Prospective Comparison of [18F]FDG and [18F]AIF-FAPI-74 PET/CT in the Evaluation of Potentially Resectable Pancreatic Ductal Adenocarcinoma.

PURPOSE: Accurate clinical staging of potentially resectable pancreatic ductal adenocarcinoma (PDAC) is critical for establishing optimal treatment strategies. While the efficacy of fluorine-18-fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) in clinical staging is unclear, PET/CT detecting fibroblast-activation protein (FAP) expression has recently received considerable attention for detecting various tumors, including PDAC, with high sensitivity. We explored the efficacy of [18F]FDG and [18F]AIF-FAPI-74 PET/CT in the initial evaluation of potentially resectable PDAC. PROCEDURES: Between 2021 and 2022, twenty participants with newly diagnosed potentially resectable PDAC were enrolled. After the initial evaluation with pancreatic CT, [18F]FDG PET/CT, and [18F]AIF-FAPI-74 PET/CT, treatment strategies were determined considering the participant's general status, clinical staging, and resectability. Pathological information from the surgical specimens was only available in 17 participants who underwent curative-intent surgery. Head-to-head comparisons of quantitative radiotracer uptake and diagnostic performance were performed among imaging modalities. RESULTS: [18F]AIF-FAPI-74 PET/CT showed a significantly higher maximum standardized uptake value than [18F]FDG PET/CT did in evaluating primary pancreatic lesions (median [interquartile range]; 12.6 [10.7-13.7] vs. 6.3 [4.8-9.2]; P < 0.001). In contrast, [18F]AIF-FAPI-74 PET/CT showed a significantly lower mean standardized uptake value than [18F]FDG PET/CT did in evaluating background organ (median [interquartile range]) 0.8 [0.7-0.9] vs. 2.6 [2.3-2.7]; P < 0.001). In addition, the sensitivity of [18F]AIF-FAPI-74 PET/CT in detecting metastatic lymph nodes was higher than that of [18F]FDG PET/CT (50.0% vs. 0.0%; P = 0.026). CONCLUSION: This study demonstrated that [18F]AIF-FAPI-74 PET/CT could improve the clinical staging of potentially resectable PDAC.

Evaluation of Fibroblast Activation Protein Expression Using 68Ga-FAPI46 PET in Hypertension-Induced Tissue Changes.

Chronic hypertension leads to injury and fibrosis in major organs. Fibroblast activation protein (FAP) is one of key molecules in tissue fibrosis, and 68Ga-labeled FAP inhibitor-46 (FAPI46) PET is a recently developed method for evaluating FAP. The aim of this study was to evaluate FAP expression and fibrosis in a hypertension model and to test the feasibility of 68Ga-FAPI46 PET in hypertension. Methods: Hypertension was induced in mice by angiotensin II infusion for 4 wk. 68Ga-FAPI46 biodistribution studies and PET scanning were conducted at 1, 2, and 4 wk after hypertension modeling, and uptake in the major organs was measured. The FAP expression and fibrosis formation of the heart and kidney tissues were analyzed and compared with 68Ga-FAPI46 uptake. Subgroups of the hypertension model underwent angiotensin receptor blocker administration and high-dose FAPI46 blocking, for comparison. As a preliminary human study, 68Ga-FAPI46 PET images of lung cancer patients were analyzed and compared between hypertension and control groups. Results: Uptake of 68Ga-FAPI46 in the heart and kidneys was significantly higher in the hypertension group than in the sham group as early as week 1 and decreased after week 2. The uptake was specifically blocked in the high-dose blocking study. Immunohistochemistry also revealed FAP expression in both heart and kidney tissues. However, overt fibrosis was observed in the heart, whereas it was absent from the kidneys. The angiotensin receptor blocker-treated group showed lower uptake in the heart and kidneys than did the hypertension group. In the pilot human study, renal uptake of 68Ga-FAPI46 significantly differed between the hypertension and control groups. Conclusion: In hypertension, FAP expression is increased in the heart and kidneys from the early phases and decreases over time. FAP expression appears to represent fibrosis activity preceding or underlying fibrotic tissue formation. 68Ga-FAPI46 PET has potential as an effective imaging method for evaluating FAP expression in progressive fibrosis by hypertension.

Development of Alginate-Based Biodegradable Radioactive Microspheres Labeled with Positron Emitter through Click Chemistry Reaction: Stability and PET Imaging Study.

