Feasibility Study of Single-Photon Emission Computed Tomography with Iodine-123 Labeled Metaiodobenzylguanidine for Preclinical Evaluation of Labetalol as a ß-Adrenergic Receptor Blocker.

Among clinically used radiopharmaceuticals, iodine-123 labeled metaiodobenzylguanidine ([123I]mIBG) serves for diagnosing neuroendocrine tumors and obtaining images of myocardial sympathetic innervation. mIBG, a structural analogue of norepinephrine (NE), a neurotransmitter acting in peripheral and central nerves, follows a pathway similar to NE, transmitting signals through the NE transporter (NET) located at synaptic terminals. It moves through the body without decomposing, enabling noninvasive image evaluation. In this study, we aimed to quantify [123I]mIBG uptake in the adrenal glands using small animal single-photon emission computed tomography/computed tomography (SPECT/CT) images post [123I]mIBG administration. We investigated the possibility of assessing the effectiveness of ß-adrenergic receptor blockers by quantifying SPECT/CT images and biodistribution results to determine the degree of [123I]mIBG uptake in the adrenal glands treated with labetalol, a known ß-adrenergic receptor blocker. Upon intravenous administration of [123I]mIBG to mice, SPECT/CT images were acquired over time to confirm the in vivo distribution pattern, revealing a clear uptake in the adrenal glands. Labetalol inhibited the uptake of [123I]mIBG in cell lines expressing NET. A decrease in [123I]mIBG uptake in the adrenal glands was observed in the labetalol-treated group compared with the normal group through SPECT/CT imaging and biodistribution studies. These results demonstrate that SPECT/CT imaging with [123I]mIBG could be applicable for evaluating the preclinical efficacy of new antihypertensive drug candidates such as labetalol, a ß-adrenergic receptor blocker.

Infectious Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Exhaled Aerosols and Efficacy of Masks During Early Mild Infection.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemiology implicates airborne transmission; aerosol infectiousness and impacts of masks and variants on aerosol shedding are not well understood. METHODS: We recruited coronavirus disease 2019 (COVID-19) cases to give blood, saliva, mid-turbinate and fomite (phone) swabs, and 30-minute breath samples while vocalizing into a Gesundheit-II, with and without masks at up to 2 visits 2 days apart. We quantified and sequenced viral RNA, cultured virus, and assayed serum samples for anti-spike and anti-receptor binding domain antibodies. RESULTS: We enrolled 49 seronegative cases (mean days post onset 3.8 ±â€…2.1), May 2020 through April 2021. We detected SARS-CoV-2 RNA in 36% of fine (≤5 µm), 26% of coarse (>5 µm) aerosols, and 52% of fomite samples overall and in all samples from 4 alpha variant cases. Masks reduced viral RNA by 48% (95% confidence interval [CI], 3 to 72%) in fine and by 77% (95% CI, 51 to 89%) in coarse aerosols; cloth and surgical masks were not significantly different. The alpha variant was associated with a 43-fold (95% CI, 6.6- to 280-fold) increase in fine aerosol viral RNA, compared with earlier viruses, that remained a significant 18-fold (95% CI, 3.4- to 92-fold) increase adjusting for viral RNA in saliva, swabs, and other potential confounders. Two fine aerosol samples, collected while participants wore masks, were culture-positive. CONCLUSIONS: SARS-CoV-2 is evolving toward more efficient aerosol generation and loose-fitting masks provide significant but only modest source control. Therefore, until vaccination rates are very high, continued layered controls and tight-fitting masks and respirators will be necessary.

Rapid High-Throughput Whole-Genome Sequencing of SARS-CoV-2 by Using One-Step Reverse Transcription-PCR Amplification with an Integrated Microfluidic System and Next-Generation Sequencing.

The long-lasting global COVID-19 pandemic demands timely genomic investigation of SARS-CoV-2 viruses. Here, we report a simple and efficient workflow for whole-genome sequencing utilizing one-step reverse transcription-PCR (RT-PCR) amplification on a microfluidic platform, followed by MiSeq amplicon sequencing. The method uses Fluidigm integrated fluidic circuit (IFC) and instruments to amplify 48 samples with 39 pairs of primers, including 35 custom-designed primer pairs and four additional primer pairs from the ARTIC network protocol v3. Application of this method on RNA samples from both viral isolates and clinical specimens demonstrates robustness and efficiency in obtaining the full genome sequence of SARS-CoV-2.

