Publications by authors named "Matthew MacKay"

23 Publications

  • Page 1 of 1

Early introductions and community transmission of SARS-CoV-2 variant B.1.1.7 in the United States.

medRxiv 2021 Feb 12. Epub 2021 Feb 12.

The emergence and spread of SARS-CoV-2 lineage B.1.1.7, first detected in the United Kingdom, has become a national public health concern in the United States because of its increased transmissibility. Over 500 COVID-19 cases associated with this variant have been detected since December 2020, but its local establishment and pathways of spread are relatively unknown. Using travel, genomic, and diagnostic testing data, we highlight the primary ports of entry for B.1.1.7 in the US and locations of possible underreporting of B.1.1.7 cases. New York, which receives the most international travel from the UK, is likely one of the key hubs for introductions and domestic spread. Finally, we provide evidence for increased community transmission in several states. Thus, genomic surveillance for B.1.1.7 and other variants urgently needs to be enhanced to better inform the public health response.
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http://dx.doi.org/10.1101/2021.02.10.21251540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885932PMC
February 2021

Cell-free DNA (cfDNA) and Exosome Profiling from a Year-Long Human Spaceflight Reveals Circulating Biomarkers.

iScience 2020 Dec 25;23(12):101844. Epub 2020 Nov 25.

Department of Physiology and Biophysics, Weill Cornell Medicine, 1305 York Avenue, Y13-05, New York, NY 10021, USA.

Liquid biopsies based on cell-free DNA (cfDNA) or exosomes provide a noninvasive approach to monitor human health and disease but have not been utilized for astronauts. Here, we profile cfDNA characteristics, including fragment size, cellular deconvolution, and nucleosome positioning, in an astronaut during a year-long mission on the International Space Station, compared to his identical twin on Earth and healthy donors. We observed a significant increase in the proportion of cell-free mitochondrial DNA (cf-mtDNA) inflight, and analysis of post-flight exosomes in plasma revealed a 30-fold increase in circulating exosomes and patient-specific protein cargo (including brain-derived peptides) after the year-long mission. This longitudinal analysis of astronaut cfDNA during spaceflight and the exosome profiles highlights their utility for astronaut health monitoring, as well as cf-mtDNA levels as a potential biomarker for physiological stress or immune system responses related to microgravity, radiation exposure, and the other unique environmental conditions of spaceflight.
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http://dx.doi.org/10.1016/j.isci.2020.101844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756145PMC
December 2020

Relative Energy Deficiency in Sport: an Orthopaedic Perspective.

J Am Acad Orthop Surg 2021 Jan;29(1):e14-e21

From the Department of Orthopedic Surgery and Sports Medicine, University of Kansas Health Systems (L. Vopat), the Department of Orthopedic Surgery, University of Kansas Medical Center (Mackay), the Department of Orthopedic Surgery and Sports Medicine, University of Kansas Health Systems (B.G. Vopat), Kansas City, KS, and Women's Sports Medicine Program, Department of Orthopaedic Surgery, Tulane University School of Medicine, New Orleans, LA (Mulcahey).

Relative energy deficiency in sport (RED-S) is a constellation of clinical findings related to low energy availability. Manifestations are variable but may include endocrine and reproductive dysfunction, impaired bone and muscle health, psychological complaints, and performance issues, among many others. Unlike the previously common terminology, the female athlete triad, RED-S encompasses a broader range of signs and symptoms and includes descriptions for the male athlete. Since first being described in 2014 by the International Olympic Committee, an abundance of research has sought to define, prevent, and treat the underlying condition of RED-S. Although medicine, and society in general, has tried to expose the hazardous training and lifestyle behaviors that can underpin RED-S, further research and education is required on the part of the clinician and athlete to reshape the culture and prevent the deleterious consequences of low energy availability.
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http://dx.doi.org/10.5435/JAAOS-D-20-00460DOI Listing
January 2021

Comprehensive Multi-omics Analysis Reveals Mitochondrial Stress as a Central Biological Hub for Spaceflight Impact.