Biodegradable radioactive microspheres labeled with positron emitters hold significant promise for diagnostic and therapeutic applications in cancers and other diseases, including arthritis. The alginate-based polymeric microspheres offer advantages such as biocompatibility, biodegradability, and improved stability, making them suitable for clinical applications. In this study, we developed novel positron emission tomography (PET) microspheres using alginate biopolymer radiolabeled with gallium-68 (68Ga) through a straightforward conjugation reaction. Polyethylenimine (PEI)-decorated calcium alginate microspheres (PEI-CAMSs) were fabricated and further modified using azadibenzocyclooctyne-N-hydroxysuccinimide ester (ADIBO-NHS). Subsequently, azide-functionalized NOTA chelator (N3-NOTA) was labeled with [68Ga]Ga to obtain [68Ga]Ga-NOTA-N3, which was then reacted with the surface-modified PEI-CAMSs using strain-promoted alkyne-azide cycloaddition (SPAAC) reaction to develop [68Ga]Ga-NOTA-PEI-CAMSs, a novel PET microsphere. The radiolabeling efficiency and radiochemical stability of [68Ga]Ga-NOTA-PEI-CAMSs were determined using the radio-instant thin-layer chromatography-silica gel (radio-ITLC-SG) method. The in vivo PET images were also acquired to study the in vivo stability of the radiolabeled microspheres in normal mice. The radiolabeling efficiency of [68Ga]Ga-NOTA-PEI-CAMSs was over 99%, and the microspheres exhibited high stability (92%) in human blood serum. PET images demonstrated the stability and biodistribution of the microspheres in mice for up to 2 h post injection. This study highlights the potential of biodegradable PET microspheres for preoperative imaging and targeted radionuclide therapy. Overall, the straightforward synthesis method and efficient radiolabeling technique provide a promising platform for the development of theranostic microspheres using other radionuclides such as 90Y, 177Lu, 188Re, and 64Cu.

Moderation of Amyloid-ß Deposition on the Effect of Cholinesterase Inhibitors on Cognition in Mild Cognitive Impairment.

Background: Clinical trial findings on cholinesterase inhibitors (ChEIs) for mild cognitive impairment (MCI) are inconclusive, offering limited support for their MCI treatment. Given that nearly half of amnestic MCI cases lack cerebral amyloid-ß (Aß) deposition, a hallmark of Alzheimer's disease; this Aß heterogeneity may explain inconsistent results. Objective: This study aimed to assess whether Aß deposition moderates ChEI effects on amnestic MCI cognition. Methods: We examined 118 individuals with amnestic MCI (ages 55-90) in a longitudinal cohort study. Baseline and 2-year follow-up assessments included clinical evaluations, neuropsychological testing, and multimodal neuroimaging. Generalized linear models were primarily analyzed to test amyloid positivity's moderation of ChEI effects on cognitive change over 2 years. Cognitive outcomes included Mini-Mental Status Examination score, the total score of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery, and Clinical Dementia Rating-sum of boxes. Results: The analysis found no significant ChEI use x amyloid positivity interaction for all cognitive outcomes. ChEI use, irrespective of Aß status, was associated with more cognitive decline over the 2-year period. Conclusions: Aß pathology does not appear to moderate ChEI effects on cognitive decline in MCI.

Moderation of thyroid hormones for the relationship between amyloid and tau pathology.

BACKGROUND: Altered thyroid hormone levels have been associated with increased risk of Alzheimer's disease (AD) dementia and related cognitive decline. However, the neuropathological substrates underlying the link between thyroid hormones and AD dementia are not yet fully understood. We first investigated the association between serum thyroid hormone levels and in vivo AD pathologies including both beta-amyloid (Aß) and tau deposition measured by positron emission tomography (PET). Given the well-known relationship between Aß and tau pathology in AD, we additionally examined the moderating effects of thyroid hormone levels on the association between Aß and tau deposition. METHODS: This cross-sectional study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. This study included a total of 291 cognitively normal adults aged 55 to 90. All participants received comprehensive clinical assessments, measurements for serum total triiodothyronine (T3), free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH), and brain imaging evaluations including [11C]-Pittsburgh compound B (PiB)- PET and [18F] AV-1451 PET. RESULTS: No associations were found between either thyroid hormones or TSH and Aß and tau deposition on PET. However, fT4 (p = 0.002) and fT3 (p = 0.001) exhibited significant interactions with Aß on tau deposition: The sensitivity analyses conducted after the removal of an outlier showed that the interaction effect between fT4 and Aß deposition was not significant, whereas the interaction between fT3 and Aß deposition remained significant. However, further subgroup analyses demonstrated a more pronounced positive relationship between Aß and tau in both the higher fT4 and fT3 groups compared to the lower group, irrespective of outlier removal. Meanwhile, neither T3 nor TSH had any interaction with Aß on tau deposition. CONCLUSION: Our findings suggest that serum thyroid hormones may moderate the relationship between cerebral Aß and tau pathology. Higher levels of serum thyroid hormones could potentially accelerate the Aß-dependent tau deposition in the brain. Further replication studies in independent samples are needed to verify the current results.