The increased amount of coffee consumption lowers the incidence of fatty liver disease in Korean men.

BACKGROUND AND AIMS: Coffee is known to have a beneficial effect on various liver diseases. The aim of this retrospective longitudinal study was to investigate an association between the amount of coffee consumption and the incidence of fatty liver disease in Korean adults. METHODS AND RESULTS: Data from a total of 91,436 male and female subjects with the mean follow-up period of 2.8 years were analyzed. The incidence of fatty liver was not associated with the amount of coffee consumption at baseline, but it was associated with the change in the amount of coffee consumption at the follow-up period. Multiple linear regression analyses showed that hazard ratios for incidence of fatty liver disease were significantly low in "increase" group comparing with "no change" group in fully adjusted model. When a subgroup analysis by gender was conducted, similar significant results were observed in male subjects, but not in females. CONCLUSIONS: The increment in the amount of coffee consumption is associated with the lower incidence of fatty liver in Korean men and suggests that increasing the coffee consumption may have a protective effect on fatty liver.

Phenotypic and Functional Characterization of Circulatory, Splenic, and Hepatic NK Cells in Simian Immunodeficiency Virus-Controlling Macaques.

NK cells are key components of the immune system because of their rapid response potential and their ability to mediate cytotoxic and immunomodulatory functions. Additionally, NK cells have recently been shown to persist for long periods in vivo and to have the capacity to establish immunologic memory. In the current study, we assessed the phenotype and function of circulatory and tissue-resident NK cells in a unique cohort of SIV-controlling rhesus macaques that maintained low to undetectable levels of viremia in the chronic phase of infection. By contrasting NK responses of these macaques with those observed in SIV-noncontrolling and uninfected macaques, we aimed to identify markers and activities of NK subpopulations associated with disease control. We show in this article that most differences among NK cells of the three groups of macaques were observed in tissue-resident cells. Although SIV infection resulted in NK cell dysfunction, double-negative NK cells and those expressing CXCR3, NKG2D, and IL-18Rα were associated with viremia control, as was Ab-dependent cytotoxic function. Our results suggest several novel targets for therapeutic intervention.

Association between sugar-sweetened beverage consumption and incident hypertension in Korean adults: a prospective study.

PURPOSE: Epidemiological information on the association between sugar-sweetened beverage (SSB) consumption and the risk for hypertension (HTN) in Koreans is very limited. We tested the hypothesis that increased SSB consumption is related to a higher risk of HTN among middle-aged Korean adults in a Korean community-based cohort. METHODS: From participants of the cohort from 2001 to 2010, we selected 5775 subjects without HTN, diabetes, cardiovascular disease, and cancer and who had no information on dietary assessment at baseline. To assess the relationship between SSB consumption and HTN, we estimated hazard ratios (HRs) and 95% confidence intervals using Cox regression analysis. In addition, stratified analysis by body mass index (BMI) was conducted. RESULTS: During the follow-up, we identified 1175 cases of incident HTN. The adjusted HR of HTN for the highest quartile of SSB consumption was 1.21 compared to the lowest quartile. Furthermore, higher consumption of SSB was significantly associated with increased incidence of HTN in subjects with BMI ≥ 25 kg/m2, whereas there was no significant association among subjects with BMI < 25 kg/m2. CONCLUSIONS: The results of this study suggest that SSB consumption was associated with an increased risk of HTN, particularly among obese participants.

Design and In Vivo Characterization of Immunoconjugates Targeting HIV gp160.

