Sustained Secretion of CCL21 via an Implantable Cell Reservoir Hydrogel Enhances the Systemic Antitumor Effect of Radiotherapy.

The combination of radiotherapy (RT) and immunotherapy shows promise in improving the clinical treatment of solid tumors; however, it faces challenges of low response rates and systemic toxicity. Herein, an implantable alginate/collagen hydrogel encapsulating C-C motif ligand 21 (CCL21)-expressing dendritic cells (CCL21-DCs@gel) was developed to potentiate the systemic antitumor effects of RT. The hydrogel functioned as a suitable reservoir for in vivo culture and proliferation of CCL21-DCs, thereby enabling sustained CCL21 release. The local CCL21 gradient induced by CCL21-DCs@gel significantly enhanced the efficacy of RT in suppressing primary tumor growth and inhibiting distant metastasis across several mouse models. Furthermore, the combination of RT with CCL21-DCs@gel provided complete prophylactic protection to mice. Mechanistic investigations revealed that CCL21-DCs@gel potentiated RT by promoting tumor lymphangiogenesis and attracting immune cell infiltration into the tumor. Collectively, these results suggest that CCL21-DCs@gel is a promising adjunct to RT for effectively eradicating tumors and preventing tumor recurrence.

Noninvasively Deciphering the Immunosuppressive Tumor Microenvironment Using Galectin-1 PET to Inform Immunotherapy Responses.

Immune checkpoint blockade (ICB) has achieved groundbreaking results in clinical cancer therapy; however, only a subset of patients experience durable benefits. The aim of this study was to explore strategies for predicting tumor responses to optimize the intervention approach using ICB therapy. Methods: We used a bilateral mouse model for proteomics analysis to identify new imaging biomarkers for tumor responses to ICB therapy. A PET radiotracer was synthesized by radiolabeling the identified biomarker-targeting antibody with 124I. The radiotracer was then tested for PET prediction of tumor responses to ICB therapy. Results: We identified galectin-1 (Gal-1), a member of the carbohydrate-binding lectin family, as a potential negative biomarker for ICB efficacy. We established that Gal-1 inhibition promotes a sensitive immune phenotype within the tumor microenvironment (TME) for ICB therapy. To assess the pre-ICB treatment status of the TME, a Gal-1-targeted PET radiotracer, 124I-αGal-1, was developed. PET imaging with 124I-αGal-1 showed the pretreatment immunosuppressive status of the TME before the initiation of therapy, thus enabling the prediction of ICB resistance in advance. Moreover, the use of hydrogel scaffolds loaded with a Gal-1 inhibitor, thiodigalactoside, demonstrated that a single dose of thiodigalactoside-hydrogel significantly potentiated ICB and adoptive cell transfer immunotherapies by remodeling the immunosuppressive TME. Conclusion: Our study underscores the potential of Gal-1-targeted PET imaging as a valuable strategy for early-stage monitoring of tumor responses to ICB therapy. Additionally, Gal-1 inhibition effectively counteracts the immunosuppressive TME, resulting in enhanced immunotherapy efficacy.

Annotation of CD8+ T-cell function via ICAM-1 imaging identifies FAK inhibition as an adjuvant to augment the antitumor immunity of radiotherapy.

Background: Radiotherapy (RT) may trigger systemic antitumor immunity, manifesting as regression of non-irradiated lesions (abscopal effect). Intracellular adhesion molecule-1 (ICAM-1) is a key molecule involved in the abscopal effect of RT. However, the specific function of ICAM-1 in CD8+ T cells during antitumor immune responses remains unclear. Herein, we investigated whether noninvasive imaging of ICAM-1 can be used to annotate CD8+ T-cell function, thereby better selecting combinational therapy to enhance the antitumor immunity induced by RT. Methods: Using knockout mouse models, we investigated the role of ICAM-1 expressed on CD8+ T cells in the antitumor immunity of RT and conducted drug screening guided by ICAM-1-targeted noninvasive imaging. Results: The systemic antitumor effect of RT relies on the expression of ICAM-1 on CD8+ T cells. ICAM-1 expression is essential for CD8+ T-cell activation, proliferation, and effector function. Noninvasive annotation of the proliferation and effector function of CD8+ T cells by ICAM-1-targeted imaging identified VS-6063, a focal adhesion kinase inhibitor, as a new adjuvant to augment systemic antitumor immunity of RT in an immunologically "cold" tumor model. Mechanistically, VS-6063 overcomes the physical barriers in tumors and promotes the migration and infiltration of CD8+ T cells primed by RT into distant tumors. Conclusion: Our findings highlight that molecular imaging of ICAM-1 levels provides a dynamic readout of the proliferation and effector function of tumor-infiltrating CD8+ T cells, which facilitates the high-throughput exploitation of new combinational drugs to maximize the systemic antitumor effect of RT.

Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway.

Currently, the effect and molecular mechanism of calycosin, the main active ingredient of Qinshi Simiao San, which can alleviate chronic prostatitis (CP), on CP remain unclear. This study aimed to elucidate the potential mechanism of action of calycosin in CP in a rat CP model. The prostate tissue morphology was evaluated based on hematoxylin-eosin staining. Enzyme-linked immunosorbent assay was conducted to evaluate inflammatory cytokine and immune factor levels (secretory immunoglobulin A [SIgA]; immunoglobulin G [IgG]) in prostate tissues and serum. Additionally, representative biomarkers of oxidative stress, including malondialdehyde, superoxide dismutase, and catalase were detected using detection kits, and reactive oxygen species release was evaluated using immunofluorescence staining. Furthermore, the p38 mitogen-activated protein kinase (p38MAPK)/NF-kappaB (NF-κB) signaling pathway was analyzed by western blotting. The results showed that calycosin substantially ameliorated the pathological damage to prostate tissues of the CP rats. Moreover, calycosin significantly downregulated interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha, IgG, and SIgA levels. Furthermore, we found that calycosin considerably suppressed oxidative stress and inhibited the activation of the p38MAPK/NF-κB signaling pathway in rats with CP. In summary, our findings revealed that calycosin protects against CP in rats by inhibiting the p38MAPK/NF-κB pathway.

Post-Modification of a Robust Covalent Organic Framework for Efficient Sequestration of 99 TcO4 - /ReO4.

Nuclear industry spent fuel reprocessing and some radioactive contamination sites often involve high acidity and salinity environments. Currently developed and reported sorbents in 99 TcO4 - sequestration from the nuclear waste are unstable and show low adsorption efficiency in harsh conditions. To address this issue, we developed a post-synthetic modification strategy by grafting imidazole-based ionic liquids (ILs) onto the backbone of covalent organic framework (COF) via vinyl polymerization. The resultant COF-polyILs sorbent exhibits fast adsorption kinetics (<5 min) and good sorption capacity (388 mg g-1 ) for ReO4 - (a nonradioactive surrogate of 99 TcO4 - ). Outstandingly, COF-polyILs composite shows superior ReO4 - removal even under highly acidic conditions and in the presence of excess competing ions of Hanford low-level radioactive waste stream, benefiting from the stable covalent bonds between the COF and polyILs, mass of imidazole rings, and hydrophobic pores in COF.

Landslide susceptibility prediction improvements based on a semi-integrated supervised machine learning model.

Differences in model application effectiveness, insufficient numbers of disaster samples, and unreasonable selection of non-hazard samples are common problems in landslide susceptibility studies. Therefore, in this paper, we propose a semi-integrated supervised approach to improve the prediction performance of machine learning (ML) models in landslide susceptibility studies. First, taking the lower reaches of the Jinsha River as the study area, a geospatial dataset consisting of 349 landslides, an equal number of randomly selected non-landslide points, and 12 environmental factors were randomly divided into training (70%) and testing (30%) datasets. Then, K-nearest neighbors (KNN), random forest (RF), and Bayesian-regularized neural network (BRNN) models were built. Second, the three models were combined to form an integrated weighted model. Very high- and low-prone areas were selected and, combined with the prediction results and remote sensing images, landslide and non-landslide samples were identified. The identified samples were then combined with the original samples to form new samples, which were used to sequentially construct the ensemble-supervised K-nearest neighbors (ESKNN), ensemble-supervised random forest (ESRF), and ensemble-supervised Bayesian-regularized neural network (ESBRNN) models. Finally, the area under the curve (AUC), true skill statistic (TSS), and frequency ratio (FR) values were used to test the accuracy of each model. The traditional ML model results and accuracy were improved by the semi-integrated supervised method. The ESRF model had the best prediction effect (AUC = 0.939, TSS = 0.440, and FR = 95.8%). The proposed semi-integrated supervised ML model solved the problems observed in traditional landslide susceptibility studies and provided insights for reducing variations in model applications, expanding landslide data sources, and improving non-landslide sample selection.