Cell 2020 Nov;183(5):1185-1201.e20

KBR, NASA Ames Research Center, Moffett Field, CA 94035, USA. Electronic address:

Spaceflight is known to impose changes on human physiology with unknown molecular etiologies. To reveal these causes, we used a multi-omics, systems biology analytical approach using biomedical profiles from fifty-nine astronauts and data from NASA's GeneLab derived from hundreds of samples flown in space to determine transcriptomic, proteomic, metabolomic, and epigenetic responses to spaceflight. Overall pathway analyses on the multi-omics datasets showed significant enrichment for mitochondrial processes, as well as innate immunity, chronic inflammation, cell cycle, circadian rhythm, and olfactory functions. Importantly, NASA's Twin Study provided a platform to confirm several of our principal findings. Evidence of altered mitochondrial function and DNA damage was also found in the urine and blood metabolic data compiled from the astronaut cohort and NASA Twin Study data, indicating mitochondrial stress as a consistent phenotype of spaceflight.
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http://dx.doi.org/10.1016/j.cell.2020.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870178PMC
November 2020

Fundamental Biological Features of Spaceflight: Advancing the Field to Enable Deep-Space Exploration.

Cell 2020 Nov;183(5):1162-1184

KBR, Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

Research on astronaut health and model organisms have revealed six features of spaceflight biology that guide our current understanding of fundamental molecular changes that occur during space travel. The features include oxidative stress, DNA damage, mitochondrial dysregulation, epigenetic changes (including gene regulation), telomere length alterations, and microbiome shifts. Here we review the known hazards of human spaceflight, how spaceflight affects living systems through these six fundamental features, and the associated health risks of space exploration. We also discuss the essential issues related to the health and safety of astronauts involved in future missions, especially planned long-duration and Martian missions.
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http://dx.doi.org/10.1016/j.cell.2020.10.050DOI Listing
November 2020

Temporal Telomere and DNA Damage Responses in the Space Radiation Environment.

Cell Rep 2020 Dec 25;33(10):108435. Epub 2020 Nov 25.

Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA; Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA. Electronic address:

Telomeres, repetitive terminal features of chromosomes essential for maintaining genome integrity, shorten with cell division, lifestyle factors and stresses, and environmental exposures, and so they provide a robust biomarker of health, aging, and age-related diseases. We assessed telomere length dynamics (changes over time) in three unrelated astronauts before, during, and after 1-year or 6-month missions aboard the International Space Station (ISS). Similar to our results for National Aeronautics and Space Administration's (NASA's) One-Year Mission twin astronaut (Garrett-Bakelman et al., 2019), significantly longer telomeres were observed during spaceflight for two 6-month mission astronauts. Furthermore, telomere length shortened rapidly after return to Earth for all three crewmembers and, overall, telomere length tended to be shorter after spaceflight than before spaceflight. Consistent with chronic exposure to the space radiation environment, signatures of persistent DNA damage responses were also detected, including mitochondrial and oxidative stress, inflammation, and telomeric and chromosomal aberrations, which together provide potential mechanistic insight into spaceflight-specific telomere elongation.
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http://dx.doi.org/10.1016/j.celrep.2020.108435DOI Listing
December 2020

Circulating miRNA Spaceflight Signature Reveals Targets for Countermeasure Development.

Cell Rep 2020 Dec 25;33(10):108448. Epub 2020 Nov 25.

KBR, Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

We have identified and validated a spaceflight-associated microRNA (miRNA) signature that is shared by rodents and humans in response to simulated, short-duration and long-duration spaceflight. Previous studies have identified miRNAs that regulate rodent responses to spaceflight in low-Earth orbit, and we have confirmed the expression of these proposed spaceflight-associated miRNAs in rodents reacting to simulated spaceflight conditions. Moreover, astronaut samples from the NASA Twins Study confirmed these expression signatures in miRNA sequencing, single-cell RNA sequencing (scRNA-seq), and single-cell assay for transposase accessible chromatin (scATAC-seq) data. Additionally, a subset of these miRNAs (miR-125, miR-16, and let-7a) was found to regulate vascular damage caused by simulated deep space radiation. To demonstrate the physiological relevance of key spaceflight-associated miRNAs, we utilized antagomirs to inhibit their expression and successfully rescue simulated deep-space-radiation-mediated damage in human 3D vascular constructs.
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http://dx.doi.org/10.1016/j.celrep.2020.108448DOI Listing
December 2020

Multi-omic, Single-Cell, and Biochemical Profiles of Astronauts Guide Pharmacological Strategies for Returning to Gravity.

