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Spaceflight induces molecular, cellular and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space1-6. Yet current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring the need for rapid development of space medicine databases, tools and protocols. Here we present the Space Omics and Medical Atlas (SOMA), an integrated data and sample repository for clinical, cellular and multi-omic research profiles from a diverse range of missions, including the NASA Twins Study7, JAXA CFE study8,9, SpaceX Inspiration4 crew10-12, Axiom and Polaris. The SOMA resource represents a more than tenfold increase in publicly available human space omics data, with matched samples available from the Cornell Aerospace Medicine Biobank. The Atlas includes extensive molecular and physiological profiles encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiome datasets, which reveal some consistent features across missions, including cytokine shifts, telomere elongation and gene expression changes, as well as mission-specific molecular responses and links to orthologous, tissue-specific mouse datasets. Leveraging the datasets, tools and resources in SOMA can help to accelerate precision aerospace medicine, bringing needed health monitoring, risk mitigation and countermeasure data for upcoming lunar, Mars and exploration-class missions.
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Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.
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Vesículas Extracelulares , Ácidos Graxos , Fígado Gorduroso , Fígado , Neoplasias Pancreáticas , Animais , Camundongos , Sistema Enzimático do Citocromo P-450/genética , Vesículas Extracelulares/metabolismo , Ácidos Graxos/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Microambiente Tumoral , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo , Neoplasias Hepáticas/secundário , Humanos , Inflamação/metabolismo , Ácido Palmítico/metabolismo , Células de Kupffer , Fosforilação Oxidativa , Proteínas rab27 de Ligação ao GTP/deficiênciaRESUMO
This paper presents an overview of the interconnection between various factors related to both cancer and type 2 diabetes mellitus (T2DM). Hyperglycemia, hyperinsulinemia, chronic inflammation, and obesity are involved in the development and progression of both diseases but, strong evidence for a direct causal relationship between diabetes and cancer, is lacking. Several studies described a relationship between hyperglycemia and cancer at the cellular, tissular and organismic levels but at the same time recent Mendelian randomization studies proved a significant causal relationship only between hyperglycemia and breast cancer. On the other hand, the association between both hyperinsulinemia and obesity and several cancer types appears to be robust as demonstrated by Mendelian randomized studies. Metabolic alterations, including the Warburg effect and excessive glucose consumption by tumors, are discussed, highlighting the potential impact of dietary restrictions, such as fasting and low-carb diets, on tumor growth and inflammation. Recent data indicates that circulating branched-chain amino acids levels, may represent novel biomarkers that may contribute to both better diabetes control and early pancreatic cancer detection. Understanding the underlying mechanisms and shared risk factors between cancer and T2DM can provide valuable insights for cancer prevention, early detection, and management strategies.
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Metastasis occurs frequently after resection of pancreatic cancer (PaC). In this study, we hypothesized that multi-parametric analysis of pre-metastatic liver biopsies would classify patients according to their metastatic risk, timing and organ site. Liver biopsies obtained during pancreatectomy from 49 patients with localized PaC and 19 control patients with non-cancerous pancreatic lesions were analyzed, combining metabolomic, tissue and single-cell transcriptomics and multiplex imaging approaches. Patients were followed prospectively (median 3 years) and classified into four recurrence groups; early (<6 months after resection) or late (>6 months after resection) liver metastasis (LiM); extrahepatic metastasis (EHM); and disease-free survivors (no evidence of disease (NED)). Overall, PaC livers exhibited signs of augmented inflammation compared to controls. Enrichment of neutrophil extracellular traps (NETs), Ki-67 upregulation and decreased liver creatine significantly distinguished those with future metastasis from NED. Patients with future LiM were characterized by scant T cell lobular infiltration, less steatosis and higher levels of citrullinated H3 compared to patients who developed EHM, who had overexpression of interferon target genes (MX1 and NR1D1) and an increase of CD11B+ natural killer (NK) cells. Upregulation of sortilin-1 and prominent NETs, together with the lack of T cells and a reduction in CD11B+ NK cells, differentiated patients with early-onset LiM from those with late-onset LiM. Liver profiles of NED closely resembled those of controls. Using the above parameters, a machine-learning-based model was developed that successfully predicted the metastatic outcome at the time of surgery with 78% accuracy. Therefore, multi-parametric profiling of liver biopsies at the time of PaC diagnosis may determine metastatic risk and organotropism and guide clinical stratification for optimal treatment selection.