Flow regime changes in the Lancang River, revealed by integrated modeling with multiple Earth observation datasets.

The flow regime change of rivers, especially transboundary rivers, affected by reservoir regulations is evident worldwide and has received much attention. Investigating dam-induced flow regime alterations is essential for understanding potential adverse downstream effects and facilitating dialogue around coordinated water use in transboundary basins, such as the Lancang River Basin (LRB). This study explored the value of combining several types of satellite Earth observation (EO) datasets that monitor different water balance components to constrain the parameter space of lumped conceptual hydrological models. Thus, we aimed to reconstruct the natural flow regimes upstream and downstream of the cascade reservoirs. Specifically, reservoir water storage changes were first estimated using satellite imagery and altimetry datasets. Then, storage changes were combined with hydrological model simulations of reservoir inflow to estimate the regulated flow regime downstream. Our results showed that integrated hydrological modeling combined with EO datasets exhibited better overall performance. Continuous warming and drying of the LRB resulted in a decrease in discharge of approximately 47 %. By comparing the simulated natural and regulated flow regimes, we revealed the pivotal role of the Xiaowan and Nuozhadu reservoirs in regulating natural flows. The wet season shortens (approximately 45 days), the flood peak flattens, and the low flow in the dry season has primarily increases. The two reservoirs attenuated 50 % of the flood peaks in the wet seasons and mitigated droughts by releasing up to 100 % of the natural flows in the dry seasons at the China-Laos border. Overall, these results enhance the understanding of upper reservoir operation, and the approaches can be applied to studies of dammed basins under climate change scenarios when knowledge of the upstream area is limited.

Environmental impacts of 222Rn, Hg and CO2 emissions from the fault zones in the western margin of the Ordos block, China.

Investigating the emissions of soil gas including radon, mercury and carbon dioxide (222Rn, Hg and CO2) from the solid earth to the atmosphere through active fault zones is of great significance for accession of atmospheric environment. In this study, the concentrations and fluxes of 222Rn, Hg and CO2 were measured at the main active fault zones at the western margin of the Ordos block, China. The concentrations of 222Rn, Hg and CO2 were in the range of 0-60.1 kBq m-3, 3-81 ng m-3 and 0.04-9.23%, respectively, while the fluxes of 222Rn, Hg and CO2 are in the range of 1.99-306.99 mBq m-2 s-1, 0-15.12 ng m-2 h-1 and 0-37.91 g m-2d-1, respectively. Most of the major fault zones at the study area are CO2 risk-free regions (CO2 concentration in soil gas < 5%). However, the extend of 222Rn pollution at the fault zones of F1, F4, F5 and F9 (the fault number) and that of Hg pollution at the fault zones of F2, F4, F5 and F7 were higher than the pollution level of 1. The annual emission of Hg and CO2 from the western margin of the Ordos block was estimated to be 2.03 kg and 0.70 Mt, respectively. Comprehensive analyses indicated that the higher emission rates of soil gases from the active fault zones were related to the seismic activities. The results suggest that the earthquake activity is a dominant factor enhancing the emission of 222Rn, Hg and CO2 from the solid earth through active fault zones and, furthermore, resulting great impact on the atmospheric environment.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

BACKGROUND: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. MAIN BODY: This commentary of highlights has resulted in 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals. CONCLUSION: Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field in various topics including new PET-labelling methods, FAPI-tracers and imaging, and radionuclide therapy being the scope of EJNMMI Radiopharmacy and Chemistry.

