforcement. This could provide a powerful new tool to allow the positive effects of gamification to reach wider contexts. This paper investigates the design and evaluation of a mobile to-do list application, 'Tamu To-Do', which utilises gamified emotional reinforcement, as seen in Figure 1. A week-long field study (N=9) recorded user activity and impressions with the application. The results supported emotional reinforcement's potential as a gamification strategy to improve user motivation and engagement.
- Published
- 2019
40. Addressing provider turnover to improve health outcomes in Nunavut
- Author
-
Maria Cherba, Gwen Healey Akearok, and W. Alexander MacDonald
- Subjects
business.industry ,Personnel Turnover ,Nunavut ,General Medicine ,Health outcomes ,Health Services Accessibility ,Nursing ,Health care ,Key (cryptography) ,Humans ,Business ,Delivery of Health Care ,Analysis ,Quality of Health Care - Abstract
KEY POINTS Nunavut’s health care system relies heavily on short-term locum physicians and nurses, many of whom come from outside the territory. Recruiting and retaining outside health care personnel is challenging in Nunavut, as in many remote regions in Canada. A recent analysis of data on
- Published
- 2019
41. Human bone marrow disorders recapitulated in vitro using organ chip technology
- Author
-
Akiko Shimamura, Carl D. Novina, Cailin E. Joyce, Lorna Ewart, Frismantas, Robert P. Hasserjian, Petar Pop-Damkov, Youngjae Choe, Sasan Jalili-Firoozinezhad, Yuka Milton, Rhiannon David, Carlos F. Ng, Alexander MacDonald, Richard M. Novak, David B. Chou, Amanda Jiang, Douglas Ferguson, Özge Vargel Bölükbaşı, Teixeira Lsm, Oren Levy, Kasiani C. Myers, Donald E. Ingber, Rech A, Elizabeth Calamari, Rachelle Prantil-Baun, and Susan Clauson
- Subjects
0303 health sciences ,Stromal cell ,CD34 ,Context (language use) ,Biology ,In vitro ,3. Good health ,Cell biology ,Blood cell ,03 medical and health sciences ,Haematopoiesis ,0302 clinical medicine ,medicine.anatomical_structure ,In vivo ,030220 oncology & carcinogenesis ,medicine ,Bone marrow ,030304 developmental biology - Abstract
Understanding human bone marrow (BM) pathophysiology in the context of myelotoxic stress induced by drugs, radiation, or genetic mutations is of critical importance in clinical medicine. However, study of these dynamic cellular responses is hampered by the inaccessibility of living BMin vivo. Here, we describe a vascularized human Bone Marrow-on-a-Chip (BM Chip) microfluidic culture device for modeling bone marrow function and disease states. The BM Chip is comprised of a fluidic channel filled with a fibrin gel in which patient-derived CD34+ cells and bone marrow-derived stromal cells (BMSCs) are co-cultured, which is separated by a porous membrane from a parallel fluidic channel lined by human vascular endothelium. When perfused with culture medium through the vascular channel, the BM Chip maintains human CD34+ cells and supports differentiation and maturation of multiple blood cell lineages over 1 month in culture. Moreover, it recapitulates human myeloerythroid injury responses to drugs and gamma radiation exposure, as well as key hematopoietic abnormalities found in patients with the genetic disorder, Shwachman-Diamond Syndrome (SDS). These data establish the BM Chip as a new humanin vitromodel with broad potential utility for studies of BM dysfunction.
