Palmer Station, Antarctica: A ground-based spaceflight analog suitable for validation of biomedical countermeasures for deep space missions.

Astronauts are known to exhibit a variety of immunological alterations during spaceflight including changes in leukocyte distribution and plasma cytokine concentrations, a reduction in T-cell function, and subclinical reactivation of latent herpesviruses. These alterations are most likely due to mission-associated stressors including circadian misalignment, microgravity, isolation, altered nutrition, and increased exposure to cosmic radiation. Some of these stressors may also occur in terrestrial situations.

Short-term isolation effects on the brain, cognitive performance, and sleep-The role of exercise.

Isolation is stressful and negatively affects sleep and mood and might also affect the structure and function of the brain. Physical exercise improves brain function. We investigated the influence of physical exercise during isolation on sleep, affect, and neurobehavioral function.

Changes in Immune Function during Initial Military Training.

Purpose: Initial military training (IMT) is a transitionary period wherein immune function may be suppressed and infection risk heightened due to physical and psychological stress, communal living, and sleep deprivation. This study characterized changes in biomarkers of innate and adaptive immune function, and potential modulators of those changes, in military recruits during IMT.

Methods: Peripheral leukocyte distribution and mitogen-stimulated cytokine profiles were measured in fasted blood samples, Epstein-Barr (EBV), varicella zoster (VZV), and herpes simplex 1 (HSV1) DNA was measured in saliva by quantitative polymerase chain reaction as an indicator of latent herpesvirus reactivation, and diet quality was determined using the healthy eating index measured by food frequency questionnaire in 61 US Army recruits (97% male) at the beginning (PRE) and end (POST) of 22-wk IMT.

Impact of diet on human nutrition, immune response, gut microbiome, and cognition in an isolated and confined mission environment.

Long-duration spaceflight impacts human physiology, including well documented immune system dysregulation. The space food system has the potential to serve as a countermeasure to maladaptive physiological changes during spaceflight. However, the relationship between dietary requirements, the food system, and spaceflight adaptation requires further investigation to adequately define countermeasures and prioritize resources on future spaceflight missions.

DNA Damage and Radiosensitivity in Blood Cells from Subjects Undergoing 45 Days of Isolation and Confinement: An Explorative Study.

The effect of confined and isolated experience on astronauts' health is an important factor to consider for future space exploration missions. The more confined and isolated humans are, the more likely they are to develop negative behavioral or cognitive conditions such as a mood decline, sleep disorder, depression, fatigue and/or physiological problems associated with chronic stress. Molecular mediators of chronic stress, such as cytokines, stress hormones or reactive oxygen species (ROS) are known to induce cellular damage including damage to the DNA.

Dermatitis during Spaceflight Associated with HSV-1 Reactivation.

Human alpha herpesviruses herpes simplex virus (HSV-1) and varicella zoster virus (VZV) establish latency in various cranial nerve ganglia and often reactivate in response to stress-associated immune system dysregulation. Reactivation of Epstein Barr virus (EBV), VZV, HSV-1, and cytomegalovirus (CMV) is typically asymptomatic during spaceflight, though live/infectious virus has been recovered and the shedding rate increases with mission duration. The risk of clinical disease, therefore, may increase for astronauts assigned to extended missions (>180 days).

Spaceflight validation of technology for point-of-care monitoring of peripheral blood WBC and differential in astronauts during space missions.

During long duration orbital space missions, astronauts experience immune system dysregulation, the persistent reactivation of latent herpesviruses, and some degree of clinical incidence. During planned NASA 'Artemis' deep space missions the stressors that cause this phenomenon will increase, while clinical care capability will likely be reduced. There is currently minimal clinical laboratory capability aboard the International Space Station (ISS).

Alterations in Saliva and Plasma Cytokine Concentrations During Long-Duration Spaceflight.

Long-duration spaceflight is known to cause immune dysregulation in astronauts. Biomarkers of immune system function are needed to determine both the need for and effectiveness of potential immune countermeasures for astronauts. Whereas plasma cytokine concentrations are a well-established biomarker of immune status, salivary cytokine concentrations are emerging as a sensitive indicator of stress and inflammation.

Arterial structure and function during and after long-duration spaceflight.

Spaceflight missions expose astronauts to increased risk of oxidative stress and inflammatory damage that might accelerate the development of asymptomatic cardiovascular disease. The purpose of this investigation was to determine whether long-duration spaceflight (>4 mo) results in structural and functional changes in the carotid and brachial arteries. Common carotid artery (CCA) intima-media thickness (cIMT), CCA distensibility and stiffness, and brachial artery endothelium-dependent and -independent vasodilation were measured in 13 astronauts (10 men, 3 women) ~180 and 60 days before launch, during the mission on ~15, 60, and 160 days of spaceflight, and within 1 wk after landing.