[Warming-needle moxibustion with different lengths of moxa stick for asthenospermia with kidney deficiency and liver depression: a randomized controlled trial].

OBJECTIVE: To explore the clinical effect of warming-needle moxibustion with different lengths of moxa stick for asthenospermia with kidney deficiency and liver depression. METHODS: A total of 240 patients with asthenospermia of kidney deficiency and liver depression were randomly divided into a 4-cm group (moxibustion with 4-cm moxa stick, 60 cases, 3 cases dropped off), a 3-cm group (moxibustion with 3-cm moxa stick, 60 cases, 4 cases dropped off), a 2-cm group (moxibustion with 2-cm moxa stick, 60 cases, 2 cases dropped off) and an acupuncture group (60 cases, 3 cases dropped off). All patients were treated with warming-needle moxibustion with different lengths of moxa stick or conventicnal acupuncture at Zhongwan (CV 12), Guanyuan (CV 4), Zhongji (CV 3), Guilai (ST 29), Yaoyangguan (GV 3), Guanyuanshu (BL 26), etc., once a day, five times a week; 4-week treatment was taken as one course, a total of two courses of treatment were given. The semen routine indexes, seminal plasma biochemical indexes, sex hormone levels and TCM syndrome score were compared before and after treatment among the 4 groups. RESULTS: After treatment, the sperm density, sperm viability, ratio of grade A sperm, ratio of grade A and B sperm, seminal plasma fructose and neutral α-glucosidase were higher than those before treatment (P<0.05, P<0.01), and the sperm deformity rates were lower than those before treatment in the 4-cm group and the 3-cm group (P<0.01, P<0.05). The ratio of grade A sperm, ratio of grade A and B sperm, seminal plasma fructose and neutral α-glucosidase in the 4-cm group were higher than the other three groups (P<0.05, P<0.01), and the sperm deformity rate was lower than the other three groups (P<0.05). After treatment, except for dizziness and tinnitus score, each-domain score and total scores of TCM syndrome scale in the 4-cm group and the 3-cm group were lower than those before treatment (P<0.01, P<0.05). The each-domain score of depression, weak waist and knees, low sexual function and total score in the 4-cm group were lower than those in the other three groups (P<0.05, P<0.01). The total effective rate was 87.7% (50/57) in the 4-cm group, which was higher than 78.6% (44/56) in the 3-cm group, 77.6% (45/58) in the 2-cm group and 70.2% (40/57) in the acupuncture group (P<0.05, P<0.01). CONCLUSION: The warming-needle moxibustion with 4-cm moxa stick could effectively improve quality and motility of sperm and clinical symptoms in patients with asthenospermia of kidney deficiency and liver depression, which is superior to moxibustion with 3-cm, 2-cm moxa sticks and conventional acupuncture.

Noninvasive interrogation of CD8+ T cell effector function for monitoring early tumor responses to immunotherapy.

Accurately identifying patients who respond to immunotherapy remains clinically challenging. A noninvasive method that can longitudinally capture information about immune cell function and assist in the early assessment of tumor responses is highly desirable for precision immunotherapy. Here, we show that PET imaging using a granzyme B-targeted radiotracer named 68Ga-grazytracer, could noninvasively and effectively predict tumor responses to immune checkpoint inhibitors and adoptive T cell transfer therapy in multiple tumor models. 68Ga-grazytracer was designed and selected from several radiotracers based on non-aldehyde peptidomimetics, and exhibited excellent in vivo metabolic stability and favorable targeting efficiency to granzyme B secreted by effector CD8+ T cells during immune responses. 68Ga-grazytracer permitted more sensitive discrimination of responders and nonresponders than did 18F-fluorodeoxyglucose, distinguishing between tumor pseudoprogression and true progression upon immune checkpoint blockade therapy in mouse models with varying immunogenicity. In a preliminary clinical trial with 5 patients, no adverse events were observed after 68Ga-grazytracer injection, and clinical responses in cancer patients undergoing immunotherapy were favorably correlated with 68Ga-grazytracer PET results. These results highlight the potential of 68Ga-grazytracer PET to enhance the clinical effectiveness of granzyme B secretion-related immunotherapies by supporting early response assessment and precise patient stratification in a noninvasive and longitudinal manner.