- Published
- 2018
42. On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology
- Author
-
David B, Chou, Viktoras, Frismantas, Yuka, Milton, Rhiannon, David, Petar, Pop-Damkov, Douglas, Ferguson, Alexander, MacDonald, Özge, Vargel Bölükbaşı, Cailin E, Joyce, Liliana S, Moreira Teixeira, Arianna, Rech, Amanda, Jiang, Elizabeth, Calamari, Sasan, Jalili-Firoozinezhad, Brooke A, Furlong, Lucy R, O'Sullivan, Carlos F, Ng, Youngjae, Choe, Susan, Marquez, Kasiani C, Myers, Olga K, Weinberg, Robert P, Hasserjian, Richard, Novak, Oren, Levy, Rachelle, Prantil-Baun, Carl D, Novina, Akiko, Shimamura, Lorna, Ewart, and Donald E, Ingber
- Subjects
Bone Marrow ,Lab-On-A-Chip Devices ,Microfluidics ,Animals ,Humans ,Antigens, CD34 ,Bone Marrow Cells ,Cell Differentiation ,Mesenchymal Stem Cells ,Cells, Cultured ,Bone Marrow Transplantation ,Cell Proliferation ,Hematopoiesis - Abstract
The inaccessibility of living bone marrow (BM) hampers the study of its pathophysiology under myelotoxic stress induced by drugs, radiation or genetic mutations. Here, we show that a vascularized human BM-on-a-chip (BM chip) supports the differentiation and maturation of multiple blood cell lineages over 4 weeks while improving CD34
- Published
- 2018
43. Abstract P6-04-01: A pre-surgical, window of opportunity study comparing the novel oral SERD AZD9496 with fulvestrant in patients with newly diagnosed ER+ HER2- primary breast cancer
- Author
-
Omar Mohamed, Li Zhou, Myria Nikolaou, Rhiannon Maudsley, A Jahan, Rachel Wuerstlein, Tinnu Sarvotham, Kwok-Leung Cheung, Martine P. Roudier, S. Henschen, Michele Moschetta, Teresa Klinowska, Nadia Harbeck, Peter A. Fasching, Richard Mather, Danielle Carroll, J Michael Dixon, Alexander MacDonald, Cliona C. Kirwan, Ashutosh Kothari, Justin P.O. Lindemann, Diansong Zhou, Laura M. Kenny, Gaia Schiavon, John F.R. Robertson, Peter Schmid, and Abigail Evans
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Fulvestrant ,business.industry ,Cmax ,Estrogen receptor ,Cancer ,medicine.disease ,Breast cancer ,Pharmacokinetics ,Internal medicine ,Pharmacodynamics ,medicine ,business ,Tamoxifen ,medicine.drug - Abstract
Background: Estrogen receptor positive (ER+) breast cancer is routinely treated with endocrine therapies targeting the ER axis. However, primary and secondary resistance ultimately limits the use of these agents. Fulvestrant (FULV) is the first-in-class selective ER degrader (SERD) clinically effective in patients with ER+ breast cancer, both naïve and resistant to tamoxifen and aromatase inhibitors. FULV has low oral bioavailability, and its dose-dependent pharmacodynamic (PD) activity and clinical efficacy is limited by the currently approved maximal feasible dose (MFD) of 500 mg, which is administered monthly as two intramuscular injections. AZD9496 is an orally bioavailable, nonsteroidal, selective and potent degrader and antagonist of ER in preclinical models. This pre-surgical, window of opportunity study (NCT03236974) compared PD changes and the PD/pharmacokinetic (PK) relationships of AZD9496 with FULV in patients with newly diagnosed ER+ HER2- breast cancer awaiting curative intent surgery.Methods: In this open-label, multicenter study, patients were randomized 1:1 to receive oral AZD9496 250 mg BID from Day 1 for 5-14 days or FULV 500 mg administered intramuscularly on Day 1 only. On-treatment image-guided core tumor biopsies were taken between Days 5 and 14. The primary objective was to compare the effects of AZD9496 and FULV on ER expression in tumor tissue using pre-dose biopsies as baseline. Secondary objectives were changes in progesterone receptor (PR) and Ki-67 biomarkers, AZD9496 and FULV plasma concentrations during treatment, and safety. Immunohistochemistry was used to determine ER and PR H-scores, and Ki-67 index, and treatment effects were compared using an analysis of covariance model. Blood samples for PK analysis were taken at on-treatment biopsy and 1-2 hours afterwards. Adverse events (AEs) were monitored from screening through to a follow-up visit 28 days after the last study dose.Results: Of the 49 women enrolled, 46 received treatment (AZD9496 n=22; FULV n=24) and of these, 35 paired biopsies were evaluable (AZD9496 n=15; FULV n=20). The least square mean estimate for the reduction in ER H-score after AZD9496 treatment was 24% (80% CI: 34.4, 14.3), and after FULV treatment was 36% (44.9, 27.7), with a least square mean difference between AZD9496 and FULV of 12% (p=0.86). AZD9496 was not superior to FULV in terms of ER modulation at