Author
Connor O'Brien
Other affiliations: University of California, San Francisco, Columbia University, Columbia University Medical Center
Bio: Connor O'Brien is an academic researcher from Stanford University. The author has contributed to research in topics: Medicine & Plasmodium falciparum. The author has an hindex of 10, co-authored 26 publications receiving 509 citations. Previous affiliations of Connor O'Brien include University of California, San Francisco & Columbia University.
Papers
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TL;DR: Intensified efforts are essential to monitor the spread of resistance, define therapeutic and operational strategies to counter its impact, and understand its molecular basis to ensure recent gains in reducing the burden of malaria are not lost.
Abstract: Purpose of reviewArtemisinin-based combination therapies (ACTs) have been deployed globally with remarkable success for more than 10 years without having lost their malaria treatment efficacy. However, recent reports from the Thai–Cambodian border reveal evidence of emerging resistance to artemisini
129 citations
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TL;DR: The nature of the preclinical challenges and potential solutions that could help overcome them are discussed, including the use of allogeneic versus autologous stem cell products, including a review of their respective advantages and disadvantages.
Abstract: Human pluripotent stem cells are known to have the capacity to renew indefinitely, being intrinsically able to differentiate into many different cell types. These characteristics have generated tremendous enthusiasm about the potential applications of these cells in regenerative medicine. However, major challenges remain with the development and testing of novel experimental stem cell therapeutics in the field. In this Review, we focus on the nature of the preclinical challenges and discuss potential solutions that could help overcome them. Furthermore, we discuss the use of allogeneic versus autologous stem cell products, including a review of their respective advantages and disadvantages, major clinical requirements, quality standards, time lines, and costs of clinical grade development.
128 citations
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Columbia University1, Cornell University2, George Washington University3, Yale University4, Universidade Federal do Rio Grande do Sul5, University Hospital of Basel6, University of Milano-Bicocca7, Carlos III Health Institute8, Hospital General Universitario Gregorio Marañón9, Tianjin Medical University10, Hospital Authority11, Aston University12, Mexican Social Security Institute13, Kyorin University14, Imperial College Healthcare15, University of São Paulo16, Tehran University of Medical Sciences17, University of Modena and Reggio Emilia18, University of Padua19, Marche Polytechnic University20, Rutgers University21, University of California, San Francisco22, Stanford University23, East Carolina University24, International Medical University25, Taiping Hospital26, Keimyung University27, University of Siena28, University of Texas Southwestern Medical Center29
87 citations
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TL;DR: The study points to the importance of P. vivax-associated severe disease in children, causing 72.5% of the malaria admissions to pediatric ICUs and WHO severity criteria demonstrated good sensitivity in predicting severe P.vivax infection in this small case series.
Abstract: Background
Plasmodium vivax is responsible for a significant proportion of malaria cases worldwide and is increasingly reported as a cause of severe disease. The objective of this study was to characterize severe vivax disease among children hospitalized in intensive care units (ICUs) in the Western Brazilian Amazon, and to identify risk factors associated with disease severity.
Methods and Findings
In this retrospective study, clinical records of 34 children, 0–14 years of age hospitalized in the 11 public pediatric and neonatal ICUs of the Manaus area, were reviewed. P. falciparum monoinfection or P. falciparum/P. vivax mixed infection was diagnosed by microscopy in 10 cases, while P. vivax monoinfection was confirmed in the remaining 24 cases. Two of the 24 patients with P. vivax monoinfection died. Respiratory distress, shock and severe anemia were the most frequent complications associated with P. vivax infection. Ninety-one children hospitalized with P. vivax monoinfections but not requiring ICU were consecutively recruited in a tertiary care hospital for infectious diseases to serve as a reference population (comparators). Male sex (p = 0.039), age less than five years (p = 0.028), parasitemia greater than 500/mm3 (p = 0.018), and the presence of any acute (p = 0.023) or chronic (p = 0.017) co-morbidity were independently associated with ICU admission. At least one of the WHO severity criteria for malaria (formerly validated for P. falciparum) was present in 23/24 (95.8%) of the patients admitted to the ICU and in 17/91 (18.7%) of controls, making these criteria a good predictor of ICU admission (p = 0.001). The only investigated criterion not associated with ICU admission was hyperbilirubinemia (p = 0.513)].
