Ultra-Low-Cost Disposable Hand-Held Clinical-Scale Propane Gas Hyperpolarizer for Pulmonary Magnetic Resonance Imaging Sensing.

Hyperpolarized magnetic resonance imaging (MRI) contrast agents are revolutionizing the field of biomedical imaging. Hyperpolarized Xe-129 was recently FDA approved as an inhalable MRI contrast agent for functional lung imaging sensing. Despite success in research settings, modern Xe-129 hyperpolarizers are expensive (up to $1M), large, and complex to site and operate. Moreover, Xe-129 sensing requires specialized MRI hardware that is not commonly available on clinical MRI scanners. Here, we demonstrate that proton-hyperpolarized propane gas can be produced on demand using a disposable, hand-held, clinical-scale hyperpolarizer via parahydrogen-induced polarization, which relies on parahydrogen as a source of hyperpolarization. The device consists of a heterogeneous catalytic reactor connected to a gas mixture storage can containing pressurized hyperpolarization precursors: propylene and parahydrogen (10 bar total pressure). Once the built-in flow valve of the storage can is actuated, the precursors are ejected from the can into a reactor, and a stream of hyperpolarized propane gas is ejected from the reactor. Robust operation of the device is demonstrated for producing proton sensing polarization of 1.2% in a wide range of operational pressures and gas flow rates. We demonstrate that the propylene/parahydrogen gas mixture can retain potency for days in the storage can with a monoexponential decay time constant of 6.0 ± 0.5 days, which is limited by the lifetime of the parahydrogen singlet spin state in the storage container. The utility of the produced sensing agent is demonstrated for phantom imaging on a 3 T clinical MRI scanner located 100 miles from the agent/device preparation site and also for ventilation imaging of excised pig lungs using a 0.35 T clinical MRI scanner. The cost of the device components is less than $35, which we envision can be reduced to less than $5 for mass-scale production. The hyperpolarizer device can be reused, recycled, or disposed.

Transfontanelle photoacoustic imaging of intraventricular brain hemorrhages in live sheep.

Intraventricular (IVH) and periventricular (PVH) hemorrhages in preterm neonates are common because the periventricular blood vessels are still developing up to 36 weeks and are fragile. Currently, transfontanelle ultrasound (US) imaging is utilized for screening for IVH and PVH, largely through the anterior fontanelle. However for mild hemorrhages, inconclusive diagnoses are common, leading to failure to detect IVH/PVH or, when other clinical symptoms are present, use of second stage neuroimaging modalities requiring transport of vulnerable patients. Yet even mild IVH/PVH increases the risk of moderate-severe neurodevelopmental impairment. Here, we demonstrate the capability of transfontanelle photoacoustic imaging (TFPAI) to detect IVH and PVH in-vivo in a large animal model. TFPAI was able to detect IVH/PVH as small as 0.3 mL in volume in the brain (p < 0.05). By contrast, US was able to detect hemorrhages as small as 0.5 mL. These preliminary results suggest TFPAI could be translated into a portable bedside imaging probe for improved diagnosis of clinically relevant brain hemorrhages in neonates.

Development and characterization of transfontanelle photoacoustic imaging system for detection of intracranial hemorrhages and measurement of brain oxygenation: Ex-vivo.

We have developed and optimized an imaging system to study and improve the detection of brain hemorrhage and to quantify oxygenation. Since this system is intended to be used for brain imaging in neonates through the skull opening, i.e., fontanelle, we called it, Transfontanelle Photoacoustic Imaging (TFPAI) system. The system is optimized in terms of optical and acoustic designs, thermal safety, and mechanical stability. The lower limit of quantification of TFPAI to detect the location of hemorrhage and its size is evaluated using in-vitro and ex-vivo experiments. The capability of TFPAI in measuring the tissue oxygenation and detection of vasogenic edema due to brain blood barrier disruption are demonstrated. The results obtained from our experimental evaluations strongly suggest the potential utility of TFPAI, as a portable imaging modality in the neonatal intensive care unit. Confirmation of these findings in-vivo could facilitate the translation of this promising technology to the clinic.

Ceramide as an endothelial cell surface receptor and a lung-specific lipid vascular target for circulating ligands.