the tested dose. AZD9496 also reduced PR H-scores and Ki-67 levels from baseline (by 33.3% and 39.9%, respectively). These effects were not statistically superior to FULV at the tested dose (PR: -68.7%, p=0.97; Ki 67: 75.4%, p=0.98).Plasma exposure of AZD9496 (AUC -40%, Cmax -25%) was lower than predicted based on PK data from the previous phase 1 study, whereas FULV exposure was consistent with historical data. No clear exposure-response relationship for plasma concentration at biopsy and PD markers for AZD9496 or FULV were observed.The median treatment duration of AZD9496 was 9.5 days (range: 6-15), and the relative dose intensity was 100% (range: 90-125); no patients discontinued AZD9496. AZD9496 and FULV were both well tolerated, and no new safety findings were identified. No grade ≥3 toxicities or serious AEs occurred. Conclusion: AZD9496 250 mg BID reduced ER, PR and Ki-67 expression, and as such, is the first pre surgical study to demonstrate an oral SERD impacting its key biological targets. These reductions were not superior to the FULV clinically approved dose, which performed as expected based on historical data. Pre-surgical studies represent an important method to test the proof of mechanism of novel SERDs early in clinical development. Citation Format: John FR Robertson, Abigail Evans, Stephan Henschen, Cliona Kirwan, Ali Jahan, Laura Kenny, J. Michael Dixon, Peter Schmid, Ashutosh Kothari, Omar Mohamed, Peter A Fasching, Kwok-Leung Cheung, Rachel Wuerstlein, Danielle Carroll, Teresa Klinowska, Justin PO Lindemann, Alexander MacDonald, Richard Mather, Rhiannon Maudsley, Michele Moschetta, Myria Nikolaou, Martine P Roudier, Tinnu Sarvotham, Gaia Schiavon, Diansong Zhou, Li Zhou, Nadia Harbeck. A pre-surgical, window of opportunity study comparing the novel oral SERD AZD9496 with fulvestrant in patients with newly diagnosed ER+ HER2- primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-04-01.
- Published
- 2020
44. Author Correction: On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology
- Author
-
Richard M. Novak, Viktoras Frismantas, Donald E. Ingber, Rhiannon David, Olga K. Weinberg, Arianna Rech, Robert P. Hasserjian, Sasan Jalili-Firoozinezhad, Susan Marquez, Elizabeth Calamari, Lucy R. O’Sullivan, Lorna Ewart, Youngjae Choe, Carl D. Novina, Amanda Jiang, Özge Vargel Bölükbaşı, Yuka Milton, Liliana Moreira Teixeira, Petar Pop-Damkov, Oren Levy, Brooke A. Furlong, David B. Chou, Rachelle Prantil-Baun, Douglas Ferguson, Carlos F. Ng, Cailin E. Joyce, Akiko Shimamura, Alexander MacDonald, and Kasiani C. Myers
- Subjects
business.industry ,Biomedical Engineering ,MEDLINE ,Medicine (miscellaneous) ,Bioengineering ,Patient specific ,Bioinformatics ,Pathophysiology ,Computer Science Applications ,Text mining ,medicine.anatomical_structure ,Medicine ,Bone marrow ,business ,Biotechnology - Published
- 2020
45. Letter to the editor
- Author
-
Alexander Macdonald and Mark Davenport
- Subjects
Pediatrics, Perinatology and Child Health ,Surgery ,General Medicine - Published
- 2020
46. A Phase I/II Study of AZD2811 Nanoparticles (NP) As Monotherapy or in Combination in Treatment-Naïve or Relapsed/Refractory AML/MDS Patients Not Eligible for Intensive Induction Therapy
- Author
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Manish R. Patel, Suzanne F. Jones, Jay Yang, Julie Charlton, William B. Donnellan, Ehab Atallah, Philip Overend, Jon Travers, Simon Smith, Giulia Fabbri, J. Elizabeth Pease, Carrie A. Adelman, Alexander MacDonald, Donald K. Strickland, Elizabeth Sainsbury, Gautam Borthakur, Adam S. Asch, Alireza Eghtedar, Jan Cosaert, and Anna Korzeniowska
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Combination therapy ,medicine.medical_treatment ,Immunology ,Neutropenia ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Medicine ,Adverse effect ,Neoadjuvant therapy ,business.industry ,Venetoclax ,Cell Biology ,Hematology ,medicine.disease ,Discontinuation ,Clinical trial ,030104 developmental biology ,chemistry ,Cohort ,business ,030215 immunology - Abstract