Countermeasures-based Improvements in Stress, Immune System Dysregulation and Latent Herpesvirus Reactivation onboard the International Space Station - Relevance for Deep Space Missions and Terrestrial Medicine.

The International Space Station (ISS) has continued to evolve from an operational perspective and multiple studies have monitored both stress and the immune system of ISS astronauts. Alterations were ascribed to a potentially synergistic array of factors, including microgravity, radiation, psychological stress, and circadian misalignment. Comparing similar data across 12 years of ISS construction and operations, we report that immunity, stress, and the reactivation of latent herpesviruses have all improved in ISS astronauts.

Single-Cell RNA-Sequencing Identifies Activation of TP53 and STAT1 Pathways in Human T Lymphocyte Subpopulations in Response to Ex Vivo Radiation Exposure.

Detrimental health consequences from exposure to space radiation are a major concern for long-duration human exploration missions to the Moon or Mars. Cellular responses to radiation are expected to be heterogeneous for space radiation exposure, where only high-energy protons and other particles traverse a fraction of the cells. Therefore, assessing DNA damage and DNA damage response in individual cells is crucial in understanding the mechanisms by which cells respond to different particle types and energies in space.

Synergistic Effects of Weightlessness, Isoproterenol, and Radiation on DNA Damage Response and Cytokine Production in Immune Cells.

The implementation of rotating-wall vessels (RWVs) for studying the effect of lack of gravity has attracted attention, especially in the fields of stem cells, tissue regeneration, and cancer research. Immune cells incubated in RWVs exhibit several features of immunosuppression including impaired leukocyte proliferation, cytokine responses, and antibody production. Interestingly, stress hormones influence cellular immune pathways affected by microgravity, such as cell proliferation, apoptosis, DNA repair, and T cell activation.

Immune System Dysregulation During Spaceflight: Potential Countermeasures for Deep Space Exploration Missions.

Recent studies have established that dysregulation of the human immune system and the reactivation of latent herpesviruses persists for the duration of a 6-month orbital spaceflight. It appears certain aspects of adaptive immunity are dysregulated during flight, yet some aspects of innate immunity are heightened. Interaction between adaptive and innate immunity also seems to be altered.

Matched-pair, Y/Y-labeled, bivalent RGD/bombesin antagonist, [RGD-Glu-[DO3A]-6-Ahx-RM2], as a potential theranostic agent for prostate cancer.

Introduction: In this study, we describe development of a true matched-pair theranostic agent that is able to target the αβ integrin and the gastrin releasing peptide receptor (GRPR). We herein describe methods to metallate and characterize the new conjugate and to validate its biological efficacy by in vitro and in vivo methods.

Methods: We have previously described the development of [RGD-Glu-6Ahx-RM2] (where RGD: Arg-Gly-Asp; Glu: glutamic acid; 6-Ahx: 6-amino hexanoic acid; RM2: (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2)) that has been conjugated to a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) bifunctional chelating agent (BFCA) to afford [RGD-Glu-[DO3A]-6-Ahx-RM2] peptide.

Evaluation of Cu-Based Radiopharmaceuticals that Target Aβ Peptide Aggregates as Diagnostic Tools for Alzheimer's Disease.

Positron emission tomography (PET) imaging agents that detect amyloid plaques containing amyloid beta (Aβ) peptide aggregates in the brain of Alzheimer's disease (AD) patients have been successfully developed and recently approved by the FDA for clinical use. However, the short half-lives of the currently used radionuclides C (20.4 min) and F (109.

Transcriptomics, NF-κB Pathway, and Their Potential Spaceflight-Related Health Consequences.

In space, living organisms are exposed to multiple stress factors including microgravity and space radiation. For humans, these harmful environmental factors have been known to cause negative health impacts such as bone loss and immune dysfunction. Understanding the mechanisms by which spaceflight impacts human health at the molecular level is critical not only for accurately assessing the risks associated with spaceflight, but also for developing effective countermeasures.

BET protein bromodomain inhibitor-based combinations are highly active against post-myeloproliferative neoplasm secondary AML cells.

Myeloproliferative neoplasms with myelofibrosis (MPN-MF) demonstrate constitutive activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling that responds to treatment with the JAK1 and 2 kinase inhibitor (JAKi) ruxolitinib. However, MPN-MF often progresses (~20%) to secondary acute myeloid leukemia (sAML), where standard induction chemotherapy or ruxolitinib is relatively ineffective, necessitating the development of novel therapeutic approaches. In the present studies, we demonstrate that treatment with BET (bromodomain and extraterminal) protein inhibitor (BETi), for example, JQ1, inhibits growth and induces apoptosis of cultured and primary, patient-derived (PD), post-MPN sAML blast progenitor cells.

