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Connor O'Brien

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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Journal ArticleDOI
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

Journal ArticleDOI
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

Journal ArticleDOI
Ellie J. Coromilas1, Stephanie M. Kochav1, Isaac L Goldenthal1, Angelo B. Biviano1, Hasan Garan1, Seth Goldbarg2, Joon Hyuk Kim2, Ilhwan Yeo2, Cynthia M. Tracy3, Shant Ayanian3, Joseph G. Akar4, Avinainder Singh4, Shashank Jain4, Leandro Ioschpe Zimerman5, Mauricio Pimentel5, Stefan Osswald6, Raphael Twerenbold6, Nicolas Schaerli6, Lia Crotti7, Daniele Fabbri7, Gianfranco Parati7, Yi Li, Felipe Atienza8, Felipe Atienza9, Eduardo Zatarain9, Eduardo Zatarain8, Gary Tse10, Gary Tse11, Keith Sai Kit Leung12, Milton E Guevara-Valdivia13, Carlos A. Rivera-Santiago13, Kyoko Soejima14, Paolo De Filippo, Paola Ferrari, Giovanni Malanchini, Prapa Kanagaratnam15, Saud Ahmed Khawaja15, Ghada W. Mikhail15, Mauricio Scanavacca16, Ludhmila Abrahão Hajjar16, Brenno Rizerio16, Luciana Sacilotto16, Reza Mollazadeh17, Masoud Eslami17, Vahideh Laleh Far17, Anna Vittoria Mattioli18, Giuseppe Boriani18, Federico Migliore19, Alberto Cipriani19, Filippo Donato19, Paolo Compagnucci20, Michela Casella20, Antonio Dello Russo20, James Coromilas21, Andrew Aboyme21, Connor O'Brien22, Fatima Rodriguez23, Paul J. Wang23, Aditi Naniwadekar24, Melissa Y.Y. Moey24, Chia Siang Kow25, Wee Kooi Cheah26, Angelo Auricchio, Giulio Conte, Jongmin Hwang27, Seongwook Han27, Pietro Enea Lazzerini28, Federico Franchi28, Amato Santoro28, Pier Leopoldo Capecchi28, Jose A. Joglar29, Anna Rosenblatt29, Marco Zardini, Serena Bricoli, Rosario Bonura, Julio Echarte-Morales, Tomás Benito-González, Carlos Minguito-Carazo, Felipe Fernández-Vázquez, Elaine Wan1 

87 citations

Journal ArticleDOI
16 Apr 2012-PLOS ONE
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

Journal ArticleDOI
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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Journal ArticleDOI
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

Journal ArticleDOI
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

Journal ArticleDOI
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

Journal ArticleDOI
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