Background: Aurora kinases (AurK) represent potential targets for anticancer therapy in hematological malignancies and solid tumors. AurK B inhibitor AZD1152 (barasertib) showed benefit (35% CR/CRi) in patients (pts) with untreated AML when given as a 7-day continuous infusion (Lowenberg B et al, Blood 2011, Kantarjian HG et al., Cancer 2013). AZD2811NP, a nanoparticle encapsulated slow-release inhibitor of AurKB, when given as 2-4hr IV on days 1 and 4, offers a prolonged drug exposure in vivo, mimicking the AZD1152 7-day continuous IV infusion. This is an update on the first-in-man dose-escalation study of AZD2811NP in pts with relapsed/refractory AML/MDS or treatment-naïve patients (pts) not eligible for intensive induction therapy (NCT03217838). The primary objectives are to determine the Maximum Tolerated Dose (MTD) and safety profile of AZD2811NP monotherapy and in combination with azacitidine. The secondary objectives are to evaluate the pharmacokinetic (PK) profile, Biologically Effective Dose (BED), and preliminary efficacy (CR, CRi, PR, 6 month OS). Methods: Pts received a 2-hour IV infusion on Day 1 and 4 of each 28-day cycle (Cy) for doses up to 600mg, extending to a 4 h IV infusion for dosages > 600 mg. In the ongoing dose escalation, 3-6 pts have been sequentially enrolled in cohorts ranging from 100 mg to 800 mg per infusion (Day 1 & 4), i.e. from 200 mg to 1,600 mg per cycle in monotherapy setting, according to a modified continuous reassessment method (mCRM) dose escalation design. AZD2811NP was also combined with azacitidine (75 mg day 1 to 7 or the 5-2-2 schedule) starting at an AZD2811NP dose of 400 mg D1 and D4 every 4 weeks. Study treatment was continued until disease progression, intolerability, or when discontinuation criteria were met. Results: Currently, 30 pts have enrolled of which 29 pts (12 females and 17 males) received study treatment in 5 monotherapy cohorts and 2 azacitidine combination cohorts, with ages ranging from 53 to 85 years. Nineteen pts had relapsed/refractory AML, 9 pts had MDS and 1pt had MDS/MPN. Monotherapy cohort 5 (800 mg D1 & D4) and combination cohort 4c (600mg D1 & D4 + Azacitidine) are currently enrolling. Of the 19 pts in monotherapy cohorts 1-5, 18 pts discontinued (due to consent withdrawal [2], early disease related deaths [2], other reason [1], or completed follow up [13; 11 pts after Cy1, 2 pts after Cy2]) and 1 pt is still on therapy. Nine pts were treated in combination with azacitidine, and of these, 3 pts are still on therapy and 6 pts have discontinued AZD2811NP (due to death [1], consent withdrawal [2], or completed follow up [3; 2 pts after Cy2, 1 pt after Cy4]). Adverse events that occurred in ≥ 20% of pts were mainly myelotoxicity, nausea and fatigue. One dose-limiting toxicity (DLT) has been observed in the monotherapy arm (esophageal infection) and one DLT in the combination setting (late neutropenia recovery). Two deaths were due to the underlying disease and 1 due to a serious adverse event of Gr 5 sepsis not related to study drug. AZD2811 total and released blood PK exposure appears broadly dose proportional with a terminal t1/2 of ~ 30-50 hours. Released blood PK exposure is ~ 1% of total PK exposure. Conclusion: AZD2811NP is documented to be well tolerated at doses up to 600 mg on Day 1 & 4 every 28 days in monotherapy setting and up to 400 mg (D1 & 4) in combination with azacitidine. The monotherapy and combination therapy dose escalations are ongoing. Updated results including preliminary efficacy data will be presented. Additional dose finding and expansion cohorts of AZD2811NP in combination with venetoclax are planned. Disclosures Atallah: Pfizer: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Helsinn: Consultancy; Novartis: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy. Yang:AstraZeneca: Research Funding; Agios: Consultancy. Eghtedar:Jazz: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Verastem Oncology: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau. Borthakur:Merck: Research Funding; Oncoceutics: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Agensys: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Eisai: Research Funding; Novartis: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics, Inc.: Research Funding. Charlton:AstraZeneca: Employment; GSK: Equity Ownership. MacDonald:AstraZeneca: Employment, Equity Ownership. Korzeniowska:AstraZeneca: Employment. Sainsbury:AstraZeneca: Employment, Equity Ownership. Strickland:Sarah Cannon Development Innovations: Employment. Overend:AstraZeneca: Employment, Equity Ownership. Adelman:AstraZeneca: Employment, Equity Ownership. Fabbri:AstraZeneca: Employment. Travers:AstraZeneca: Employment. Smith:AstraZeneca: Employment, Equity Ownership. Pease:AstraZeneca: Employment, Equity Ownership. Cosaert:AstraZeneca: Employment. OffLabel Disclosure: AZD2811NP, a nanoparticle encapsulated slow-release inhibitor of Aurora Kinase B (AurKB), is an investigational agent in clinical trials for human cancers including AML/MDS.
