Matthew MacKay's research while affiliated with Weill Cornell Medical College and other places

Publications (52)

Preprint
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The SpaceX Inspiration4 mission provided a unique opportunity to study the impact of spaceflight on the human body. Biospecimen samples were collected from the crew at different stages of the mission, including before (L-92, L-44, L-3 days), during (FD1, FD2, FD3), and after (R+1, R+45, R+82, R+194 days) spaceflight, creating a longitudinal sample...
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Introduction: Cancer tumorigenesis and progression are driven by genetic and epigenetic alterations, giving rise to transcriptional and pathway dysregulation. An approach considering the level of pathway disruption and underlying genomic drivers may provide a more comprehensive understanding of tumor biology than assessing either factor alone. Here...
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Background: Next-generation sequencing of circulating tumor DNA (ctDNA) and solid-tissue can identify clinically actionable genomic variants that may be used for both treatment selection and disease surveillance. Due to differences in tumor biology and assay design, ctDNA and solid biopsies may identify unique variants. Here, we investigate a real-...
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Background: Recent groundbreaking work has shown that patients with lower levels of HER2-expression (HER2-low) may benefit from treatment with trastuzumab deruxtecan—an HER2 antibody-drug conjugate FDA-approved for treatment for HER2-positive (HER2+) patients and thus can represent a new molecular subtype. In fact, this HER2-low patient population...
Preprint
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Maintenance of astronaut health during spaceflight will require monitoring and potentially modulating their microbiomes, which play a role in some space-derived health disorders. However, documenting the response of microbiota to spaceflight has been difficult thus far due to mission constraints that lead to limited sampling. Here, we executed a si...
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Background: The combined impact of immunity and SARS-CoV-2 variants on viral kinetics during infections has been unclear. Methods: We characterized 1,280 infections from the National Basketball Association occupational health cohort identified between June 2020 and January 2022 using serial RT-qPCR testing. Logistic regression and semi-mechanistic...
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Widespread generation and analysis of omics data have revolutionized molecular medicine on Earth, yet its power to yield new mechanistic insights and improve occupational health during spaceflight is still to be fully realized in humans. Nevertheless, rapid technological advancements and ever-regular spaceflight programs mean that longitudinal, sta...
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Background: Actionable genomic alterations can be identified through either a biopsy of solid tissue or the detection of circulating tumor DNA from plasma. Little is known about the concordance rates of pathogenic variants between cell free DNA (cfDNA) and solid biopsies, including how concordance varies over time, by cancer type, or by treatment....
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Tissue-based next-generation sequencing (NGS) in metastatic breast cancer (mBC) is limited by the inability to noninvasively track tumor evolution. Cell-free DNA (cfDNA) NGS has made sequential testing feasible; however, the relationship between cfDNA and tissue-based testing in mBC is not well understood. Here, we evaluate concordance between tiss...
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3017 Background: Next generation sequencing (NGS) of tumor tissue and plasma (circulating tumor DNA [ctDNA]) are used clinically to identify actionable genomic alterations, with implications for treatment selection and disease surveillance. Early studies have observed that solid tumor tissue and ctDNA testing may capture both overlapping and comple...
Preprint
Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis and has been associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIFs), but the long-lasting effect of hypoxia beyond the immediate HIF regulation remains less understoo...
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Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic revealed a worldwide lack of effective molecular surveillance networks at local, state, and national levels, which are essential to identify, monitor, and limit viral community spread. SARS-CoV-2 variants of concern (VOCs) such as Alpha and Omicron, which show...
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(150 words) The molecular mechanisms underlying the clinical manifestations of COVID-19 and what distinguishes them from common seasonal influenza virus and other lung injury states such as Acute Respiratory Distress Syndrome, remains poorly understood. To address these challenges, we combine transcriptional profiling of 646 clinical nasopharyngeal...
Preprint
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Background. The Omicron SARS-CoV-2 variant is responsible for a major wave of COVID-19, with record case counts reflecting high transmissibility and escape from prior immunity. Defining the time course of Omicron viral proliferation and clearance is crucial to inform isolation protocols aiming to minimize disease spread. Methods. We obtained longit...
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We performed a Phase I clinical trial of donor derived CD19-specific chimeric antigen receptor T-cells (CAR T-cells) for B-cell malignancy that relapsed or persisted after matched related allogeneic hemopoietic stem cell transplant. To overcome the cost and transgene capacity limitations of traditional viral vectors, CAR T-cells were produced using...
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With the emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants that may increase transmissibility and/or cause escape from immune responses, there is an urgent need for the targeted surveillance of circulating lineages. It was found that the B.1.1.7 (also 501Y.V1) variant, first detected in the United Kingdom, could be...