Cell Rep 2020 Dec 25;33(10):108429. Epub 2020 Nov 25.

Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA; The WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY 10065, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA; The Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address:

The National Aeronautics and Space Administration (NASA) Twins Study created an integrative molecular profile of an astronaut during NASA's first 1-year mission on the International Space Station (ISS) and included comparisons to an identical Earth-bound twin. The unique biochemical profiles observed when landing on Earth after such a long mission (e.g., spikes in interleukin-1 [IL-1]/6/10, c-reactive protein [CRP], C-C motif chemokine ligand 2 [CCL2], IL-1 receptor antagonist [IL-1ra], and tumor necrosis factor alpha [TNF-α]) opened new questions about the human body's response to gravity and how to plan for future astronauts, particularly around initiation or resolution of inflammation. Here, single-cell, multi-omic (100-plex epitope profile and gene expression) profiling of peripheral blood mononuclear cells (PBMCs) showed changes to blood cell composition and gene expression post-flight, specifically for monocytes and dendritic cell precursors. These were consistent with flight-induced cytokine and immune system stress, followed by skeletal muscle regeneration in response to gravity. Finally, we examined these profiles relative to 6-month missions in 28 other astronauts and detail potential pharmacological interventions for returning to gravity in future missions.
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http://dx.doi.org/10.1016/j.celrep.2020.108429DOI Listing
December 2020

Telomere Length Dynamics and DNA Damage Responses Associated with Long-Duration Spaceflight.

Cell Rep 2020 Dec 25;33(10):108457. Epub 2020 Nov 25.

Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA; Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA. Electronic address:

Telomere length dynamics and DNA damage responses were assessed before, during, and after one-year or shorter duration missions aboard the International Space Station (ISS) in a comparatively large cohort of astronauts (n = 11). Although generally healthy individuals, astronauts tended to have significantly shorter telomeres and lower telomerase activity than age- and sex-matched ground controls before and after spaceflight. Although telomeres were longer during spaceflight irrespective of mission duration, telomere length shortened rapidly upon return to Earth, and overall astronauts had shorter telomeres after spaceflight than they did before; inter-individual differences were identified. During spaceflight, all crewmembers experienced oxidative stress, which positively correlated with telomere length dynamics. Significantly increased frequencies of chromosomal inversions were observed during and after spaceflight; changes in cell populations were also detected. We propose a telomeric adaptive response to chronic oxidative damage in extreme environments, whereby the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway is transiently activated in normal somatic cells.
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http://dx.doi.org/10.1016/j.celrep.2020.108457DOI Listing
December 2020

Clonal Hematopoiesis Before, During, and After Human Spaceflight.

Cell Rep 2020 Dec 25;33(10):108458. Epub 2020 Nov 25.

Department of Physiology and Biophysics, Weill Cornell Medicine, New York, 10065, USA; The Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, New York, NY, USA; The WorldQuant Initiative for Quantitative Prediction, New York, NY, USA; The Feil Family Brain and Mind Research Institute, New York, NY, USA. Electronic address:

Clonal hematopoiesis (CH) occurs when blood cells harboring an advantageous mutation propagate faster than others. These mutations confer a risk for hematological cancers and cardiovascular disease. Here, we analyze CH in blood samples from a pair of twin astronauts over 4 years in bulk and fractionated cell populations using a targeted CH panel, linked-read whole-genome sequencing, and deep RNA sequencing. We show CH with distinct mutational profiles and increasing allelic fraction that includes a high-risk, TET2 clone in one subject and two DNMT3A mutations on distinct alleles in the other twin. These astronauts exhibit CH almost two decades prior to the mean age at which it is typically detected and show larger shifts in clone size than age-matched controls or radiotherapy patients, based on a longitudinal cohort of 157 cancer patients. As such, longitudinal monitoring of CH may serve as an important metric for overall cancer and cardiovascular risk in astronauts.
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http://dx.doi.org/10.1016/j.celrep.2020.108458DOI Listing
December 2020

Identification of Radioresponsive Genes in Esophageal Cancer from Longitudinal and Single Cell Exome Sequencing.