Estimating land evapotranspiration from potential evapotranspiration constrained by soil water at daily scale.

Accurate simulation of evapotranspiration is of substantial importance to hydrology, ecology, agriculture, and water resources management. Evapotranspiration is equal to the fraction of potential evapotranspiration (PET) constrained by soil water. PET can be calculated from meteorological observations with a wide global distribution and high density. However, it is necessary to determine how to accurately simulate daily evapotranspiration through PET. We have developed a non-linear function for simulating evapotranspiration through PET constrained by soil water at daily scale. The evaluation results show that the accuracy of the evapotranspiration simulation using the non-linear function was higher than that of linear relations and complementary relationship (CR) methods. In the temperature-based PET equations, the Hargreaves-Samani equation was the closest to the Penman-Monteith calculation values. The simulation accuracy of the CR methods obviously improved after parameter calibration. The accuracy has a large variability at the global scale. Daily evapotranspiration can be simulated with PET data in some regions with a high accuracy (Nash and Sutcliffe efficiency coefficient > 0.60), including most regions of Eurasia, eastern and southern North America, and northern South America. However, other regions showed a poor performance (Nash and Sutcliffe efficiency coefficient < 0.20), including western North America, the Mediterranean region, and the eastern and western coastal regions of Australia. Our results indicate that the accurate simulation of daily evapotranspiration can be achieved based on meteorological data in most regions of the world. Owing to the wide distribution of global meteorological observations, the accurate simulation of the daily evapotranspiration method proposed in this study can be applied in other regions across the globe.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

BACKGROUND: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development. RESULTS: This commentary of highlights has resulted in 23 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals and also a contribution in relation to MRI-agents is included. CONCLUSION: Trends in (radio)chemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry.

A self-triggered radioligand therapy agent for fluorescence imaging of the treatment response in prostate cancer.

PURPOSE: Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is emerging as an effective treatment option for metastatic castration-resistant prostate cancer (mCRPC). An imaging-based method to quantify early treatment responses can help to understand and optimize RLT. METHODS: We developed a self-triggered probe 2 targeting the colocalization of PSMA and caspase-3 for fluorescence imaging of RLT-induced apoptosis. RESULTS: The probe binds to PSMA potently with a Ki of 4.12 nM, and its fluorescence can be effectively switched on by caspase-3 with a Km of 67.62 µM. Cellular and in vivo studies demonstrated its specificity for imaging radiation-induced caspase-3 upregulation in prostate cancer. To identify the detection limit of our method, we showed that probe 2 could achieve 1.79 times fluorescence enhancement in response to 177Lu-RLT in a medium PSMA-expressing 22Rv1 xenograft model. CONCLUSION: Probe 2 can potently bind to PSMA, and the fluorescence signal can be sensitively switched on by caspase-3 both in vitro and in vivo. This method may provide an effective tool to investigate and optimize PSMA-RLT.

Galectin expression detected by 68Ga-galectracer PET as a predictive biomarker of radiotherapy resistance.

PURPOSE: Hypoxia is a hallmark of solid tumors that is related to radiotherapy resistance. As galectin members, such as galectin-1 and galectin-3, are associated with tumor hypoxia, herein we aimed to investigate whether positron emission tomography (PET) imaging of galectin expression can be employed to effectively pinpoint tumor hypoxia, and to predict radiotherapy resistance. METHODS: We synthesized a galectin-targeting radiotracer, designated 68Ga-galectracer, by radiolabeling a thiodigalactoside derivative. The properties of 68Ga-galectracer for PET imaging of tumor hypoxia were characterized in three tumor hypoxia mouse models. Additionally, preliminary PET/CT was performed in two patients with lung cancer to investigate the potential application of 68Ga-galectracer for clinical imaging. RESULTS: High-contrast imaging was achieved in the murine acute hypoxia tumor model, A549 natural hypoxia model, and sorafenib treatment-induced hypoxic 4T1 tumor model by PET using 68Ga-galectracer. In fact, 68Ga-galectracer exhibited superior hypoxia detection to that of 18F-misonidazole in the 4T1 tumors. Moreover, tumors with high galectin expression levels, as detected by 68Ga-galectracer PET, exhibited significantly lower responses to subsequent radiotherapy compared to those with low galectin expression levels. In patients with lung cancer, PET imaging using 68Ga-galectracer provided data that were complementary to that of the glucose metabolic PET radiotracer 18F-fluorodeoxyglucose. CONCLUSION: 68Ga-galectracer is a promising radiotracer for PET-based imaging of tumor hypoxia in vivo. Thus, hypoxia PET with 68Ga-galectracer could provide a noninvasive approach to proactively predict radiotherapy efficacy. TRIAL REGISTRATION: Chictr.org.cn (ChiCTR2000029522). Registered 03 February 2020.