The vascular endothelium from individual organs is functionally specialized, and it displays a unique set of accessible molecular targets. These serve as endothelial cell receptors to affinity ligands. To date, all identified vascular receptors have been proteins. Here, we show that an endothelial lung-homing peptide (CGSPGWVRC) interacts with C16-ceramide, a bioactive sphingolipid that mediates several biological functions. Upon binding to cell surfaces, CGSPGWVRC triggers ceramide-rich platform formation, activates acid sphingomyelinase and ceramide production, without the associated downstream apoptotic signaling. We also show that the lung selectivity of CGSPGWVRC homing peptide is dependent on ceramide production in vivo. Finally, we demonstrate two potential applications for this lipid vascular targeting system: i) as a bioinorganic hydrogel for pulmonary imaging and ii) as a ligand-directed lung immunization tool against COVID-19. Thus, C16-ceramide is a unique example of a lipid-based receptor system in the lung vascular endothelium targeted in vivo by circulating ligands such as CGSPGWVRC.

Unraveling Lifelong Brain Morphometric Dynamics: A Protocol for Systematic Review and Meta-Analysis in Healthy Neurodevelopment and Ageing.

A high incidence and prevalence of neurodegenerative diseases and neurodevelopmental disorders justify the necessity of well-defined criteria for diagnosing these pathologies from brain imaging findings. No easy-to-apply quantitative markers of abnormal brain development and ageing are available. We aim to find the characteristic features of non-pathological development and degeneration in distinct brain structures and to work out a precise descriptive model of brain morphometry in age groups. We will use four biomedical databases to acquire original peer-reviewed publications on brain structural changes occurring throughout the human life-span. Selected publications will be uploaded to Covidence systematic review software for automatic deduplication and blinded screening. Afterwards, we will manually review the titles, abstracts, and full texts to identify the papers matching eligibility criteria. The relevant data will be extracted to a 'Summary of findings' table. This will allow us to calculate the annual rate of change in the volume or thickness of brain structures and to model the lifelong dynamics in the morphometry data. Finally, we will adjust the loss of weight/thickness in specific brain areas to the total intracranial volume. The systematic review will synthesise knowledge on structural brain change across the life-span.

Multimodal diagnostics in multiple sclerosis: predicting disability and conversion from relapsing-remitting to secondary progressive disease course - protocol for systematic review and meta-analysis.

BACKGROUND: The number of patients diagnosed with multiple sclerosis (MS) has increased significantly over the last decade. The challenge is to identify the transition from relapsing-remitting to secondary progressive MS. Since available methods to examine patients with MS are limited, both the diagnostics and prognostication of disease progression would benefit from the multimodal approach. The latter combines the evidence obtained from disparate radiologic modalities, neurophysiological evaluation, cognitive assessment and molecular diagnostics. In this systematic review we will analyse the advantages of multimodal studies in predicting the risk of conversion to secondary progressive MS. METHODS AND ANALYSIS: We will use peer-reviewed publications available in Web of Science, Medline/PubMed, Scopus, Embase and CINAHL databases. In vivo studies reporting the predictive value of diagnostic methods will be considered. Selected publications will be processed through Covidence software for automatic deduplication and blind screening. Two reviewers will use a predefined template to extract the data from eligible studies. We will analyse the performance metrics (1) for the classification models reflecting the risk of secondary progression: sensitivity, specificity, accuracy, area under the receiver operating characteristic curve, positive and negative predictive values; (2) for the regression models forecasting disability scores: the ratio of mean absolute error to the range of values. Then, we will create ranking charts representing performance of the algorithms for calculating disability level and MS progression. Finally, we will compare the predictive power of radiological and radiomical correlates of clinical disability and cognitive impairment in patients with MS. ETHICS AND DISSEMINATION: The study does not require ethical approval because we will analyse publicly available literature. The project results will be published in a peer-review journal and presented at scientific conferences. PROSPERO REGISTRATION NUMBER: CRD42022354179.

Nitrogen-15 and Fluorine-19 Relaxation Dynamics and Spin-Relayed SABRE-SHEATH Hyperpolarization of Fluoro-[15N3]metronidazole.