Int J Radiat Oncol Biol Phys 2020 Nov 17;108(4):1103-1114. Epub 2020 Jun 17.

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China. Electronic address:

Purpose: The majority (70%) of the esophageal squamous cell carcinoma (ESCC) cases in the world occur in China, where radiation therapy is the most common treatment. Yet the majority of ESCC patients still relapse.

Methods And Materials: To better understand the genetic basis of radiation therapy resistance for ESCC, we performed longitudinal, whole-exome sequencing throughout radiation therapy on 42 patient tumor samples, including single-cell whole-exome sequencing for 147 cells for 2 patients.

Results: Significant allelic changes were observed during clinical irradiation, with 42 recurrent radioresponsive genes (sensitive and resistant) identified in multiple patients, including NOTCH1, MAML3, CDKN2A, NFE2L2, GAS2L2, OBSCN and TP53, with the last 3 genes implicated as radioresponsive in both bulk and single-cell whole-exome sequencing. Most (37/42) radioresponsive genes showed regional variegation in both radioresistant and radiosensitive mutations, with a paucity of resistant-only mutations (2.5%). A subset of sensitive mutations in 10 genes and resistant mutations in 18 genes defined a significantly improved prognosis and the shortest time for locoregional recurrence, respectively, indicating possible clinical utility. We also confirmed these significant mutational signatures in orthogonal Cancer Genome Atlas ESCC cohorts.

Conclusions: Overall, our results quantify the allelic shifts underlying radioresponse in bulk and single-cell ESCC exomes for the first time, provide a temporal resolution to such mutational dynamics, and offer new therapeutic target genes and loci for esophageal and potentially other cancers.
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http://dx.doi.org/10.1016/j.ijrobp.2020.06.015DOI Listing
November 2020

Shotgun Transcriptome and Isothermal Profiling of SARS-CoV-2 Infection Reveals Unique Host Responses, Viral Diversification, and Drug Interactions.

bioRxiv 2020 May 1. Epub 2020 May 1.

Department of Physiology and Biophysics, Weill Cornell Medicine, NY, USA.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused thousands of deaths worldwide, including >18,000 in New York City (NYC) alone. The sudden emergence of this pandemic has highlighted a pressing clinical need for rapid, scalable diagnostics that can detect infection, interrogate strain evolution, and identify novel patient biomarkers. To address these challenges, we designed a fast (30-minute) colorimetric test (LAMP) for SARS-CoV-2 infection from naso/oropharyngeal swabs, plus a large-scale shotgun metatranscriptomics platform (total-RNA-seq) for host, bacterial, and viral profiling. We applied both technologies across 857 SARS-CoV-2 clinical specimens and 86 NYC subway samples, providing a broad molecular portrait of the COVID-19 NYC outbreak. Our results define new features of SARS-CoV-2 evolution, nominate a novel, NYC-enriched viral subclade, reveal specific host responses in interferon, ACE, hematological, and olfaction pathways, and examine risks associated with use of ACE inhibitors and angiotensin receptor blockers. Together, these findings have immediate applications to SARS-CoV-2 diagnostics, public health, and new therapeutic targets.
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http://dx.doi.org/10.1101/2020.04.20.048066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255793PMC
May 2020

The therapeutic landscape for cells engineered with chimeric antigen receptors.

Nat Biotechnol 2020 02 6;38(2):233-244. Epub 2020 Jan 6.

Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.

Despite the global rapid increase in the number of clinical trials employing chimeric antigen receptors (CARs), no comprehensive survey of their scope, targets and design exists. In this study, we present an interactive CAR clinical trial database, spanning 64 targets deployed in T cells (CAR-T), natural killer cells (CAR-NK) or mixtures (CAR-NK/T) from over 500 clinical trials in 20 countries, encompassing >20,000 patients. By combining these data with transcriptional and proteomic data, we create a 'targetable landscape' for CAR cell therapies based on 13,206 proteins and RNAs across 78 tissues, 124 cell types and 20 cancer types. These data suggest a landscape of over 100 single targets and over 100,000 target pairs using logical switches for CAR cell engineering. Our analysis of the CAR cellular therapeutic landscape may aid the design of future therapies, improve target-to-patient matching, and ultimately help inform our understanding of CAR therapy's safety and efficacy.
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http://dx.doi.org/10.1038/s41587-019-0329-2DOI Listing
February 2020

Translating current biomedical therapies for long duration, deep space missions.