Optimization of micelle-encapsulated extremely small sized iron oxide nanoparticles as a T1 contrast imaging agent: biodistribution and safety profile.

BACKGROUND: Iron oxide nanoparticles (IONPs) have been cleared by the Food and Drug Administration (FDA) for various clinical applications, such as tumor-targeted imaging, hyperthermia therapy, drug delivery, and live-cell tracking. However, the application of IONPs as T1 contrast agents has been restricted due to their high r2 values and r2/r1 ratios, which limit their effectiveness in T1 contrast enhancement. Notably, IONPs with diameters smaller than 5 nm, referred to as extremely small-sized IONPs (ESIONs), have demonstrated potential in overcoming these limitations. To advance the clinical application of ESIONs as T1 contrast agents, we have refined a scale-up process for micelle encapsulation aimed at improving the hydrophilization of ESIONs, and have carried out comprehensive in vivo biodistribution and preclinical toxicity assessments. RESULTS: The optimization of the scale-up micelle-encapsulation process, specifically employing Tween60 at a concentration of 10% v/v, resulted in ESIONs that were uniformly hydrophilized, with an average size of 9.35 nm and a high purification yield. Stability tests showed that these ESIONs maintained consistent size over extended storage periods and dispersed effectively in blood and serum-mimicking environments. Relaxivity measurements indicated an r1 value of 3.43 mM- 1s- 1 and a favorable r2/r1 ratio of 5.36, suggesting their potential as T1 contrast agents. Biodistribution studies revealed that the ESIONs had extended circulation times in the bloodstream and were primarily cleared via the hepatobiliary route, with negligible renal excretion. We monitored blood clearance and organ distribution using positron emission tomography and magnetic resonance imaging (MRI). Additionally, MRI signal variations in a dose-dependent manner highlighted different behaviors at varying ESIONs concentrations, implying that optimal dosages might be specific to the intended imaging application. Preclinical safety evaluations indicated that ESIONs were tolerable in rats at doses up to 25 mg/kg. CONCLUSIONS: This study effectively optimized a scale-up process for the micelle encapsulation of ESIONs, leading to the production of hydrophilic ESIONs at gram-scale levels. These optimized ESIONs showcased properties conducive to T1 contrast imaging, such as elevated r1 relaxivity and a reduced r2/r1 ratio. Biodistribution study underscored their prolonged bloodstream presence and efficient clearance through the liver and bile, without significant renal involvement. The preclinical toxicity tests affirmed the safety of the ESIONs, supporting their potential use as T1 contrast agent with versatile clinical application.

An epidermal growth factor receptor-targeting immunotoxin based on IgG shows potent antitumor activity against head and neck cancer.

The epidermal growth factor receptor (EGFR) is an important target for cancer therapies. Many head and neck cancer (HNC) cells have been reported to overexpress EGFR; therefore, anti-EGFR therapies have been attempted in patients with HNC. However, its clinical efficacy is limited owing to the development of drug resistance. In this study, we developed an EGFR-targeting immunotoxin consisting of a clinically proven anti-EGFR IgG (cetuximab; CTX) and a toxin fragment (LR-LO10) derived from Pseudomonas exotoxin A (PE) using a novel site-specific conjugation technology (peptide-directed photo-crosslinking reaction), as an alternative option. The immunotoxin (CTX-LR-LO10) showed specific binding to EGFR and properties of a typical IgG, such as stability, interactions with receptors of immune cells, and pharmacokinetics, and inhibited protein synthesis via modification of elongation factor-2. Treatment of EGFR-positive HNC cells with the immunotoxin resulted in apoptotic cell death and the inhibition of cell migration and invasion. The efficacy of CTX-LR-LO10 was evaluated in xenograft mouse models, and the immunotoxin exhibited much stronger tumor suppression than CTX or LR-LO10. Transcriptome analyses revealed that the immunotoxins elicited immune responses and altered the expression of genes related to its mechanisms of action. These results support the notion that CTX-LR-LO10 may serve as a new therapeutic agent targeting EGFR-positive cancers.