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The discovery that primary tumors condition distant organ sites of future metastasis for seeding by disseminating tumor cells through a process described as the pre-metastatic niche (PMN) formation revolutionized our understanding of cancer progression and opened new avenues for therapeutic interventions. Given the inherent inefficiency of metastasis, PMN generation is crucial to ensure the survival of rare tumor cells in the otherwise hostile environments of metastatic organs. Early on, it was recognized that preparing the "soil" of the distal organ to support the outgrowth of metastatic cells is the initiating event in PMN development, achieved through the remodeling of the organ's extracellular matrix (ECM). Remote restructuring of ECM at future sites of metastasis under the influence of primary tumor-secreted factors is an iterative process orchestrated through the crosstalk between resident stromal cells, such as fibroblasts, epithelial and endothelial cells, and recruited innate immune cells. In this review, we will explore the ECM changes, cellular effectors, and the mechanisms of ECM remodeling throughout PMN progression, as well as its impact on shaping the PMN and ultimately promoting metastasis. Moreover, we highlight the clinical and translational implications of PMN ECM changes and opportunities for therapeutically targeting the ECM to hinder PMN formation.
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MicroRNAs (miRNAs) are a type of non-coding RNA whose dysregulation is frequently associated with the onset and progression of human cancers. miR-142, an ultra-conserved miRNA with both active -3p and -5p mature strands and wide-ranging physiological targets, has been the subject of countless studies over the years. Due to its preferential expression in hematopoietic cells, miR-142 has been found to be associated with numerous types of lymphomas and leukemias. This review elucidates the multifaceted role of miR-142 in human physiology, its influence on hematopoiesis and hematopoietic cells, and its intriguing involvement in exosome-mediated miR-142 transport. Moreover, we offer a comprehensive exploration of the genetic and molecular landscape of the miR-142 genomic locus, highlighting its mutations and dysregulation within hematological malignancies. Finally, we discuss potential avenues for harnessing the therapeutic potential of miR-142 in the context of hematological malignancies.
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Exossomos , Neoplasias Hematológicas , Leucemia , MicroRNAs , Humanos , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Leucemia/genética , Leucemia/terapia , Exossomos/genética , Genômica , MicroRNAs/genéticaRESUMO
Composite materials with a polymer matrix are used on a large scale to make light structures that involve high responsibility. The failure mechanisms of composite materials are very complex and for this reason, advanced techniques for damage detection and the assessment of structural integrity are required. The continuous structural health monitoring (SHM) uses nondestructive testing (NDT) techniques, sensors integrated into the structures, computers and dedicated software. This article presents a new automatic and precise method for detecting the orientation of strain gauges glued onto composite materials with a polymer matrix. The automatic identification of both the directions of the reinforcing fibers and that of the orientation of the strain gauge, respectively, allows for the calculation of the angle between these two directions. By knowing the difference between the nominal value of this angle and the value actually obtained after gluing the strain gauge, corrections obtained by calculation on the experimental values can be applied, using equations found in specialized literature. In this way, a drastic reduction of measurement errors introduced by the misalignment of strain gauges glued on composite materials can be achieved, resulting in a significant increase of measurement accuracy, which contributes to increasing the security of the monitored structures.