Efficient 15N-hyperpolarization of [15N3]metronidazole was reported previously using the Signal Amplification By Reversible Exchange in SHield Enabled Alignment Transfer (SABRE-SHEATH) technique. This hyperpolarized FDA-approved antibiotic is a potential contrast agent because it can be administered in a large dose and because previous studies revealed long-lasting HP states with exponential decay constant T1 values of up to 10 min. Possible hypoxia-sensing applications have been proposed using hyperpolarized [15N3]metronidazole. In this work, we report on the functionalization of [15N3]metronidazole with a fluorine-19 moiety via a one-step reaction to substitute the -OH group. SABRE-SHEATH hyperpolarization studies of fluoro-[15N3]metronidazole revealed efficient hyperpolarization of all three 15N sites with maximum %P15N values ranging from 4.2 to 6.2%, indicating efficient spin-relayed polarization transfer in microtesla fields via the network formed by 2J15N-15N. The corresponding 15N to 19F spin-relayed polarization transfer was found to be far less efficient with %P19F of 0.16%, i.e., more than an order of magnitude lower than that of 15N. Relaxation dynamics studies in microtesla fields support a spin-relayed polarization transfer mechanism because all 15N and 19F spins share the same T1 value of ca. 16-20 s and the same magnetic field profile for the SABRE-SHEATH polarization process. We envision the use of fluoro-[15N3]metronidazole as a potential hypoxia sensor. It is anticipated that under hypoxic conditions, the nitro group of fluoro-[15N3]metronidazole undergoes electronic stepwise reduction to an amino derivative. Ab initio calculations of 15N and 19F chemical shifts of fluoro-[15N3]metronidazole and its putative hypoxia-induced metabolites clearly indicate that the chemical shift dispersions of all three 15N sites and the 19F site are large enough to enable the envisioned hypoxia-sensing approaches.

Bilirubin-biliverdin concentration measurement using photoacoustic spectroscopic analysis for determining hemorrhage age.

The onset of intracerebral hemorrhage and its progression toward acute brain injury have been correlated with the concentration of unconjugated bilirubin (BR). In addition, BR has been considered a novel predictor of outcome from intracranial hemorrhage. Since the existing invasive approach for determining localized BR and biliverdin (BV) concentration within the hemorrhagic brain lesion is not feasible, the predictive capability of BR in terms of determining the onset of hemorrhage and understanding the consequences of its progression (age) is unknown. In this study, we have demonstrated a photoacoustic (PA) approach to the noninvasive measurement of BR-BV ratio that can be utilized longitudinally to approximate the onset of the hemorrhage. The PA imaging-based measurements of BV and BR in tissues and fluids can potentially be used to determine hemorrhage "age," quantitatively evaluate the hemorrhage resorption or detect a rebleeding, and assess responses to therapy and prognosis.

Low- and high-cocaine intake affects the spatial and temporal dynamics of class IIa HDAC expression-activity in the nucleus accumbens and hippocampus of male rats as measured by [18F]TFAHA PET/CT neuroimaging.

Repeated cocaine alters neuronal function in the nucleus accumbens (NAc), a brain region involved in cocaine taking, and in hippocampus (HC), known for contextual and associative learning. [18F]TFAHA is a histone deacetylase (HDAC) class IIa-specific radiotracer for positron emission tomography (PET)-imaging developed by our group to study epigenetic mechanisms. Here, [18F]TFAHA was used to conduct PET-imaging coupled with computed tomography (CT) of rat brains at baseline and after repeated cocaine intravenous self-administration (cocaine-IVSA) in low-intake versus high-intake cocaine groups. A 3 h-access FR1-schedule of cocaine-IVSA (0.5 mg/kg/infusion) for 12 continuous days was used with male Sprague Dawley rats following jugular vein catheterization. PET/CT neuroimaging with [18F]TFAHA was acquired in a dynamic mode over 40 min post-radiotracer administration at baseline and on day 12 of cocaine-IVSA using a longitudinal, repeated design. This study shows that high-cocaine intake significantly decreases class IIa HDAC expression-activity in NAc, while low-cocaine intake significantly decreases expression-activity in HC in male rats. These findings suggest the individual rats with low-cocaine intake had epigenetic changes in HC, where drug-associative changes occur. Alternatively, individuals with high-cocaine intake had robust epigenetic changes in NAc, where rewared-related behaviors originate. These findings are the first longitudinal data obtained in vivo to implicate class IIa HDACs in the persistent behavioral effects of cocaine. Furthermore, our results are consistent with published research implicating class IIa HDACs in cocaine-induced brain changes and studies suggesting a relationship between an individual's drug-taking behavior and regional pattern of epigenetic changes in the brain.