The envelope (Env) glycoprotein of HIV is expressed on the surface of productively infected cells and can be used as a target for cytotoxic immunoconjugates (ICs), in which cell-killing moieties, including toxins, drugs, or radionuclides, are chemically or genetically linked to monoclonal antibodies (MAbs) or other targeting ligands. Such ICs could be used to eliminate persistent reservoirs of HIV infection. We have found that MAbs which bind to the external loop of gp41, e.g., MAb 7B2, make highly effective ICs, particularly when used in combination with soluble CD4. We evaluated the toxicity, immunogenicity, and efficacy of the ICs targeted with 7B2 in mice and in simian-human immunodeficiency virus-infected macaques. In the macaques, we tested immunotoxins (ITs), consisting of protein toxins bound to the targeting agent. ITs were well tolerated and initially efficacious but were ultimately limited by their immunogenicity. In an effort to decrease immunogenicity, we tested different toxic moieties, including recombinant toxins, cytotoxic drugs, and tubulin inhibitors. ICs containing deglycosylated ricin A chain prepared from ricin toxin extracted from castor beans were the most effective in killing HIV-infected cells. Having identified immunogenicity as a major concern, we show that conjugation of IT to polyethylene glycol limits immunogenicity. These studies demonstrate that cytotoxic ICs can target virus-infected cells in vivo but also highlight potential problems to be addressed. IMPORTANCE: It is not yet possible to cure HIV infection. Even after years of fully effective antiviral therapy, a persistent reservoir of virus-infected cells remains. Here we propose that a targeted conjugate consisting of an anti-HIV antibody bound to a toxic moiety could function to kill the HIV-infected cells that constitute this reservoir. We tested this approach in HIV-infected cells grown in the lab and in animal infections. Our studies demonstrated that these immunoconjugates are effective both in vitro and in test animals. In particular, ITs constructed with the deglycosylated A chain prepared from native ricin were the most effective in killing cells, but their utility was blunted because they provoked immune reactions that interfered with the therapeutic effects. We then demonstrated that coating of the ITs with polyethylene glycol minimized the immunogenicity, as has been demonstrated with other protein therapies.

Two-Year Follow-Up of Macaques Developing Intermittent Control of the Human Immunodeficiency Virus Homolog Simian Immunodeficiency Virus SIVmac251 in the Chronic Phase of Infection.

UNLABELLED: Off-therapy control of viremia by HIV-infected individuals has been associated with two likely players: a restricted viral reservoir and an efficient cell-mediated immune response. We previously showed that a combination of highly suppressive antiretroviral therapy and two experimental drugs, i.e., auranofin and buthionine sulfoximine, was able to reduce the viral reservoir, elicit efficient cell-mediated antiviral responses, and induce intermittent posttherapy viral load control in chronically SIVmac251-infected macaques. We here show that the macaques that had received this drug combination and then stopped antiretroviral therapy were also able to maintain low numbers of activated CD4+ T cells at viral rebound. Moreover, these macaques consistently displayed low-level simian immunodeficiency virus (SIV) diversity, which was in line with the strong and broadly reactive cell-mediated immune responses against conserved Gag antigens. Extended follow-up showed that the two macaques that had received the complete drug combination remained healthy and did not develop AIDS in 2 years of follow-up after therapy suspension. This disease-free survival is longer than twice the average time of progression to AIDS in SIVmac251-infected rhesus macaques. These results suggest that limited numbers of activated T cells at viral rebound and subsequent development of broadly reactive cell-mediated responses may be interrelated in reducing the viral reservoir. IMPORTANCE: The HIV reservoir in CD4+ T cells represents one main obstacle to HIV eradication. Recent studies, however, show that a drastic reduction of this reservoir is insufficient for inducing a functional cure of AIDS. In the present work, we thoroughly studied and subjected to long-term follow-up two macaques showing intermittent control of the virus following suspension of antiretroviral therapy plus an experimental antireservoir treatment, i.e., the gold salt auranofin and the investigational chemotherapeutic agent buthionione sulfoximine (BSO). We found that these drugs were able to decrease the number of activated CD4+ T cells, which are preferential targets for HIV infection. Then, efficient immune responses against the virus were developed in the macaques, which remained healthy during 2 years of follow-up. This result may furnish another building block for future attempts to cure HIV/AIDS.

High levels of serum vitamin D are associated with a decreased risk of metabolic diseases in both men and women, but an increased risk for coronary artery calcification in Korean men.