Preprint
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Several genomic epidemiology tools have been developed to track the public and population health impact of SARS-CoV-2 community spread worldwide. A SARS-CoV-2 Variant of Concern (VOC) B.1.1.7, known as 501Y.V1, which shows increased transmissibility, has rapidly become the dominant VOC in the United States (US). Our objective was to develop an evid...
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Erythropoiesis involves complex interrelated molecular signals influencing cell survival, differentiation, and enucleation. Diseases associated with ineffective erythropoiesis, such as β-thalassemias, exhibit erythroid expansion and defective enucleation. Clear mechanistic determinants of what make erythropoiesis effective are lacking. We previousl...
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The emergence and spread of SARS-CoV-2 lineage B.1.1.7, first detected in the United Kingdom, has become a global public health concern because of its increased transmissibility. Over 2500 COVID-19 cases associated with this variant have been detected in the US since December 2020, but the extent of establishment is relatively unknown. Using travel...
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In less than nine months, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) killed over a million people, including >25,000 in New York City (NYC) alone. The COVID-19 pandemic caused by SARS-CoV-2 highlights clinical needs to detect infection, track strain evolution, and identify biomarkers of disease course. To address these challen...
Preprint
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus has infected over 115 million people and caused over 2.5 million deaths worldwide. Yet, the molecular mechanisms underlying the clinical manifestations of COVID-19, as well as what distinguishes them from common seasonal influenza virus and other lung injury states such as Acute...
Preprint
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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...
Preprint
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With the emergence of SARS-CoV-2 variants that may increase transmissibility and/or cause escape from immune responses1-3, there is an urgent need for the targeted surveillance of circulating lineages. It was found that the B.1.1.7 (also 501Y.V1) variant first detected in the UK4,5 could be serendipitously detected by the ThermoFisher TaqPath COVID...
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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, l...
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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...
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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 ast...
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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...
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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 ac...
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Graphical Abstract Highlights d Spaceflight miRNA signature validated in multiple organism models d Components of miRNA signature related to space radiation and microgravity d Downstream targets and circulating dependence of miRNAs in NASA Twins Study d Inhibition of key microvasculature miRNAs mitigates space radiation impact (C.E.M.), afshin.behe...
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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, met...
Preprint
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The health impact of prolonged space flight on the human body is not well understood. Liquid biopsies based on cell-free DNA (cfDNA) or exosome analysis provide a noninvasive approach to monitor the dynamics of genomic, epigenomic and proteomic biomarkers, and the occurrence of DNA damage, physiological stress, and immune responses. To study the mo...
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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 alter...
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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, w...
Preprint
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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...
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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)...
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It is been previously 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 multi-year, multi-omic study of human response to space flight in the NASA Twin S...
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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 derive...
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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...
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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, telomer...
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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...
Article
Recent studies have shown that mutations at non-coding elements, such as the TERT promoter and ESR1 enhancer, can act as cancer drivers. However, an important class of non-coding elements, namely CTCF/cohesin insulators, has been overlooked in the previous driver analyses. It is known that promoter and enhancer interactions are facilitated by parti...
Article
During tumor progression, tumor cells invade the primary tumor microenvironment and intravasate into blood vessels, where they are referred to as circulating tumor cells (CTCs). These CTCs disseminate to other organs, and a subset of these cells will form metastasis. The growing interest for CTCs is confronted with the difficulty associated with th...
Article
N 6-methyladenosine (m6A) is a nucleotide modification in mRNA that is required for the acquisition of cell fate in embryonic stem cells. Recent studies have indicated that methylation writers can act as both oncogenes and tumor suppressor genes. Here we show that m6A is a critical regulator of myeloid differentiation of human hematopoietic stem an...
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N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m6A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m6A-forming en...
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Due to the advance in technologies for rare cell isolation, circulating tumor cells (CTC) have recently received vast interest. During tumor progression tumor cells invade the primary tumor microenvironment and intravasate into blood vessels, where they are referred as CTCs. These CTCs disseminate to other organs and a subset of these cells will be...

Citations

... The time period of each phase is drawn can be found in Table S1. For each infected individual, PATAT randomly draws a withinhost viral load trajectory over the duration of infection, which impacts the sensitivity of Ag-RDTs 40 , based on known distributions for Omicron BA.1 41 . Similar viral load trajectories were drawn for both asymptomatic and symptomatic infected individuals 42 using a stochastic model modified from the one previously developed by Quilty et al. 43 A baseline Ct value (Ct baseline ) of 40 is established upon exposure. ...