Real-time COVID-19 detection via graphite oxide-based field-effect transistor biosensors decorated with Pt/Pd nanoparticles.

Coronavirus 2019 (COVID-19) spreads an extremely infectious disease where there is no specific treatment. COVID-19 virus had a rapid and unexpected spread rate which resulted in critical difficulties for public health and unprecedented daily life disruption. Thus, accurate, rapid, and early diagnosis of COVID-19 virus is critical to maintain public health safety. A graphite oxide-based field-effect transistor (GO-FET) was fabricated and functionalized with COVID-19 antibody for the purpose of real-time detection of COVID-19 spike protein antigen. Thermal evaporation process was used to deposit the gold electrodes on the surface of the sensor substrate. Graphite oxide channel was placed between the gold electrodes. Bimetallic nanoparticles of platinum and palladium were generated via an ultra-high vacuum (UHV) compatible system by sputtering and inert-gas condensation technique. The biosensor graphite oxide channel was immobilized with specific antibodies against the COVID-19 spike protein to achieve selectivity and specificity. This technique uses the attractive semiconductor characteristics of the graphite oxide-based materials resulting in highly specific and sensitive detection of COVID-19 spike protein. The GO-FET biosensor was decorated with bimetallic nanoparticles of platinum and palladium to investigate the improvement in the sensor sensitivity. The in-house developed biosensor limit of detection (LOD) is 1 fg/mL of COVID-19 spike antigen in phosphate-buffered saline (PBS). Moreover, magnetic labelled SARS-CoV-2 spike antibody were studied to investigate any enhancement in the sensor performance. The results indicate the successful fabrication of a promising field effect transistor biosensor for COVID-19 diagnosis.

COVID-19 Detection via Silicon Nanowire Field-Effect Transistor: Setup and Modeling of Its Function.

Biomolecular detection methods have evolved from simple chemical processes to laboratory sensors capable of acquiring accurate measurements of various biological components. Recently, silicon nanowire field-effect transistors (SiNW-FETs) have been drawing enormous interest due to their potential in the biomolecular sensing field. SiNW-FETs exhibit capabilities such as providing real-time, label-free, highly selective, and sensitive detection. It is highly critical to diagnose infectious diseases accurately to reduce the illness and death spread rate. In this work, a novel SiNW-FET sensor is designed using a semiempirical approach, and the electronic transport properties are studied to detect the COVID-19 spike protein. Various electronic transport properties such as transmission spectrum, conductance, and electronic current are investigated by a semiempirical modeling that is combined with a nonequilibrium Green's function. Moreover, the developed sensor selectivity is tested by studying the electronic transport properties for other viruses including influenza, rotavirus, and HIV. The results indicate that SiNW-FET can be utilized for accurate COVID-19 identification with high sensitivity and selectivity.

Deep Learning-Based Automatic Assessment of Lung Impairment in COVID-19 Pneumonia: Predicting Markers of Hypoxia With Computer Vision.

Background: Hypoxia is a potentially life-threatening condition that can be seen in pneumonia patients. Objective: We aimed to develop and test an automatic assessment of lung impairment in COVID-19 associated pneumonia with machine learning regression models that predict markers of respiratory and cardiovascular functioning from radiograms and lung CT. Materials and Methods: We enrolled a total of 605 COVID-19 cases admitted to Al Ain Hospital from 24 February to 1 July 2020 into the study. The inclusion criteria were as follows: age ≥ 18 years; inpatient admission; PCR positive for SARS-CoV-2; lung CT available at PACS. We designed a CNN-based regression model to predict systemic oxygenation markers from lung CT and 2D diagnostic images of the chest. The 2D images generated by averaging CT scans were analogous to the frontal and lateral view radiograms. The functional (heart and breath rate, blood pressure) and biochemical findings (SpO2, H C O 3 - , K +, Na +, anion gap, C-reactive protein) served as ground truth. Results: Radiologic findings in the lungs of COVID-19 patients provide reliable assessments of functional status with clinical utility. If fed to ML models, the sagittal view radiograms reflect dyspnea more accurately than the coronal view radiograms due to the smaller size and the lower model complexity. Mean absolute error of the models trained on single-projection radiograms was approximately 11÷12% and it dropped by 0.5÷1% if both projections were used (11.97 ± 9.23 vs. 11.43 ± 7.51%; p = 0.70). Thus, the ML regression models based on 2D images acquired in multiple planes had slightly better performance. The data blending approach was as efficient as the voting regression technique: 10.90 ± 6.72 vs. 11.96 ± 8.30%, p = 0.94. The models trained on 3D images were more accurate than those on 2D: 8.27 ± 4.13 and 11.75 ± 8.26%, p = 0.14 before lung extraction; 10.66 ± 5.83 and 7.94 ± 4.13%, p = 0.18 after the extraction. The lung extraction boosts 3D model performance unsubstantially (from 8.27 ± 4.13 to 7.94 ± 4.13%; p = 0.82). However, none of the differences between 3D and 2D were statistically significant. Conclusion: The constructed ML algorithms can serve as models of structure-function association and pathophysiologic changes in COVID-19. The algorithms can improve risk evaluation and disease management especially after oxygen therapy that changes functional findings. Thus, the structural assessment of acute lung injury speaks of disease severity.