Plasma Leptin and Alzheimer Protein Pathologies Among Older Adults.

Importance: Many epidemiologic studies have suggested that low levels of plasma leptin, a major adipokine, are associated with increased risk of Alzheimer disease (AD) dementia and cognitive decline. Nevertheless, the mechanistic pathway linking plasma leptin and AD-related cognitive decline is not yet fully understood. Objective: To examine the association of plasma leptin levels with in vivo AD pathologies, including amyloid-beta (Aß) and tau deposition, through both cross-sectional and longitudinal approaches among cognitively unimpaired older adults. Design, Setting, and Participants: This was a longitudinal cohort study from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer Disease. Data were collected from January 1, 2014, to December 31, 2020, and data were analyzed from July 11 to September 6, 2022. The study included a total of 208 cognitively unimpaired participants who underwent baseline positron emission tomography (PET) scans for brain Aß deposition. For longitudinal analyses, 192 participants who completed both baseline and 2-year follow-up PET scans for brain Aß deposition were included. Exposure: Plasma leptin levels as assessed by enzyme-linked immunosorbent assay. Main Outcomes and Measures: Baseline levels and longitudinal changes of global Aß and AD-signature region tau deposition measured by PET scans. Results: Among the 208 participants, the mean (SD) age was 66.0 (11.3) years, 114 were women (54.8%), and 37 were apolipoprotein E ε4 carriers (17.8%). Lower plasma leptin levels had a significant cross-sectional association with greater brain Aß deposition (ß = -0.04; 95% CI, -0.09 to 0.00; P = .046), while there was no significant association between plasma leptin levels and tau deposition (ß = -0.02; 95% CI, -0.05 to 0.02; P = .41). In contrast, longitudinal analyses revealed that there was a significant association between lower baseline leptin levels and greater increase of tau deposition over 2 years (ß = -0.06; 95% CI, -0.11 to -0.01; P = .03), whereas plasma leptin levels did not have a significant association with longitudinal change of Aß deposition (ß = 0.006; 95% CI, 0.00-0.02; P = .27). Conclusions and Relevance: The present findings suggest that plasma leptin may be protective for the development or progression of AD pathology, including both Aß and tau deposition.

In Vivo Reactive Astrocyte Imaging in Patients With Schizophrenia Using Fluorine 18-Labeled THK5351.

Importance: In vivo imaging studies of reactive astrocytes are crucial for understanding the pathophysiology of schizophrenia because astrocytes play a critical role in glutamate imbalance and neuroinflammation. Objective: To investigate in vivo reactive astrocytes in patients with schizophrenia associated with positive symptoms using monoamine oxidase B (MAO-B)-binding fluorine 18 ([18F])-labeled THK5351 positron emission tomography (PET). Design, Setting, and Participants: In this case-control study, data were collected from October 1, 2021, to January 31, 2023, from the internet advertisement for the healthy control group and from the outpatient clinics of Seoul National University Hospital in Seoul, South Korea, for the schizophrenia group. Participants included patients with schizophrenia and age- and sex-matched healthy control individuals. Main Outcomes and Measures: Standardized uptake value ratios (SUVrs) of [18F]THK5351 in the anterior cingulate cortex (ACC) and hippocampus as primary regions of interest (ROIs), with other limbic regions as secondary ROIs, and the correlation between altered SUVrs and Positive and Negative Syndrome Scale (PANSS) positive symptom scores. Results: A total of 68 participants (mean [SD] age, 32.0 [7.0] years; 41 men [60.3%]) included 33 patients with schizophrenia (mean [SD] age, 32.3 [6.3] years; 22 men [66.7%]) and 35 healthy controls (mean [SD] age, 31.8 [7.6] years; 19 men [54.3%]) who underwent [18F]THK5351 PET scanning. Patients with schizophrenia showed significantly higher SUVrs in the bilateral ACC (left, F = 5.767 [false discovery rate (FDR)-corrected P = .04]; right, F = 5.977 [FDR-corrected P = .04]) and left hippocampus (F = 4.834 [FDR-corrected P = .04]) than healthy controls. Trend-level group differences between the groups in the SUVrs were found in the secondary ROIs (eg, right parahippocampal gyrus, F = 3.387 [P = .07]). There were positive correlations between the SUVrs in the bilateral ACC and the PANSS positive symptom scores (left, r = 0.423 [FDR-corrected P = .03]; right, r = 0.406 [FDR-corrected P = .03]) in patients with schizophrenia. Conclusions and Relevance: This case-control study provides novel in vivo imaging evidence of reactive astrocyte involvement in the pathophysiology of schizophrenia. Reactive astrocytes in the ACC may be a future target for the treatment of symptoms of schizophrenia, especially positive symptoms.