BACKGROUND: There are conflicting results for relationships between serum vitamin D levels and metabolic diseases. The aim of this study was to investigate whether serum vitamin D levels were associated with various metabolic diseases including insulin resistance (IR), metabolic syndrome (MS), fatty liver (FL), and coronary artery calcification (CAC), along with assessing gender differences for these relationships in Korean adults. METHODS: A total of 180,918 subjects (98,412 men and 82,506 women) who participated in a comprehensive health examination in the 2012-2013 period at Kangbuk Samsung Hospital, College of Medicine, Sungkyunkwan University were included. Serum vitamin D and metabolic markers were analyzed and CAC was estimated. Subjects were divided according to quartile groups of serum vitamin D. To examine the relationships of serum vitamin D to metabolic diseases and metabolic factors, multivariate logistic analysis was conducted. RESULTS: High levels of serum vitamin D was associated with lower ORs for MS, IR and FL both in men and women (all p < 0.05). For men, ORs for CAC were significantly higher in third and the highest quartile groups for serum vitamin D in all the analyzed models (all p < 0.05). However, women showed no significant results between serum vitamin D and CAC. CONCLUSIONS: High levels of serum vitamin D were associated with lower risk of MS, IR and FL in both Korean men and women, but were associated with higher risk of CAC only in men, and not in women.

Application of peptide displaying phage as a novel diagnostic probe for human lung adenocarcinoma.

Despite the increasing lung cancer-associated death rate, its therapy has been constrained by impasse of early diagnosis. To apply non-invasive imaging for potential cancer diagnosis system, we screened human lung adenocarcinoma-specific peptides using the phage display technique. For in vivo phage-displayed peptide screening, M13 phage library displaying 2.9 × 10(9) random peptides was injected through tail vein to lung adenocarcinoma cell-derived xenograft mouse model. Through four rounds of biopanning, a specific peptide sequence (CAKATCPAC) was screened out with the highest frequency and was named as Pep-1, and it was analyzed for its targeting ability as an imaging probe by in vitro competitive assay to test its cell-binding ability, immunohistochemical detection in the tumor tissue, and in vivo NIR fluorescent optical imaging. The specificity of Pep-1 toward lung cancer was ensured by in vivo imaging using xenograft animals of various cancer types. The results suggest that Pep-1 is a promising diagnostic lead molecule for rapid and accurate detection of human lung adenocarcinoma. In addition, it was found that the targeting ability was much enhanced by ionizing radiation in both cell-derived and patient-derived lung adenocarcinoma xenografts, suggesting the possibility of applying Pep-1 for prognostic diagnosis after radiotherapy. Taken together, this study suggests that Pep-1 possesses a specific-targeting ability for human lung adenocarcinoma and that this peptide could be directly used as a clinically applicable imaging probe.

Development of real-time PCR for quantitation of simian immunodeficiency virus 2-LTR circles.

BACKGROUND: Non-human primates infected with simian immunodeficiency virus (SIV) represent a robust model to evaluate pre-clinical efficacy of HIV-1 preventive strategies and to determine the size of reservoir. METHODS: We developed a real-time qPCR assay to specifically quantify episomal 2-LTR circular DNA in peripheral blood mononuclear cells and brain tissues from SIV-infected macaques. RESULTS: This assay has sensitivity, accuracy and reproducibility over seven orders of magnitude. High copy numbers of SIV 2-LTR circles were correlated to high proviral DNA levels in brains of two SIV encephalitic animals. In contrast, no 2-LTR circles were detectable in two SIV-infected animals with no sign of encephalitis or two animals that had mild encephalitis with low levels of proviral DNA. CONCLUSIONS: These results suggest that simultaneous application of total proviral DNA and 2-LTR circle assays provides quantitative evaluation of pathogenesis and outcome of SIV infection in macaques.

Novel peptides functionally targeting in vivo human lung cancer discovered by in vivo peptide displayed phage screening.