Spatial and temporal dynamics of HDACs class IIa following mild traumatic brain injury in adult rats.

The fundamental role of epigenetic regulatory mechanisms involved in neuroplasticity and adaptive responses to traumatic brain injury (TBI) is gaining increased recognition. TBI-induced neurodegeneration is associated with several changes in the expression-activity of various epigenetic regulatory enzymes, including histone deacetylases (HDACs). In this study, PET/CT with 6-([18F]trifluoroacetamido)-1- hexanoicanilide ([18F]TFAHA) to image spatial and temporal dynamics of HDACs class IIa expression-activity in brains of adult rats subjected to a weight drop model of diffuse, non-penetrating, mild traumatic brain injury (mTBI). The mTBI model was validated by histopathological and immunohistochemical analyses of brain tissue sections for localization and magnitude of expression of heat-shock protein-70 kDa (HSP70), amyloid precursor protein (APP), cannabinoid receptor-2 (CB2), ionized calcium-binding adapter protein-1 (IBA1), histone deacetylase-4 and -5 (HDAC4 and HDAC5). In comparison to baseline, the expression-activities of HDAC4 and HDAC5 were downregulated in the hippocampus, nucleus accumbens, peri-3rd ventricular part of the thalamus, and substantia nigra at 1-3 days post mTBI, and remained low at 7-8 days post mTBI. Reduced levels of HDAC4 and HDAC5 expression observed in neurons of these brain regions post mTBI were associated with the reduced nuclear and neuropil levels of HDAC4 and HDAC5 with the shift to perinuclear localization of these enzymes. These results support the rationale for the development of therapeutic strategies to upregulate expression-activity of HDACs class IIa post-TBI. PET/CT (MRI) with [18F]TFAHA can facilitate the development and clinical translation of unique therapeutic approaches to upregulate the expression and activity of HDACs class IIa enzymes in the brain after TBI.

Patterns of structure-function association in normal aging and in Alzheimer's disease: Screening for mild cognitive impairment and dementia with ML regression and classification models.

Background: The combined analysis of imaging and functional modalities is supposed to improve diagnostics of neurodegenerative diseases with advanced data science techniques. Objective: To get an insight into normal and accelerated brain aging by developing the machine learning models that predict individual performance in neuropsychological and cognitive tests from brain MRI. With these models we endeavor to look for patterns of brain structure-function association (SFA) indicative of mild cognitive impairment (MCI) and Alzheimer's dementia. Materials and methods: We explored the age-related variability of cognitive and neuropsychological test scores in normal and accelerated aging and constructed regression models predicting functional performance in cognitive tests from brain radiomics data. The models were trained on the three study cohorts from ADNI dataset-cognitively normal individuals, patients with MCI or dementia-separately. We also looked for significant correlations between cortical parcellation volumes and test scores in the cohorts to investigate neuroanatomical differences in relation to cognitive status. Finally, we worked out an approach for the classification of the examinees according to the pattern of structure-function associations into the cohorts of the cognitively normal elderly and patients with MCI or dementia. Results: In the healthy population, the global cognitive functioning slightly changes with age. It also remains stable across the disease course in the majority of cases. In healthy adults and patients with MCI or dementia, the trendlines of performance in digit symbol substitution test and trail making test converge at the approximated point of 100 years of age. According to the SFA pattern, we distinguish three cohorts: the cognitively normal elderly, patients with MCI, and dementia. The highest accuracy is achieved with the model trained to predict the mini-mental state examination score from voxel-based morphometry data. The application of the majority voting technique to models predicting results in cognitive tests improved the classification performance up to 91.95% true positive rate for healthy participants, 86.21%-for MCI and 80.18%-for dementia cases. Conclusion: The machine learning model, when trained on the cases of this of that group, describes a disease-specific SFA pattern. The pattern serves as a "stamp" of the disease reflected by the model.