Preoperative evaluation of mediastinal lymph nodes in non-small cell lung cancer using [68Ga]FAPI-46 PET/CT: a prospective pilot study.

PURPOSE: Mediastinal nodal staging is crucial for surgical candidate selection in non-small cell lung cancer (NSCLC), but conventional imaging has limitations often necessitating invasive staging. We investigated the additive clinical value of fibroblast activation protein inhibitor (FAPI) PET/CT, an imaging technique targeting fibroblast activation protein, for mediastinal nodal staging of NSCLC. METHODS: In this prospective pilot study, we enrolled patients scheduled for surgical resection of NSCLC based on specific criteria designed to align with indications for invasive staging procedures. Patients were included when meeting at least one of the following: (1) presence of FDG-positive N2 lymph nodes, (2) clinical N1 stage, (3) central tumor location or tumor diameter of ≥ 3 cm, and (4) adenocarcinoma exhibiting high FDG uptake. [68Ga]FAPI-46 PET/CT was performed before surgery after a staging workup including [18F]FDG PET/CT. The diagnostic accuracy of [68Ga]FAPI-46 PET/CT for "N2" nodes was assessed through per-patient visual assessment and per-station quantitative analysis using histopathologic results as reference standards. RESULTS: Twenty-three patients with 75 nodal stations were analyzed. Histopathologic examination confirmed that nine patients (39.1%) were N2-positive. In per-patient assessment, [68Ga]FAPI-46 PET/CT successfully identified metastasis in eight patients (sensitivity 0.89 (0.52-1.00)), upstaging three patients compared to [18F]FDG PET/CT. [18F]FDG PET/CT detected FDG-avid nodes in six (42.8%) of 14 N2-negative patients. Among them, five were considered non-metastatic based on calcification and distribution pattern, and one was considered metastatic. In contrast, [68Ga]FAPI-46 PET/CT correctly identified all non-metastatic patients solely based on tracer avidity. In per-station analysis, [68Ga]FAPI-46 PET/CT discriminated metastasis more effectively compared to [18F]FDG PET/CT-based (AUC of ROC curve 0.96 (0.88-0.99) vs. 0.68 (0.56-0.78), P < 0.001). CONCLUSION: [68Ga]FAPI-46 PET/CT holds promise as an imaging tool for preoperative mediastinal nodal staging in NSCLC, with improved sensitivity and the potential to reduce false-positive results, optimizing the need for invasive staging procedures.

Association between brain amyloid deposition and longitudinal changes of white matter hyperintensities.

BACKGROUND: Growing evidence suggests that not only cerebrovascular disease but also Alzheimer's disease (AD) pathological process itself cause cerebral white matter degeneration, resulting in white matter hyperintensities (WMHs). Some preclinical evidence also indicates that white matter degeneration may precede or affect the development of AD pathology. This study aimed to clarify the direction of influence between in vivo AD pathologies, particularly beta-amyloid (Aß) and tau deposition, and WMHs through longitudinal approach. METHODS: Total 282 older adults including cognitively normal and cognitively impaired individuals were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aß deposition, [18F] AV-1451 PET for measuring tau deposition, and MRI scans with fluid-attenuated inversion recovery image for measuring WMH volume. The relationships between Aß or tau deposition and WMH volume were examined using multiple linear regression analysis. In this analysis, baseline Aß or tau were used as independent variables, and change of WMH volume over 2 years was used as dependent variable to examine the effect of AD pathology on increase of WMH volume. Additionally, we set baseline WMH volume as independent variable and longitudinal change of Aß or tau deposition for 2 years as dependent variables to investigate whether WMH volume could precede AD pathologies. RESULTS: Baseline Aß deposition, but not tau deposition, had significant positive association with longitudinal change of WMH volume over 2 years. Baseline WMH volume was not related with any of longitudinal change of Aß or tau deposition for 2 years. We also found a significant interaction effect between baseline Aß deposition and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aß deposition was associated with increase of WMH volume over 2 years in female, but not in male. CONCLUSIONS: Our findings suggest that Aß deposition accelerates cerebral WMHs, particularly in female, whereas white matter degeneration appears not influence on longitudinal Aß increase. The results also did not support any direction of influence between tau deposition and WMHs.