LINC00265 promotes the viability, proliferation, and migration of bladder cancer cells via the miR-4677-3p/FGF6 axis.

BACKGROUND: Bladder cancer (BCa) is a common genitourinary malignancy with higher incidence in males. Long intergenic non-protein coding RNA 265 (LINC00265) is identified as an oncogene in many malignancies, while its role in BCa development remains unknown. PURPOSE: To explore the functions and mechanism of LINC00265 in BCa. RESEARCH DESIGN: Reverse transcription quantitative polymerase chain reaction was performed to examine LINC00265 expression in BCa cells. Cell counting kit-8 assays, colony formation assays, TdT-mediated dUTP Nick-End Labeling assays, and Transwell assays were conducted to examine BCa cell viability, proliferation, apoptosis, and migration. Luciferase reporter assays and RNA immunoprecipitation assays were carried out to explore the binding capacity between miR-4677-3p and messenger RNA fibroblast growth factor 6 (FGF6) (or LINC00265). Xenograft tumor model was established to explore the role of LINC00265 in vivo. RESULTS: LINC00265 was highly expressed in BCa cells. LINC00265 knockdown inhibited xenograft tumor growth and BCa cell viability, proliferation and migration while enhancing cell apoptosis. Moreover, LINC00265 interacted with miR-4677-3p to upregulate the expression of FGF6. FGF6 overexpression reversed the suppressive effect of LINC00265 knockdown on malignant phenotypes of BCa cells. CONCLUSIONS: LINC00265 promotes the viability, proliferation, and migration of BCa cells by binding with miR-4677-3p to upregulate FGF6 expression.

JFK Is a Hypoxia-Inducible Gene That Functions to Promote Breast Carcinogenesis.

Many carcinomas feature hypoxia, a condition has long been associated with tumor progression and poor prognosis, as well as resistance to chemoradiotherapy. Here, we report that the F-box protein JFK promotes mammary tumor initiation and progression in MMTV-PyMT murine model of spontaneous breast cancer. We find that JFK is inducible under hypoxic conditions, in which hypoxia-inducible factor HIF-1α binds to and transcriptionally activates JFK in breast cancer cells. Consistently, analysis of public clinical datasets reveals that the mRNA level of JFK is positively correlated with that of HIF-1α in breast cancer. We show that JFK deficiency leads to a decrease in HIF-1α-induced glycolysis in breast cancer and sensitizes hypoxic breast cancer cells to ionizing radiation and chemotherapeutic treatment. These results indicate that JFK is an important player in hypoxic response, supporting the pursuit of JFK as a potential therapeutic target for breast cancer intervention.

Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapy.