- Published
- 2019
47. Phase I study of orally administered
- Author
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Alexander, MacDonald, Graeme, Scarfe, Dominic, Magirr, Tinnu, Sarvotham, Julie, Charlton, Wolfram, Brugger, and Emma, Dean
- Subjects
Male ,Morpholines ,Administration, Oral ,Antineoplastic Agents ,Mechanistic Target of Rapamycin Complex 2 ,Mechanistic Target of Rapamycin Complex 1 ,Middle Aged ,Pyrimidines ,Area Under Curve ,Neoplasms ,Benzamides ,Humans ,Female ,Carbon Radioisotopes ,Protein Kinase Inhibitors ,Aged - Abstract
Vistusertib is an orally bioavailable dual target of rapamycin complex (TORC) 1/2 kinase inhibitor currently under clinical investigation in various solid tumour and haematological malignancy settings. The pharmacokinetic, metabolic and excretion profiles ofFour patients with advanced solid malignancies received a single oral solution dose ofThe pharmacokinetic (PK) profile of vistusertib is similar to previous studies using the same dosing regimen in solid malignancy patients. The majority of vistusertib elimination occurred via hepatic metabolic routes.
- Published
- 2018
48. Exploring fetal fibronectin testing as a predictor of labour onset: In parturient women from isolated communities
- Author
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Gwen K, Healey, William Alexander, Macdonald, Stefan, Grzybowski, Robert, Nevin, Jude, Kornelsen, and William E, Hogg
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Rural Population ,Predictive Value of Tests ,Pregnancy ,Research ,Humans ,Labor Onset ,Female ,Gestational Age ,Nunavut ,Cervix Uteri ,Prospective Studies ,Fibronectins - Abstract
To investigate whether the fetal fibronectin assay would be useful for determining if a woman was close to a term delivery. If effective, this test would allow parturient women to stay in their communities longer.This feasibility study used a prospective cohort design to examine the negative predictive value of the fetal fibronectin test at term.Iqaluit, NU.A total of 30 parturient women from rural and isolated communities in Nunavut.Starting at 36 weeks' gestation, women were tested every 2 days, and after 39 weeks this increased to every day until labour.The negative predictive value of the fetal fibronectin test was assessed.Women were no more likely to give birth at 7 or more days after their last negative fetal fibronectin test result relative to their likelihood of giving birth at 6 or fewer days after their last negative test result. Hence, the presence of fetal fibronectin in cervical secretion did not predict term delivery.This project indicated that the fetal fibronectin test did not have adequate sensitivity or specificity as a diagnostic measure to predict a delay of labour at term.
- Published
- 2018
49. Estimating the Price of ROCs
- Author
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Alexander MacDonald, Ian Lange, and Jeffrey Bryan
- Subjects
business.industry ,Certificate ,A share ,Renewable energy ,Unit (housing) ,Microeconomics ,Management of Technology and Innovation ,Market price ,Production (economics) ,Electricity ,Arbitrage ,Business and International Management ,business ,Energy (miscellaneous) - Abstract
Under the U.K. government's Renewable Obligation system of tradable quotas, each unit of generation from renewables creates a renewable obligation certificate (ROC). Electricity generators can earn ROCs through their own production, purchase ROCs in the market, or pay the buyout price to comply with the quota set by the RO. A unique aspect of this regulation is that all entities holding ROCs receive a share of the buyout fund – the sum of all compliance purchases using the buyout price. This setup ensures that the difference between the market price for ROCs and the buyout price should equal the expected share of the buyout fund, as regulated entities arbitrage these two compliance options. An analysis finds that minimum temperature in the U.K. is correlated with the buyout price differential, while the price of natural gas is not.
- Published
- 2015
50. Towards an Interplanetary Spaceship: The Potential Role of Long-Duration Deep Space Habitation and Transportation in the Evolution and Organization of Human Spaceflight and Space Exploration
- Author
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Alexander MacDonald
- Subjects
Geography ,Human spaceflight ,NASA Deep Space Network ,Interplanetary spaceflight ,Short duration ,Space exploration ,Astrobiology - Published
- 2017
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