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Due to its physical and mechanical properties, glass-fiber-reinforced polymer (GFRP) is utilized in wind turbine blades. The loads given to the blades of wind turbines, particularly those operating offshore, are relatively significant. In addition to the typical static stresses, there are also large dynamic stresses, which are mostly induced by wind-direction changes. When the maximum stresses resulting from fatigue loading change direction, the reinforcing directions of the material used to manufacture the wind turbine blades must also be considered. In this study, sandwich-reinforced GFRP materials were subjected to tensile testing in three directions. The parameters of the stress-strain curve were identified and identified based on the three orientations in which samples were cut from the original plate. Strain gauge sensors were utilized to establish the three-dimensional elasticity of a material. After a fracture was created by tensile stress, SEM images were taken to highlight the fracture's characteristics. Using finite element analyses, the stress-strain directions were determined. In accordance to the three orientations and the various reinforcements used, it was established that the wind turbine blades are operational.
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High speed weigh-in-motion (WIM) sensors are utilized as components of complex traffic monitoring and measurement systems. They should be able to determine the weights on wheels, axles and vehicle gross weights, and to help the classification of vehicles (depending on the number of axles). WIM sensors must meet the following main requirements: good accuracy, high endurance, low price and easy installation in the road structure. It is not advisable to use cheap materials in constructing these devices for lower prices, since the sensors are normally working in harsh environmental conditions such as temperatures between -40 °C and +70 °C, dust, temporary water immersion, shocks and vibrations. Consequently, less expensive manufacturing technologies are recommended. Because the installation cost in the road structure is high and proportional to the WIM sensor cross section (especially with its thickness), the device needs to be made as flat as possible. The WIM sensor model presented and analyzed in this paper uses a spring element equipped with strain gages. Using Finite Element Analysis (FEA), the authors have attempted to obtain a more sensitive, reliable, lower profile and overall cheaper elastic element for a new WIM sensor.
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In order to effectively manage and cure cancer we should move beyond the general view of cancer as a random process of genetic alterations leading to uncontrolled cell proliferation or simply a predictable evolutionary process involving selection for traits that increase cell fitness. In our view, cancer is a systemic disease that involves multiple interactions not only among cells within tumors or between tumors and surrounding tissues but also with the entire organism and its internal "milieu". We define the internal body climate as an emergent property resulting from spatial and temporal interactions among internal components themselves and with the external environment. The body climate itself can either prevent, promote or support cancer initiation and progression (top-down effect; i.e., body climate-induced effects on cancer), as well as be perturbed by cancer (bottom-up effect; i.e., cancer-induced body climate changes) to further favor cancer progression and spread. This positive feedback loop can move the system towards a "cancerized" organism and ultimately results in its demise. In our view, cancer not only affects the entire system; it is a reflection of an imbalance of the entire system. This model provides an integrated framework to study all aspects of cancer as a systemic disease, and also highlights unexplored links that can be altered to both prevent body climate changes that favor cancer initiation, progression and dissemination as well as manipulate or restore the body internal climate to hinder the success of cancer inception, progression and metastasis or improve therapy outcomes. To do so, we need to (i) identify cancer-relevant factors that affect specific climate components, (ii) develop 'body climate biomarkers', (iii) define 'body climate scores', and (iv) develop strategies to prevent climate changes, stop or slow the changes, or even revert the changes (climate restoration).
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Squamous cell carcinomas of the esophagus (ESCC) and of the head and neck (HNSCC) are two neoplasms that share common risk factors and have the same embryological origin, but a very different prognosis, the 5-year survival of HNSCC being almost double (40-50%) compared to the 5-year survival of ESCC (20%). Current guidelines emphasize the importance of screening for ESCC in patients diagnosed with head and neck cancers. A liquid biopsy is a novel tool for diagnosis, prognostic stratification, and personalized therapy. Liquid biopsy biomarkers for these two malignancies could help both their early detection, facilitate residual disease identification, and provide prognosis information. The present systematic review of the literature was aimed at describing the liquid biopsy biomarkers present in these two malignancies, with an emphasis on potential clinical applications.