NLRP3 inflammasome activation and NETosis positively regulate each other and exacerbate proinflammatory responses: implications of NETosis inhibition for acne skin inflammation treatment.

Inflammasomes are multiprotein complexes involved in the host immune response to pathogen infections. Thus, inflammasomes participate in many conditions, such as acne. Recently, it was shown that NETosis, a type of neutrophil cell death, is induced by bacterial infection and is involved in inflammatory diseases such as delayed wound healing in patients with diabetes. However, the relationship between inflammasomes and NETosis in the pathogenesis of inflammatory diseases has not been well studied. In this study, we determined whether NETosis is induced in P. acnes-induced skin inflammation and whether activation of the nucleotide-binding domain, leucine-rich family, and pyrin domain-containing-3 (NLRP3) inflammasome is one of the key factors involved in NETosis induction in a mouse model of acne skin inflammation. We found that NETosis was induced in P. acnes-induced skin inflammation in mice and that inhibition of NETosis ameliorated P. acnes-induced skin inflammation. In addition, our results demonstrated that inhibiting inflammasome activation could suppress NETosis induction in mouse skin. These results indicate that inflammasomes and NETosis can interact with each other to induce P. acnes-induced skin inflammation and suggest that targeting NETosis could be a potential treatment for inflammasome-mediated diseases as well as NETosis-related diseases.

Surface triggered stabilization of metastable charge-ordered phase in SrTiO3.

Charge ordering (CO), characterized by a periodic modulation of electron density and lattice distortion, has been a fundamental topic in condensed matter physics, serving as a potential platform for inducing novel functional properties. The charge-ordered phase is known to occur in a doped system with high d-electron occupancy, rather than low occupancy. Here, we report the realization of the charge-ordered phase in electron-doped (100) SrTiO3 epitaxial thin films that have the lowest d-electron occupancy i.e., d1-d0. Theoretical calculation predicts the presence of a metastable CO state in the bulk state of electron-doped SrTiO3. Atomic scale analysis reveals that (100) surface distortion favors electron-lattice coupling for the charge-ordered state, and triggering the stabilization of the CO phase from a correlated metal state. This stabilization extends up to six unit cells from the top surface to the interior. Our approach offers an insight into the means of stabilizing a new phase of matter, extending CO phase to the lowest electron occupancy and encompassing a wide range of 3d transition metal oxides.

Liquid plasma promotes angiogenesis through upregulation of endothelial nitric oxide synthase-induced extracellular matrix metabolism: potential applications of liquid plasma for vascular injuries.

BACKGROUND: Applications of nonthermal plasma have expanded beyond the biomedical field to include antibacterial, anti-inflammatory, wound healing, and tissue regeneration. Plasma enhances epithelial cell repair; however, the potential damage to deep tissues and vascular structures remains under investigation. RESULT: This study assessed whether liquid plasma (LP) increased nitric oxide (NO) production in human umbilical vein endothelial cells by modulating endothelial NO synthase (eNOS) phosphorylation and potential signaling pathways. First, we developed a liquid plasma product and confirmed the angiogenic effect of LP using the Matrigel plug assay. We found that the NO content increased in plasma-treated water. NO in plasma-treated water promoted cell migration and angiogenesis in scratch and tube formation assays via vascular endothelial growth factor mRNA expression. In addition to endothelial cell proliferation and migration, LP influenced extracellular matrix metabolism and matrix metalloproteinase activity. These effects were abolished by treatment with NG-L-monomethyl arginine, a specific inhibitor of NO synthase. Furthermore, we investigated the signaling pathways mediating the phosphorylation and activation of eNOS in LP-treated cells and the role of LKB1-adenosine monophosphate-activated protein kinase in signaling. Downregulation of adenosine monophosphate-activated protein kinase by siRNA partially inhibited LP-induced eNOS phosphorylation, angiogenesis, and migration. CONCLUSION: The present study suggests that LP treatment may be a novel strategy for promoting angiogenesis in vascular damage. Video Abstract.

Development of finely tuned liposome nanoplatform for macrophage depletion.