SIRT2 Deacetylates and Inhibits the Peroxidase Activity of Peroxiredoxin-1 to Sensitize Breast Cancer Cells to Oxidant Stress-Inducing Agents.

SIRT2 is a protein deacetylase with tumor suppressor activity in breast and liver tumors where it is mutated; however, the critical substrates mediating its antitumor activity are not fully defined. Here we demonstrate that SIRT2 binds, deacetylates, and inhibits the peroxidase activity of the antioxidant protein peroxiredoxin (Prdx-1) in breast cancer cells. Ectopic overexpression of SIRT2, but not its catalytically dead mutant, increased intracellular levels of reactive oxygen species (ROS) induced by hydrogen peroxide, which led to increased levels of an overoxidized and multimeric form of Prdx-1 with activity as a molecular chaperone.

Metabolically Stabilized (68)Ga-NOTA-Bombesin for PET Imaging of Prostate Cancer and Influence of Protease Inhibitor Phosphoramidon.

Peptide receptor-based targeted molecular imaging and therapy of cancer is on the current forefront of nuclear medicine preclinical research and clinical practice. The frequent overexpression of gastrin-releasing peptide (GRP) receptors in prostate cancer stimulated the development of radiolabeled bombesin derivatives as high affinity peptide ligands for selective targeting of the GRP receptor. In this study, we have evaluated a novel (68)Ga-labeled bombesin derivative for PET imaging of prostate cancer in vivo.

Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib.

Mantle cell lymphoma (MCL) cells exhibit increased B-cell receptor and nuclear factor (NF)-κB activities. The bromodomain and extra-terminal (BET) protein bromodomain 4 is essential for the transcriptional activity of NF-κB. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and cyclin-dependent kinase (CDK)4/6, inhibits the nuclear RelA levels and the expression of NF-κB target genes, including Bruton tyrosine kinase (BTK) in MCL cells.

Rerouting the metabolic pathway of (18)F-labeled peptides: the influence of prosthetic groups.

Current translational cancer research is directed to the development of high affinity peptide ligands for targeting neuropeptide receptors overexpressed in different types of cancer. Besides their desired high binding affinity to the receptor, the suitability of radiolabeled peptides as targeting vectors for molecular imaging and therapy depends on additional aspects such as high tumor-to-background ratio, favorable clearance pattern from nontarget tissue, and sufficient metabolic stability in vivo. This study reports how a switch from the prosthetic group, N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB), to 2-deoxy-2-[(18)F]fluoro-d-glucose ([(18)F]FDG) effects the metabolic pathway of an (18)F-labeled bombesin derivative, QWAV-Sar-H-FA01010-Tle-NH2.

Monitoring of biodistribution and persistence of conditionally replicative adenovirus in a murine model of ovarian cancer using capsid-incorporated mCherry and expression of human somatostatin receptor subtype 2 gene.

A significant limiting factor to the human clinical application of conditionally replicative adenovirus (CRAd)-based virotherapy is the inability to noninvasively monitor these agents and their potential persistence. To address this issue, we proposed a novel imaging approach that combines transient expression of the human somatostatin receptor (SSTR) subtype 2 reporter gene with genetic labeling of the viral capsid with mCherry fluorescent protein. To test this dual modality system, we constructed the Ad5/3Δ24pIXcherry/SSTR CRAd and validated its capacity to generate fluorescent and nuclear signals in vitro and following intratumoral injection.

Cross-inhibition of NMBR and GRPR signaling maintains normal histaminergic itch transmission.

We previously showed that gastrin-releasing peptide receptor (GRPR) in the spinal cord is important for mediating nonhistaminergic itch. Neuromedin B receptor (NMBR), the second member of the mammalian bombesin receptor family, is expressed in a largely nonoverlapping pattern with GRPR in the superficial spinal cord, and its role in itch transmission remains unclear. Here, we report that Nmbr knock-out (KO) mice exhibited normal scratching behavior in response to intradermal injection of pruritogens.

Triazine-based tool box for developing peptidic PET imaging probes: syntheses, microfluidic radiolabeling, and structure-activity evaluation.

This study was aimed at developing a triazine-based modular platform for targeted PET imaging. We synthesized mono- or bis-cyclo(RGDfK) linked triazine-based conjugates specifically targeting integrin αvβ3 receptors. The core molecules could be easily linked to targeting peptide and radiolabeled bifunctional chelator.