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Methods to predict the fracture of thin carbon fibre-reinforced polymers (CFRPs) under load are of great interest in the automotive industry. The manufacturing of composites involves a high risk of defect occurrence, and the identification of those that lead to failure increases the functional reliability and decreases costs. The performance of CFRPs can be significantly reduced in assembled structures containing stress concentrators. This paper presents a hybrid experimental-numerical method based on the Tsai-Hill criterion for behavior of thin CFRPs at complex loadings that can emphasize the threshold of stress by tracing the σ-τ envelope. Modified butterfly samples were made for shearing, traction, or shearing-with-traction tests in the weakened section by changing the angle of force application α. ANSYS simulations were used to determine the zones of maximum stress concentration. For thin CFRP samples tested with stacking sequences [0]8 and [(45/0)2]s, the main mechanical characteristics have been determined using a Dynamic Mechanical Analyzer (DMA) and ultrasound tests. A modified Arcan device (AD) was used to generate data in a biaxial stress state, leading to the characterization of the material as a whole. The generated failure envelope allows for the prediction of failure for other combinations of normal and shear stress, depending on the thickness of the laminations, the stacking order, the pretension of the fasteners, and the method used to produce the laminations. The experimental data using AD and the application of the Tsai-Hill criterion serve to the increase the safety of CFRP components.
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Advanced cancer is one of the major problems in oncology as currently, despite the recent technological and scientific advancements, the mortality of metastatic disease remains very high at 70-90%. The field of oncology is in urgent need of novel ideas in order to improve quality of life and prognostic of cancer patients. The Cancer and Evolution Symposium organized online October 14-16, 2020 brought together a group of specialists from different fields that presented innovative strategies for better understanding, preventing, diagnosing, and treating cancer. Today still, the main reasons behind the high incidence and mortality of advanced cancer are, on one hand, the paucity of funding and effort directed to cancer prevention and early detection, and, on the other hand, the lack of understanding of the cancer process itself. I argue that besides being a disease, cancer is also a form of life, and, this frame of reference may provide a fresh look on this complex process. Here, I provide a different angle to several contemporary cancer theories discussing them from the perspective of "cancer-forms of life" (i.e. bionts) point of view. The perspectives and the several "bionts" introduced here, by no means exclusive or comprehensive, are just a shorthand that will hopefully encourage the readers, to further explore the contemporary oncology theoretical landscape.
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Neoplasias , Qualidade de Vida , HumanosRESUMO
The vulnerabilities of cancer at the cellular and, recently, with the introduction of immunotherapy, at the tissue level, have been exploited with variable success. Evaluating the cancer system vulnerabilities at the organismic level through analysis of network topology and network dynamics can potentially predict novel anti-cancer drug targets directed at the macroscopic cancer networks. Theoretical work analyzing the properties and the vulnerabilities of the multi-scale network of cancer needs to go hand-in-hand with experimental research that uncovers the biological nature of the relevant networks and reveals new targetable vulnerabilities. It is our hope that attacking cancer on different spatial scales, in a concerted integrated approach, may present opportunities for novel ways to prevent treatment resistance.
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Neoplasias , Biologia de Sistemas , Humanos , Neoplasias/tratamento farmacológicoRESUMO
The use of blood liquid biopsy is increasingly being incorporated into the clinical setting of gastrointestinal cancers care. Clonal hematopoiesis (CH) occurs naturally as a result of the accumulation of somatic mutations and the clonal proliferation of hematopoietic stem cells with normal aging. The identification of CH-mutations has been described as a source of biological noise in blood liquid biopsy. Incorrect interpretation of CH events as cancer related can have a direct impact on cancer diagnosis and treatment. This review summarizes the current understanding of CH as a form of biological noise in blood liquid biopsy and the reported clinical significance of CH in patients with GI cancers.