Discovery of the cancer-specific peptidic ligands have been emphasized for active targeting drug delivery system and non-invasive imaging. For the discovery of useful and applicable peptidic ligands, in vivo peptide-displayed phage screening has been performed in this study using a xenograft mouse model as a mimic microenvironment to tumor. To seek human lung cancer-specific peptides, M13 phage library displaying 2.9 × 10(9) random peptides was intravenously injected into mouse model bearing A549-derived xenograft tumor through the tail vein. Then the phages emerged from a course of four rounds of biopanning in the xenograft tumor tissue. Novel peptides were categorized into four groups according to a sequence-homology phylogenicity, and in vivo tumor-targeting capacity of these peptides was validated by whole body imaging with Cy5.5-labeled phages in various cancer types. The result revealed that novel peptides accumulated only in adenocarcinoma lung cancer cell-derived xenograft tissue. For further confirmation of the specific targeting ability, in vitro cell-binding assay and immunohistochemistry in vivo tumor tissue were performed with a selected peptide. The peptide was found to bind intensely to lung cancer cells both in vitro and in vivo, which was efficiently compromised with unlabeled phages in an in vitro competition assay. In conclusion, the peptides specifically targeting human lung cancer were discovered in this study, which is warranted to provide substantive feasibilities for drug delivery and imaging in terms of a novel targeted therapeutics and diagnostics.

Transcription profiling of CD4⁺ T cells in rhesus macaques that infected with simian-human immunodeficiency virus and re-challenged with SIVmac251.

BACKGROUND: Insights into the host factors that contribute to an effective antiviral immune response may be obtained by examining global gene expression in simian-human immunodeficiency virus (SHIV)-infected non-human primates that exhibit different virological outcomes. METHODS: Six chronically SHIV-infected macaques were rectally challenged with SIVmac251. Viral RNA and proviral DNA load in blood were measured. Gene expression profiles in CD4+ T cells were examined and compared between animals with different levels of infection following challenge. RESULTS AND CONCLUSIONS: Viral RNA was markedly controlled in four challenged animals, whereas two animals had persistent high viremia. Analysis of the gene expression profiles at early infection revealed gene expression signatures between protectors and non-protectors and identified potential protective biomarkers. Pathway analyses revealed that IFN pathway genes are down-regulated in protectors compared to unprotectors. This study suggests that high levels of expression of type 1 IFN-related genes may paradoxically promote virus replication.

Effects of blood lead levels on airflow limitations in Korean adults: findings from the 5th KNHNES 2011.

This study aimed to examine whether blood levels of heavy metals, such as lead, mercury and cadmium, are related with pulmonary function in Korean adults. This investigation included 870 Korean adults (≥ 40 years) who received pulmonary function testing in the Korea National Health and Nutrition Examination Survey (KNHANES) V-2, 2011. Data of blood levels of heavy metals, pulmonary function tests and anthropometric measurements were acquired. Blood lead levels showed inverse correlations with the FEV1/FVC ratio before (r = -0.276, p < 0.001) and after adjustment of multiple compounding factors (r = -0.115, p = 0.001). A logistic multiple regression analysis revealed that blood lead levels were a significant influencing factor for the FEV1/FVC ratio (ß = -0.017, p = 0.001, adjusted R(2) = 0.267). The odds ratios (ORs) for the FEV1/FVC ratio were significantly lower in the highest tertile group of the blood lead levels than in the lowest tertile group in Model 1 (OR = 0.007, 95% CI = 0.000-0.329) and Model 2 (OR = 0.006, 95% CI = 0.000-0.286). These findings imply that environmental exposure to lead might be an important factor that may cause airflow limitations in Korean adults.

Association between age at menarche and diabetes in Korean post-menopausal women: results from the Korea National Health and Nutrition Examination Survey (2007-2009).

Early menarche is known to be associated with diabetes, however this association remains controversial. Our study aimed to investigate the possible association between age at menarche and diabetes prevalence in post-menopausal Korean women. This study included 3,254 post-menopausal Korean women aged 50-85 years from the Korea National Health and Nutrition Examination Survey IV (KNHANES 2007-2009). Logistic regression analyses were used to estimate odds ratios (ORs) for diabetes prevalence. Levels of biochemical markers were compared according to groups by age at menarche. Women in the earlier menarche age group (10-12 years) showed higher levels of fasting blood glucose (FBG) and scores of homeostatic model assessment in the insulin resistance (HOMA-IR) index than other groups (p <0.05). After adjusting for potential confounding factors, early age at menarche was significantly associated with a higher prevalence of diabetes (OR 1.86, 95% confidence intervals [CI] 1.07-3.23). The observed association remained significant despite additional adjustment for body mass index and waist circumference (OR 1.82, 95% CI 1.03-3.23) and despite further adjustments for FBG levels and HOMA-IR index (OR 2.25, 95% CI 1.11-4.55). Our findings strengthen the hypothesis that younger age at menarche is associated with increased diabetes prevalence in the Korean population.