... A variety of biospecimen collection methods have been used in human spaceflight studies to date [24]. For frequent sampling, particularly in-flight, non-invasive or minimally invasive sample collection methods (e.g. ...
... 11,84 A study by Liu et al analysed 300 MBCpaired tissues and liquid biopsies from MBC patients using NGS and found significant concordance between tissue and cfDNA. 85 They observed that 77.8% of pathogenic tissue variants were detected in cfDNA, and similarly, 75.7% of pathogenic cfDNA variants were identified in tissue when the tests were conducted within a 7-day interval. However, these percentages decreased to 50.3% and 51.8%, respectively, when the time gap between tests exceeded 365 days. ...
... At the beginning of the study, the Delta VOC was prevalent, but the Omicron sublineage BA.1 variant became dominant in January 2021, followed by the emergence of the Omicron 2 variant thereafter. Later, with the emergence of the Omicron sublineage BA.2 (characterized by the absence of the ∆69-70 mutation) and the progressive disappearance of Delta variant circulation, the SGTF result was applied to distinguish between Omicron BA.1 and BA.2 lineages (Figure 2) [18]. ACAAAGTTTTCAGATCCTCAGT 47-171 Del69-70, T95I, G142D, Del143-145, and Del144 TCCATAAGAAAAGGCTGAGA TGCTTTACTAATGTCTATGCAGA 399-616 K417T/N, D428E, N440K, G446S, L452R, Q474R, S477N, T478K, E484A/Q/K, Q493R, G496S, Q498R, N501Y, Y505H, T547K, A570D, and D614G ACAGGGACTTCTGTGCAGT GTTTAACAGGCACAGGTGT 552-722 D614G, H655Y, N679K, P681H/R, and T716I CACTGGTAGAATTTCTGTGGTA ...
... A large autopsy study investigating multiple organs (heart, lung, kidney, liver, and lymph nodes) showed that the cellular and functional gene signatures from each organ's major cell types (e.g., cardiomyocytes in the heart) decrease as a function of the viral load. More specifically in the heart (n = 41 from patient autopsy samples), despite no histological change, many heart functional markers (e.g., TNNI3, TNNT2, MYBPC3, PLN, and HAND1) showed decreased levels resulting from COVID-19 infection [35]. Another study showed the presence of SARS-CoV-2 in the myocardial heart tissue from autopsy cases, suggested to be tied to myocardial injury [36]. ...
... To validate our hypothesis that isolation may be a selection pressure to further drive the evolution of viral phenotypes, we additionally used the longitudinal viral load of SARS-CoV-2 from the BA.1 subvariant in 49 infected patients 41 (Table S1), and similarly analyzed those data together with the same data for the Delta variant (see METHODS in detail). The individual viral loads for the Delta variant (red) and BA.1 subvariant (green) are described in Fig. S8, and the estimated population parameters are shown in Table S5. ...
... Given the widespread infection and vaccination leading to high-level population immunity worldwide, this factor could have a profound impact on the evolution of the virus. Some studies suggest that COVID-19 vaccinations may affect the SARS-CoV-2 infection dynamics 32,39 . Accordingly, we conducted further analysis to investigate the impact of prior immunity caused by vaccinations or prior infections on our findings. ...
... Telomeres were significantly elongated during spaceflight in all crewmembers and in all in-flight samples analyzed (blood, and in one case also urine), irrespective of mission duration or means of measurement. In addition, mitochondrial dysregulation, increased oxidative stress and inflammation (evidenced by elevated 8-oxoG, TNF, PGF2) as well as genome instability were observed during spaceflight in these crew members, and astronauts in general 25,27,[29][30][31] . Consistent with a rapid human response to spaceflight, telomere elongation and upregulation of pathways related to oxidative stress were evident during and post the 3-day high elevation orbital mission for all four Inspiration4 crew members 28 . ...
... For more accurately evaluating the off-target effect of CRISPR editing, GUIDE-Seq will use to test the safety of SHP-1 editing in future work [8]. Compared with virus-transduced CAR T cells, very few clinical trials have applied CAR T cells prepared using PiggyBac system, and more attention needs to be paid on the safety of novel vector systems in future clinical trials [9]. ...
... 3 Sequence analysis of VOC revealed the S-gene as a site bearing numerous mutations, some of which are shared among different VOC. [3][4][5][6]8 This finding highlights the important need of a genotyping approach for tracking mutations of concern (MOC) expressed in SARS-CoV-2 variants. Indeed, disease monitoring programs should exhibit high sensitivity and quick turn-around-times, while workflows should remain largely unaffected by varying positivity rates. ...