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PURPOSE: Management of head and neck cancers (HNC) in older adults is a common but challenging clinical scenario. We assess the impact of Stereotactic Body Radiation Therapy (SBRT) on survival utilizing the Geriatric-8 (G8) questionnaire. MATERIALS AND METHODS: 171 HNC patients, deemed medically unfit for definitive treatment, were treated with SBRT ± systemic therapy. G8 questionnaires were collected at baseline, at 4-6 weeks, and at 2-3 months post-treatment. Patients were stratified according to their baseline G8 score: <11 as 'vulnerable', 11-14 as 'intermediate', and >14 as 'fit'. Overall survival (OS) was assessed through univariate Kaplan Meier analysis. Repeated measures ANOVA was used to determine if baseline characteristics affected G8 score changes. RESULTS: Median follow-up was seventeen months. 60% of patients presented with recurrent HNC, 30% with untreated HNC primaries, and 10% with metastatic non-HNC primaries. Median age was 75 years. Median Charlson Comorbidity Index score was 2. 51% of patients were 'vulnerable', 37% were 'intermediate', and 12% were 'fit' at baseline, with median survival of 13.2, 24.3, and 41.0 months, respectively (p = .004). Patients who saw a decrease in their follow-up G8 score (n = 69) had significantly lower survival than patients who had stable or increased follow-up G8 scores (n = 102), with median survival of 8.6 vs 36.0 months (p < .001). CONCLUSION: The G8 questionnaire may be a useful tool in upfront treatment decision-making to predict prognosis and prevent older patients from receiving inappropriate anti-cancer treatment. Decline in follow-up G8 scores may also predict worse survival and aid in goals of care following treatment.
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Neoplasias de Cabeça e Pescoço , Radiocirurgia , Idoso , Avaliação Geriátrica , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Recidiva Local de Neoplasia , Inquéritos e QuestionáriosRESUMO
Human endogenous retroviruses (HERVs) have been implicated in a variety of human diseases including cancers. However, technical challenges in analyzing HERV sequence data have limited locus-specific characterization of HERV expression. Here, we use the software Telescope (developed to identify expressed transposable elements from metatranscriptomic data) on 43 paired tumor and adjacent normal tissue samples from The Cancer Genome Atlas Program to produce the first locus-specific retrotranscriptome of head and neck cancer. Telescope identified over 3000 expressed HERVs in tumor and adjacent normal tissue, and 1078 HERVs were differentially expressed between the two tissue types. The majority of differentially expressed HERVs were expressed at a higher level in tumor tissue. Differentially expressed HERVs were enriched in members of the HERVH family. Hierarchical clustering based on HERV expression in tumor-adjacent normal tissue resulted in two distinct clusters with significantly different survival probability. Together, these results highlight the importance of future work on the role of HERVs across a range of cancers.
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Retrovirus Endógenos/genética , Neoplasias de Cabeça e Pescoço/virologia , Retrovirus Endógenos/fisiologia , Feminino , Regulação Viral da Expressão Gênica , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Estadiamento de NeoplasiasRESUMO
AIM: Current guidelines recommend p16 immunohistochemistry (IHC) for testing human papillomavirus (HPV) in oropharyngeal carcinoma (OPSCC). We evaluated the value of adding DNA in situ hybridization (ISH) to p16 IHC. METHODS: Fifty patients with OPSCC were analyzed. Concordance between HPV-DNA ISH and p16 IHC was measured by Gwet's agreement coefficient. RESULTS: p16 IHC was positive in 35/48 (72.9%), negative in 8/48 (16.7%) patients. Wide spectrum DNA-ISH was positive in 9/23 (39%) and negative in 14/23 (60.9%) patients. High-risk 16/18 (HR) HPV DNA-ISH was positive in 11/23 (47.8%) and negative in 12 (52.2%) patients. The agreement between HPV DNA-ISH and p16 IHC is fair (Gwet's AC1 = 0.318). CONCLUSION: The agreement between p16 IHC and HPV-DNA ISH was fair. However, ISH sensitivity was low. Our findings add to the current data that p16 IHC testing is reliable and may be enough as a stand-alone test for HPV detection in OPSCC.