Precis Clin Med 2019 Dec 15;2(4):259-269. Epub 2019 Nov 15.

Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA.

It is been shown that spaceflight-induced molecular, cellular, and physiologic changes cause alterations across many modalities of the human body, including cardiovascular, musculoskeletal, hematological, immunological, ocular, and neurological systems. The Twin Study, a multi-year, multi-omic study of human response to spaceflight, provided detailed and comprehensive molecular and cellular maps of the human response to radiation, microgravity, isolation, and stress. These rich data identified epigenetic, gene expression, inflammatory, and metabolic responses to spaceflight, facilitating a better biomedical roadmap of features that should be monitored and safe-guarded in upcoming missions. Further, by exploring new developments in pre-clinical models and clinical trials, we can begin to design potential cellular interventions for exploration-class missions to Mars and potentially farther. This paper will discuss the overall risks astronauts face during spaceflight, what is currently known about human response to these risks, what pharmaceutical interventions exist for use in space, and which tools of precision medicine and cellular engineering could be applied to aerospace and astronaut medicine.
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http://dx.doi.org/10.1093/pcmedi/pbz022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927098PMC
December 2019

Circulating Tumor Cells Exhibit Metastatic Tropism and Reveal Brain Metastasis Drivers.

Cancer Discov 2020 01 10;10(1):86-103. Epub 2019 Oct 10.

Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California.

Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D as a regulator of tumor cell transmigration through the blood-brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis. SIGNIFICANCE: Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that -cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain..
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http://dx.doi.org/10.1158/2159-8290.CD-19-0384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954305PMC
January 2020

Identification of Cancer Drivers at CTCF Insulators in 1,962 Whole Genomes.

Cell Syst 2019 05 8;8(5):446-455.e8. Epub 2019 May 8.

Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA; Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address:

Recent studies have shown that mutations at non-coding elements, such as promoters and enhancers, can act as cancer drivers. However, an important class of non-coding elements, namely CTCF insulators, has been overlooked in the previous driver analyses. We used insulator annotations from CTCF and cohesin ChIA-PET and analyzed somatic mutations in 1,962 whole genomes from 21 cancer types. Using the heterogeneous patterns of transcription-factor-motif disruption, functional impact, and recurrence of mutations, we developed a computational method that revealed 21 insulators showing signals of positive selection. In particular, mutations in an insulator in multiple cancer types, including 16% of melanoma samples, are associated with TGFB1 up-regulation. Using CRISPR-Cas9, we find that alterations at two of the most frequently mutated regions in this insulator increase cell growth by 40%-50%, supporting the role of this boundary element as a cancer driver. Thus, our study reveals several CTCF insulators as putative cancer drivers.
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http://dx.doi.org/10.1016/j.cels.2019.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917527PMC
May 2019

The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight.

Science 2019 04;364(6436)

Northwestern University, Evanston, IL, USA.

To understand the health impact of long-duration spaceflight, one identical twin astronaut was monitored before, during, and after a 1-year mission onboard the International Space Station; his twin served as a genetically matched ground control. Longitudinal assessments identified spaceflight-specific changes, including decreased body mass, telomere elongation, genome instability, carotid artery distension and increased intima-media thickness, altered ocular structure, transcriptional and metabolic changes, DNA methylation changes in immune and oxidative stress-related pathways, gastrointestinal microbiota alterations, and some cognitive decline postflight. Although average telomere length, global gene expression, and microbiome changes returned to near preflight levels within 6 months after return to Earth, increased numbers of short telomeres were observed and expression of some genes was still disrupted. These multiomic, molecular, physiological, and behavioral datasets provide a valuable roadmap of the putative health risks for future human spaceflight.
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http://dx.doi.org/10.1126/science.aau8650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580864PMC
April 2019

The Impact of Heterogeneity on Single-Cell Sequencing.