The role of noninvasive diagnostic imaging in monitoring pregnancy and detecting patients at risk for preterm birth: a review of quantitative approaches.

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. The ability to predict patients at risk for preterm birth remains a major health challenge. The currently available clinical diagnostics such as cervical length and fetal fibronectin may detect only up to 30% of patients who eventually experience a spontaneous preterm birth. This paper reviews ongoing efforts to improve the ability to conduct a risk assessment for preterm birth. In particular, this work focuses on quantitative methods of imaging using ultrasound-based techniques, magnetic resonance imaging, and optical imaging modalities. While ultrasound imaging is the major modality for preterm birth risk assessment, a summary of efforts to adopt other imaging modalities is also discussed to identify the technical and diagnostic limits associated with adopting them in clinical settings. We conclude the review by proposing a new approach using combined photoacoustic, ultrasound, and elastography as a potential means to better assess cervical tissue remodeling, and thus improve the detection of patients at-risk of PTB.

Endocavity ultrasound and photoacoustic system for fetal and maternal imaging: design, implementation, and ex-vivo validation.

Purpose: Transvaginal ultrasound (TVUS) is a widely used real-time and non-invasive imaging technique for fetal and maternal care. It can provide structural and functional measurements about the fetal brain, such as blood vessel diameter and blood flow. However, it lacks certain biochemical estimations, such as hemoglobin oxygen saturation ( SO 2 ), which limits its ability to indicate a fetus at risk of birth asphyxia. Photoacoustic (PA) imaging has been steadily growing in recognition as a complement to ultrasound (US). Studies have shown PA imaging is capable of providing such biochemical estimations as SO 2 at relatively high penetration depth (up to 30 mm). Approach: In this study, we have designed and developed a multi-modal (US, PA, and Doppler) endocavity imaging system (ECUSPA) around a commercialized TVUS probe (Philips ATL C9-5). Results: The integrated system was evaluated through a set of in-vitro, ex-vivo, and in-vivo studies. Imaging of excised sheep brain tissue demonstrated the system's utility and penetration depth in transfontanelle imaging conditions. The accuracy of using the spectroscopic PA imaging (sPA) method to estimate SO 2 was validated by comparing sPA oximetry results with the gold standard measurements indicated by a blood gas analyzer. The ability of US and Doppler to measure moving blood volume was evaluated in-vivo. Spectral unmixing capabilities were tested using fluorophores within sheep brains. Conclusion: The developed system is a high resolution (about 200 µ m at 30 mm depth), real-time (at 30 Hz), and quantitative ( SO 2 estimation error < 10 % ) imaging tool with a total diameter less than 30 mm, making it suitable for intrapartum applications such as fetal and maternal diagnostics.

Evaluation of Class IIa Histone Deacetylases Expression and In Vivo Epigenetic Imaging in a Transgenic Mouse Model of Alzheimer's Disease.

Epigenetic regulation by histone deacetylase (HDAC) is associated with synaptic plasticity and memory formation, and its aberrant expression has been linked to cognitive disorders, including Alzheimer's disease (AD). This study aimed to investigate the role of class IIa HDAC expression in AD and monitor it in vivo using a novel radiotracer, 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]TFAHA). A human neural cell culture model with familial AD (FAD) mutations was established and used for in vitro assays. Positron emission tomography (PET) imaging with [18F]TFAHA was performed in a 3xTg AD mouse model for in vivo evaluation. The results showed a significant increase in HDAC4 expression in response to amyloid-ß (Aß) deposition in the cell model. Moreover, treatment with an HDAC4 selective inhibitor significantly upregulated the expression of neuronal memory-/synaptic plasticity-related genes. In [18F]TFAHA-PET imaging, whole brain or regional uptake was significantly higher in 3xTg AD mice compared with WT mice at 8 and 11 months of age. Our study demonstrated a correlation between class IIa HDACs and Aßs, the therapeutic benefit of a selective inhibitor, and the potential of using [18F]TFAHA as an epigenetic radiotracer for AD, which might facilitate the development of AD-related neuroimaging approaches and therapies.