Conclusions
Our study points to the importance of P. vivax-associated severe disease in children, causing 72.5% of the malaria admissions to pediatric ICUs. WHO severity criteria demonstrated good sensitivity in predicting severe P. vivax infection in this small case series.
64 citations
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University of Louisville1, University of Miami2, University of Florida3, Baylor College of Medicine4, University of Minnesota5, Stanford University6, Indiana University7, Johns Hopkins University8, Harvard University9, Center for Cell and Gene Therapy10, University of Texas Health Science Center at Houston11, National Institutes of Health12, University of Kansas13
TL;DR: AIMS CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure caused by ischaemic cardiomyopathy.
Abstract: AIMS CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. METHODS AND RESULTS Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. CONCLUSIONS This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.
60 citations
Cited by
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TL;DR: This Clinical Practice Guideline presents updated recommendations for the optimal management of HBV infection, and future treatment strategies to achieve 'cure' of disease and new biomarkers are discussed.
3,016 citations
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1,835 citations
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TL;DR: The progress in applications of iPSC technology that are particularly relevant to drug discovery and regenerative medicine are discussed, and the remaining challenges and the emerging opportunities in the field are considered.
Abstract: Since the advent of induced pluripotent stem cell (iPSC) technology a decade ago, human iPSCs have been widely used for disease modelling, drug discovery and cell therapy development. This article discusses progress in applications of iPSC technology that are particularly relevant to drug discovery and regenerative medicine, including the powerful combination of human iPSC technology with recent developments in gene editing.
985 citations
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TL;DR: In this paper, the authors discuss the biological role of extracellular vesicles and how they can be applied as drug carriers, focusing on the current state of their manufacturing and existing challenges.
Abstract: Extracellular-vesicle-based cell-to-cell communication is conserved across all kingdoms of life. There is compelling evidence that extracellular vesicles are involved in major (patho)physiological processes, including cellular homoeostasis, infection propagation, cancer development and cardiovascular diseases. Various studies suggest that extracellular vesicles have several advantages over conventional synthetic carriers, opening new frontiers for modern drug delivery. Despite extensive research, clinical translation of extracellular-vesicle-based therapies remains challenging. Here, we discuss the uniqueness of extracellular vesicles along with critical design and development steps required to utilize their full potential as drug carriers, including loading methods, in-depth characterization and large-scale manufacturing. We compare the prospects of extracellular vesicles with those of the well established liposomes and provide guidelines to direct the process of developing vesicle-based drug delivery systems. In this Review the authors discuss the biological role of extracellular vesicles and how they can be applied as drug carriers, focusing on the current state of their manufacturing and existing challenges.
481 citations
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TL;DR: It is shown that haem, rather than free ferrous iron, is predominantly responsible for artemisinin activation, which derives primarily from the parasite's haem biosynthesis pathway at the early ring stage and from haemoglobin digestion at the latter stages.
Abstract: The mechanism of action of artemisinin and its derivatives, the most potent of the anti-malarial drugs, is not completely understood. Here we present an unbiased chemical proteomics analysis to directly explore this mechanism in Plasmodium falciparum. We use an alkyne-tagged artemisinin analogue coupled with biotin to identify 124 artemisinin covalent binding protein targets, many of which are involved in the essential biological processes of the parasite. Such a broad targeting spectrum disrupts the biochemical landscape of the parasite and causes its death. Furthermore, using alkyne-tagged artemisinin coupled with a fluorescent dye to monitor protein binding, we show that haem, rather than free ferrous iron, is predominantly responsible for artemisinin activation. The haem derives primarily from the parasite's haem biosynthesis pathway at the early ring stage and from haemoglobin digestion at the latter stages. Our results support a unifying model to explain the action and specificity of artemisinin in parasite killing.
449 citations