Front Genet 2019 1;10. Epub 2019 Mar 1.

Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, United States.

The importance of diversity and cellular specialization is clear for many reasons, from population-level diversification, to improved resiliency to unforeseen stresses, to unique functions within metazoan organisms during development and differentiation. However, the level of cellular heterogeneity is just now becoming clear through the integration of genome-wide analyses and more cost effective Next Generation Sequencing (NGS). With easy access to single-cell NGS (scNGS), new opportunities exist to examine different levels of gene expression and somatic mutational heterogeneity, but these assays can generate yottabyte scale data. Here, we model the importance of heterogeneity for large-scale analysis of scNGS data, with a focus on the utilization in oncology and other diseases, providing a guide to aid in sample size and experimental design.
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http://dx.doi.org/10.3389/fgene.2019.00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405636PMC
March 2019

Appropriateness of CT scans for patients with non-traumatic acute abdominal pain.

Br J Radiol 2018 Jul 5;91(1088):20180158. Epub 2018 Jun 5.

1 Department of General Surgery, Capital and Coast DHB , Wellington , New Zealand.

Objective: Acute abdominal pain is the most common reason for surgical admission. CT scans are increasingly used to aid early diagnosis. Excessive use of CT scans is associated with increased length of stay, healthcare costs and radiation. The aim of this study was to evaluate the appropriateness of CT scans for patients presenting with acute abdominal pain.

Methods: We examined 100 consecutive patients presenting with new acute abdominal pain who underwent a CT scan. Clinical information available at the time the scan was ordered, was summarised and reviewed independently by five consultant general surgeons and five consultant radiologists.

Results: A CT scan was judged to be not indicated in a median of 21% of cases (range 12-53%), more information was required in a median of 16% (0-41%) and in a median of 58% (37-88%) the CT scan was considered indicated. There was a good level of agreement (Cronbach's α 0.704) across the 10 experts.

Conclusion: These data suggest that a large proportion of CT scans for patients with acute abdominal pain are not clinically indicated or are being performed prior to adequate clinical work-up. Optimising CT scan requests for this patient group will improve use of healthcare resources. Advances in knowledge: Both radiologists and general surgeons agree that there is no indication for an abdominal CT scan for a patient presenting with acute abdominal pain in a median of 21% of the cases.
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http://dx.doi.org/10.1259/bjr.20180158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209493PMC
July 2018

The N-methyladenosine (mA)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells.

Nat Med 2017 Nov 18;23(11):1369-1376. Epub 2017 Sep 18.

Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

N-methyladenosine (mA) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the mA modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the mA-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of mA coupled with ribosome profiling reveals that mA promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia.
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http://dx.doi.org/10.1038/nm.4416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677536PMC
November 2017

Strongly magnetic iron nanoparticles improve the diagnosis of small tumours in the reticuloendothelial system by magnetic resonance imaging.

PLoS One 2013 20;8(2):e56572. Epub 2013 Feb 20.

Malaghan Institute of Medical Research and School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.

Despite advances in non-invasive medical imaging, accurate nodal staging of malignancy continues to rely on surgery. Superparamagnetic iron oxide nanoparticles (IONP) with lymphotropic qualities have shown some promise as contrast agents for MRI of the lymph nodes, but recent large-scale studies failed to show consistent detection of tumours below 5 mm. Herein we compare imaging of splenic and lymph node tissue using iron/iron oxide core/shell nanoparticles (Fe NP) that have superior magnetic qualities to IONP, to determine whether improved negative contrast in T(2)-weighted MRI can enhance the diagnosis of small tumours in the reticuloendothelial system. To provide an in vivo pre-clinical model of human lymph node micrometastases, breast cancer cells were injected into the spleens of mice, providing localised areas of tumour growth. MR images of groups of tumour-bearing and sham-treated animals were generated using a 1.5 T imaging system and analysed by two independent, blinded radiologists. Fe NP improved the sensitivity and specificity of MRI when compared to IONP, enabling accurate detection of tumours as small as 1-3 mm. The use of Fe NP as contrast agents have the potential to improve the diagnostic accuracy of MRI in cancer patients, leading to more rapid and effective treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0056572PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577855PMC
September 2013