Targeting a cell surface vitamin D receptor on tumor-associated macrophages in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive tumor with limited treatment options and poor prognosis. We applied the in vivo phage display technology to isolate peptides homing to the immunosuppressive cellular microenvironment of TNBC as a strategy for non-malignant target discovery. We identified a cyclic peptide (CSSTRESAC) that specifically binds to a vitamin D receptor, protein disulfide-isomerase A3 (PDIA3) expressed on the cell surface of tumor-associated macrophages (TAM), and targets breast cancer in syngeneic TNBC, non-TNBC xenograft, and transgenic mouse models. Systemic administration of CSSTRESAC to TNBC-bearing mice shifted the cytokine profile toward an antitumor immune response and delayed tumor growth. Moreover, CSSTRESAC enabled ligand-directed theranostic delivery to tumors and a mathematical model confirmed our experimental findings. Finally, in silico analysis showed PDIA3-expressing TAM in TNBC patients. This work uncovers a functional interplay between a cell surface vitamin D receptor in TAM and antitumor immune response that could be therapeutically exploited.

In Vivo Evaluation of the Combined Anticancer Effects of Cisplatin and SAHA in Nonsmall Cell Lung Carcinoma Using [18F]FAHA and [18F]FDG PET/CT Imaging.

Combining standard drugs with low doses of histone deacetylase inhibitors (HDACIs) is a promising strategy to increase the efficacy of chemotherapy. The ability of well-tolerated doses of HDACIs that act as chemosensitizers for platinum-based chemotherapeutics has recently been proven in many types and stages of cancer in vitro and in vivo. Detection of changes in HDAC activity/expression may provide important prognostic and predictive information and influence treatment decision-making. Use of [18F] FAHA, a HDAC IIa-specific radionuclide, for molecular imaging may enable longitudinal, noninvasive assessment of HDAC activity/expression in metastatic cancer. We evaluated the synergistic anticancer effects of cisplatin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in xenograft models of nonsmall cell lung cancer (NSCLC) using [18F] FAHA and [18F] FDG PET/CT imaging. Cisplatin alone significantly increased [18F] FAHA accumulation and reduced [18F] FDG accumulation in H441 and PC14 xenografts; coadministration of cisplatin and SAHA resulted in the opposite effects. Immunochemical staining for acetyl-histone H3 confirmed the PET/CT imaging findings. Moreover, SAHA had a more significant effect on the acetylome in PC14 (EGFR exon 19 deletion mutation) xenografts than H441 (wild-type EGFR and KRAS codon 12 mutant) xenografts. In conclusion, [18F] FAHA enables quantitative visualization of HDAC activity/expression in vivo, thus, may represent a clinically useful, noninvasive tool for the management of patients who may benefit from synergistic anticancer therapy.

Synthetic Approaches for 15 N-Labeled Hyperpolarized Heterocyclic Molecular Imaging Agents for 15 N NMR Signal Amplification by Reversible Exchange in Microtesla Magnetic Fields.

NMR hyperpolarization techniques enhance nuclear spin polarization by several orders of magnitude resulting in corresponding sensitivity gains. This enormous sensitivity gain enables new applications ranging from studies of small molecules by using high-resolution NMR spectroscopy to real-time metabolic imaging in vivo. Several hyperpolarization techniques exist for hyperpolarization of a large repertoire of nuclear spins, although the 13 C and 15 N sites of biocompatible agents are the key targets due to their widespread use in biochemical pathways. Moreover, their long T1 allows hyperpolarized states to be retained for up to tens of minutes. Signal amplification by reversible exchange (SABRE) is a low-cost and ultrafast hyperpolarization technique that has been shown to be versatile for the hyperpolarization of 15 N nuclei. Although large sensitivity gains are enabled by hyperpolarization, 15 N natural abundance is only ∼0.4 %, so isotopic labeling of the molecules to be hyperpolarized is required in order to take full advantage of the hyperpolarized state. Herein, we describe selected advances in the preparation of 15 N-labeled compounds with the primary emphasis on using these compounds for SABRE polarization in microtesla magnetic fields through spontaneous polarization transfer from parahydrogen. Also, these principles can certainly be applied for hyperpolarization of these emerging contrast agents using dynamic nuclear polarization and other techniques.