BACKGROUND: Immunotherapy with clodronate-encapsulated liposomes, which induce macrophage depletion, has been studied extensively. However, previously reported liposomal formulation-based drugs (Clodrosome® and m-Clodrosome®) are limited by their inconsistent size and therapeutic efficacy. Thus, we aimed to achieve consistent therapeutic effects by effectively depleting macrophages with uniform-sized liposomes. RESULTS: We developed four types of click chemistry-based liposome nanoplatforms that were uniformly sized and encapsulated with clodronate, for effective macrophage depletion, followed by conjugation with Man-N3 and radiolabeling. Functionalization with Man-N3 improves the specific targeting of M2 macrophages, and radioisotope labeling enables in vivo imaging of the liposome nanoplatforms. The functionalized liposome nanoplatforms are stable under physiological conditions. The difference in the biodistribution of the four liposome nanoplatforms in vivo were recorded using positron emission tomography imaging. Among the four platforms, the clodronate-encapsulated mannosylated liposome effectively depleted M2 macrophages in the normal liver and tumor microenvironment ex vivo compared to that by Clodrosome® and m-Clodrosome®. CONCLUSION: The newly-developed liposome nanoplatform, with finely tuned size control, high in vivo stability, and excellent ex vivo M2 macrophage targeting and depletion effects, is a promising macrophage-depleting agent.

Comprehensive characterization of early-programmed tumor microenvironment by tumor-associated macrophages reveals galectin-1 as an immune modulatory target in breast cancer.

Background: In recent years, there has been considerable interest in the therapeutic targeting of tumor-associated macrophages (TAMs) to modulate the tumor microenvironment (TME), resulting in antitumoral phenotypes. However, key mediators suitable for TAM-mediated remodeling of the TME remain poorly understood. Methods: In this study, we used single-cell RNA sequencing analyses to analyze the landscape of the TME modulated by TAMs in terms of a protumor microenvironment during early tumor development. Results: Our data revealed that the depletion of TAMs leads to a decreased epithelial-to-mesenchymal transition (EMT) signature in cancer cells and a distinct transcriptional state characterized by CD8+ T cell activation. Moreover, notable alterations in gene expression were observed upon the depletion of TAMs, identifying Galectin-1 (Gal-1) as a crucial molecular factor responsible for the observed effect. Gal-1 inhibition reversed immune suppression via the reinvigoration of CD8+ T cells, impairing tumor growth and potentiating immune checkpoint inhibitors in breast tumor models. Conclusion: These results provide comprehensive insights into TAM-mediated early tumor microenvironments and reveal immune evasion mechanisms that can be targeted by Gal-1 to induce antitumor immune responses.

Intrathecal [64Cu]Cu-albumin PET reveals age-related decline of lymphatic drainage of cerebrospinal fluid.

Age-related cognitive decline is associated with dysfunctional lymphatic drainage of cerebrospinal fluid (CSF) through meningeal lymphatic vessels. In this study, intrathecal [64Cu]Cu-albumin positron emission tomography (PET) was applied in mice to evaluate lymphatic drainage of CSF and its variation with age. [64Cu]Cu-albumin PET was performed at multiple time points after intrathecal injection of [64Cu]Cu-albumin at an infusion rate of 700 nl/min in adult and aged mice (15-25 months old). CSF clearance and paravertebral lymph nodes were quantified after injection and during the stationary phase. Stationary phase of the next day followed the initial perturbed state by injection of 6 ul (1/7 of total CSF volume) and CSF clearance half-time from the subarachnoid space was 93.4 ± 19.7 and 123.3 ± 15.6 min in adult and aged mice (p = 0.01), respectively. While the % injected dose of CSF space were higher, the activity of the paravertebral lymph nodes were lower in the aged mice on the next day. [64Cu]Cu-albumin PET enabled us to quantify CSF-lymphatic drainage across all levels of brain spinal cords and to visualize and quantify lymph node activity due to CSF drainage. [64Cu]Cu-albumin PET revealed the age-related decrease of the lymphatic drainage of CSF due to this decreased drainage from the subarachnoid space, especially during the stationary phase, in aged mice.

Body mass index and two-year change of in vivo Alzheimer's disease pathologies in cognitively normal older adults.