BACKGROUND: Adoptive T cell transfer-based immunotherapy yields unsatisfactory results in the treatment of solid tumors, partially owing to limited tumor infiltration and the immunosuppressive microenvironment in solid tumors. Therefore, strategies for the noninvasive tracking of adoptive T cells are critical for monitoring tumor infiltration and for guiding the development of novel combination therapies. METHODS: We developed a radiolabeling method for cytotoxic T lymphocytes (CTLs) that comprises metabolically labeling the cell surface glycans with azidosugars and then covalently conjugating them with 64Cu-1,4,7-triazacyclononanetriacetic acid-dibenzo-cyclooctyne (64Cu-NOTA-DBCO) using bioorthogonal chemistry. 64Cu-labeled control-CTLs and ovalbumin-specific CTLs (OVA-CTLs) were tracked using positron emission tomography (PET) in B16-OVA tumor-bearing mice. We also investigated the effects of focal adhesion kinase (FAK) inhibition on the antitumor efficacy of OVA-CTLs using a poly(lactic-co-glycolic) acid (PLGA)-encapsulated nanodrug (PLGA-FAKi). RESULTS: CTLs can be stably radiolabeled with 64Cu with a minimal effect on cell viability. PET imaging of 64Cu-OVA-CTLs enables noninvasive mapping of their in vivo behavior. Moreover, 64Cu-OVA-CTLs PET imaging revealed that PLGA-FAKi induced a significant increase in OVA-CTL infiltration into tumors, suggesting the potential for a combined therapy comprising OVA-CTLs and PLGA-FAKi. Further combination therapy studies confirmed that the PLGA-FAKi nanodrug markedly improved the antitumor effects of adoptive OVA-CTLs transfer by multiple mechanisms. CONCLUSION: These findings demonstrated that metabolic radiolabeling followed by PET imaging can be used to sensitively profile the early-stage migration and tumor-targeting efficiency of adoptive T cells in vivo. This strategy presents opportunities for predicting the efficacy of cell-based adoptive therapies and for guiding combination regimens.

Molecular PET/CT Profiling of ACE2 Expression In Vivo: Implications for Infection and Outcome from SARS-CoV-2.

Rapid progress has been made to identify and study the causative agent leading to coronavirus disease 2019 (COVID-19) but many questions including who is most susceptible and what determines severity remain unanswered. Angiotensin-converting enzyme 2 (ACE2) is a key factor in the infection process of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In this study, molecularly specific positron emission tomography imaging agents for targeting ACE2 are first developed, and these novel agents are evaluated in vitro, in preclinical model systems, and in a first-in-human translational ACE2 imaging of healthy volunteers and a SARS-CoV-2 recovered patient (NCT04422457). ACE2 expression levels in different organs in live subjects are quantitatively delineated and observable differences are measured in the patient recovered from COVID-19. Surprising sites of uptake in the breast, reproductive system and very low uptake in pulmonary tissues are reported. This novel method can add a unique tool to facilitate SARS-CoV-2 related research and improve understanding of this enigmatic disease. Molecular imaging provides quantitative annotation of ACE2, the SARS-CoV-2 entry receptor, to noninvasively monitor organs impacted by the COVID-19.

ICAM-1 orchestrates the abscopal effect of tumor radiotherapy.

Compelling evidence indicates that radiotherapy (RT) has a systemic inhibitory effect on nonirradiated lesions (abscopal effect) in addition to the ablation of irradiated tumors. However, this effect occurs only in rare circumstances in clinical practice, and mechanisms underlying the abscopal effect of RT are neither fully understood nor therapeutically utilized. Here we identified that intercellular adhesion molecule-1 (ICAM-1), an inducible glycoprotein of the immunoglobulin superfamily, is up-regulated in nonirradiated tumors responsive to RT. ICAM-1 expression in preclinical animal models can be noninvasively detected by optical imaging and positron emission tomography (PET) using near-infrared fluorescence dye- and 64Cu-labeled imaging probes that we synthesized, respectively. Importantly, the expression levels of ICAM-1 determined by quantitative PET imaging showed a strong negative linear correlation with the growth of nonirradiated tumors. Moreover, genetic or pharmacologic up-regulation of ICAM-1 expression by either an intratumoral injection of engineered recombinant adenovirus or systemic administration of a Toll-like receptor 7 agonist-capsulated nanodrug could induce markedly increased abscopal responses to local RT in animal models. Mechanistic investigation revealed that ICAM-1 expression can enhance both the activation and tumor infiltration of CD8+ T cells to improve the responses of the nonirradiated tumors to RT. Together, our findings suggest that noninvasive PET imaging of ICAM-1 expression could be a powerful means to predict the responses of nonirradiated tumors to RT, which could facilitate the exploration of new combination RT strategies for effective ablation of primary and disseminated lesions.