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Photons, electrons and protons have therapeutic use however positrons have only been used for diagnostic imaging purposes. The energies of positrons (ß+) from F-18 (0.633 MeV) and electrons (ß-) from I-131 (0.606 MeV) are very close and have similar equilibrium dose constants. Since [18F]-fluorodeoxyglucose (18F-FDG) clears rapidly from circulation, administration of 37-74 GBq (1-2 Ci) of 18F-FDG is relatively safe from an internal radiation dosimetry point of view. We initiated a phase I dose escalation study to assess the safety, toxicity, and potential therapeutic utility of administering 100-200 mCi/m2 18F-FDG delivered over a 1 to 5 day period in patients with advanced lymphomas and solid tumors refractory to standard of care treatment (SCT). Here we report the results of the first four patients treated. Four patients with advanced cancers received a single dose of 3.7-7.4 GBq/m2 (100-200 mCi/m2) 18F-FDG. We monitored the patients for adverse effects and for response. No treatment-related toxicities were observed. There was no increased radiation exposure to personnel. Two patients showed decrease in the index lesions' SUVs by 17-33% (Day 1) and 25-31% (Day 30) post treatment. The two other patients showed stable disease on 18F-PET-CT. Interestingly, responses were seen at low radiotherapy doses (below 1 Gy). This exploratory study demonstrated the safety of therapeutic administration of up to 14.2 GBq (385 mCi) 18F-FDG. In patients with 18F-FDG-avid cancers, targeted radionuclide 18F-FDG therapy appears safe and may offer clinical benefit.
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BACKGROUND AND PURPOSE: Patients with locally advanced oropharynx squamous cell carcinoma have suboptimal outcomes with standard chemoradiation. Here, we evaluated toxicity and oncologic outcomes of dose escalation using radiosurgical boost for patients with unfavorable oropharynx squamous cell carcinoma. MATERIALS AND METHODS: Between 2010-2017, Thirty four patients with intermediate- or high-risk oropharynx squamous cell carcinoma were enrolled onto this prospective phase I trial. Each patient received concurrent cisplatin and fractionated radiotherapy totaling 60 Gy or 66 Gy followed by radiosurgery boost to areas of residual gross tumor: single fraction of 8 Gy or 10 Gy, or two fractions of 5 Gy each. Primary endpoint was treatment toxicity. Secondary endpoints were local, regional, and distant disease control. RESULTS: Eleven, sixteen and seven patients received radiosurgery boost with 8 Gy in 1 fraction, 10 Gy in 1 fraction, and 10 Gy in 2 fractions respectively. Acute toxicities include 4 patients with tumor necrosis causing grade 3 dysphagia, of which 3 developed grade 4 pharyngeal hemorrhage requiring surgical intervention. At 24 months after treatment, 7%, 9%, and 15% had grade 2 dysgeusia, xerostomia, and dysphagia, respectively, and two patients remained feeding tube dependent. No grade 5 toxicities occurred secondary to treatment. Local, regional, and distant control at a median follow up of 4.2 years were 85.3%, 85.3% and 88.2%, respectively. Five patients died resulting in overall survival of 85.3%. CONCLUSIONS: This study is the first to report the use of radiosurgery boost dose escalation in patients with unfavorable oropharynx squamous cell carcinoma. Longer follow-up, larger cohorts, and further refinement of boost methodology are needed prior to implementation in routine clinical practice. TRIAL REGISTRATION: Northwell Health Protocol #09-309A (NCT02703493) ( https://clinicaltrials.gov/ct2/show/NCT02703493 ).