BACKGROUND: Low body mass index (BMI) or underweight status in late life is associated with an increased risk of dementia or Alzheimer's disease (AD). However, the relationship between late-life BMI and prospective longitudinal changes of in-vivo AD pathology has not been investigated. METHODS: This prospective longitudinal study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE). A total of 194 cognitive normal older adults were included in the analysis. BMI at baseline was measured, and two-year changes in brain Aß and tau deposition on PET imaging were used as the main outcomes. Linear mixed-effects (LME) models were used to examine the relationships between late-life BMI and longitudinal change in AD neuropathological biomarkers. RESULTS: A lower BMI at baseline was significantly associated with a greater increase in tau deposition in AD-signature region over 2 years (ß, -0.018; 95% CI, -0.028 to -0.004; p = .008), In contrast, BMI was not related to two-year changes in global Aß deposition (ß, 0.0002; 95% CI, -0.003 to 0.002, p = .671). An additional exploratory analysis for each sex showed lower baseline BMI was associated with greater increases in tau deposition in males (ß, -0.027; 95% CI, -0.046 to -0.009; p = 0.007), but not in females. DISCUSSION: The findings suggest that lower BMI in late-life may predict or contribute to the progression of tau pathology over the subsequent years in cognitively unimpaired older adults.

Serum Adiponectin and In Vivo Brain Amyloid Deposition in Cognitively Normal Older Adults: A Cohort Study.

High blood adiponectin has been associated with Alzheimer's disease (AD) dementia and related cognitive decline. We aimed to investigate the association between serum adiponectin level and in vivo AD pathologies. Cross-sectional and longitudinal study designs for the data of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease, an ongoing prospective cohort study that began in 2014. A total of 283 cognitively normal older adults between 55 and 90 years of age were included in community and memory clinic setting. Participants underwent comprehensive clinical assessments, measurement of serum adiponectin level, and multimodal brain imaging, including Pittsburgh compound-B positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and MRI at baseline and 2-year follow-up. Serum adiponectin level was positively associated with global beta-amyloid protein (Aß) retention and change therein over 2 years, but not with other AD neuroimaging markers including tau deposition, AD-related neurodegeneration, and white matter hyperintensities. Blood adiponectin level is associated with increased brain amyloid deposition, which suggests that adiponectin may be a potential target for therapeutic and preventive strategies against AD.

Performance evaluation of SimPET-L and SimPET-XL: MRI-compatible small-animal PET systems with rat-body imaging capability.

BACKGROUND: SimPET-L and SimPET-XL have recently been introduced with increased transaxial fields of view (FOV) compared with their predecessors (SimPET™ and SimPET-X), enabling whole-body positron emission tomography (PET) imaging of rats. We conducted performance evaluations of SimPET-L and SimPET-XL and rat-body imaging with SimPET-XL to demonstrate the benefits of increased axial and transaxial FOVs. PROCEDURES: The detector blocks in SimPET-L and SimPET-XL consist of two 4 × 4 silicon photomultiplier arrays coupled with 20 × 9 array lutetium oxyorthosilicate crystals. SimPET-L and SimPET-XL have an inner diameter (bore size) of 7.6 cm, and they are composed of 40 and 80 detector blocks yielding axial lengths of 5.5 and 11 cm, respectively. Each system was evaluated according to the National Electrical Manufacturers Association NU4-2008 protocol. Rat imaging studies, such as 18F-NaF and 18F-FDG PET, were performed using SimPET-XL. RESULTS: The radial resolutions at the axial center measured using the filtered back projection, 3D ordered-subset expectation maximization (OSEM), and 3D OSEM with point spread functions correction were 1.7, 0.82, and 0.82 mm FWHM in SimPET-L and 1.7, 0.91, and 0.91 mm FWHM in SimPET-XL, respectively. The peak sensitivities of SimPET-L and SimPET-XL were 6.30% and 10.4% for an energy window of 100-900 keV and 4.44% and 7.25% for a window of 250-750 keV, respectively. The peak noise equivalent count rate with an energy window of 250-750 keV was 249 kcps at 44.9 MBq for SimPET-L and 349 kcps at 31.3 MBq for SimPET-XL. In SimPET-L, the uniformity was 4.43%, and the spill-over ratios in air- and water-filled chambers were 5.54% and 4.10%, respectively. In SimPET-XL, the uniformity was 3.89%, and the spill-over ratio in the air- and water-filled chambers were 3.56% and 3.60%. Moreover, SimPET-XL provided high-quality images of rats. CONCLUSION: SimPET-L and SimPET-XL show adequate performance compared with other SimPET systems. In addition, their large transaxial and long axial FOVs provide imaging capability for rats with high image quality.