Composition of dietary macronutrient intake is not associated with prevalence of coronary artery calcification in healthy Korean adults.

BACKGROUND AND AIMS: There is little information supporting the relationships between macronutrients and pre-clinical atherosclerosis. The aim of this study was to identify whether dietary macronutrient content is related with CAC. METHODS: 10,793 healthy Korean adults in a cohort were enrolled. Subjects were divided into CAC (CAC score >0) or non-CAC group (CAC score = 0). Intake of energy, carbohydrate (CHO), protein and fat were obtained using food frequency questionnaire (FFQ). Macronutrient composition was expressed as the ratio of energy from each macronutrient to total energy. Subjects were classified into three groups according to tertiles of intake for each macronutrient. To investigate the association between macronutrient intake and CAC, multiple regression analysis was conducted according to tertile groups of each macronutrient. RESULTS: The prevalence of CAC significantly differed among tertile groups of CHO and fat intake in men (p < 0.001, p < 0.01) and women (p < 0.05, p < 0.01). However, multiple logistic regression analysis revealed that the odds ratios (ORs) for CAC were not significantly different among tertile groups of each macronutrient intake after adjustment in men (CHO: OR = 0.965 [95% CI = 0.826-1.129]; protein: OR = 1.029 [95% CI = 0.881-1.201]; fat: OR = 1.015 [95% CI = 0.868-1.188]) and women (CHO: OR = 1.158 [95% CI = 0.550-2.438]; protein: OR = 1.261 [95% CI = 0.629-2.528]; fat: OR = 0.625 [95% CI = 0.286-1.365]). CONCLUSIONS: The prevalence of CAC may not be associated with composition of dietary macronutrient intake in in healthy Korean adults.

Implementation of a multidisciplinary clinical pathway for the management of postpartum hemorrhage: a retrospective study.

OBJECTIVE: To compare the outcomes of postpartum hemorrhage (PPH) episodes before and after the introduction of a clinical pathway known as the Severance Protocol to save postpartum bleeding through Expeditious care Delivery (SPEED). DESIGN: This study was designed as a retrospective analysis. SETTING: The study was conducted in a hospital implementing SPEED. PARTICIPANTS: The non-SPEED group included 74 patients with PPH who were treated before the introduction of SPEED, whereas the SPEED group included 155 patients. METHODS: Differences in outcomes were compared between groups. MAIN OUTCOME MEASURES: Reduction in treatment duration was the primary outcome measure, whereas uterus preservation was the secondary. RESULTS: No significant intergroup differences were observed for hemoglobin levels, hematocrit values and vital signs upon patients' emergency room arrival. The turnaround time for hemoglobin, mean duration until treatment by obstetricians and gynecologists and duration between chest radiography ordering and performance significantly differed between the two groups (SPEED, 10.0 [1.0-30.0], 3.0 [0-25.0] and 23.0 [1.0-86.0] min, respectively; non-SPEED, 17.0 [1.0-37.0], 12.0 [0-62.0] and 46.0 [1.0-580.0] min, respectively; P < 0.001). Similarly, the mean duration until transfusion of cross-matched red blood cells (SPEED, 77.6 ± 58.6 min; non-SPEED, 103.4 ± 64.4 min; P = 0.015) and uterus preservation rate (SPEED, 90.1% [136/151]; non-SPEED, 81.7% [58/71]; P = 0.043) also differed significantly between the groups. CONCLUSIONS: Clinical pathways enable prompt and efficient care for patients experiencing PPH through faster evaluation and access to red blood cell transfusion, resulting in a decrease in maternal mortality.

Arginase inhibition restores endothelial function in diet-induced obesity.

Arginase may play a major role in the regulation of vascular function in various cardiovascular disorders by impairing nitric oxide (NO) production. In the current study, we investigated whether supplementation of the arginase inhibitor N(ω)-hydroxy-nor-l-arginine (nor-NOHA) could restore endothelial function in an animal model of diet-induced obesity. Arginase 1 expression was significantly lower in the aorta of C57BL/6J mice fed a high-fat diet (HFD) supplemented with nor-NOHA (40mgkg(-1)/day) than in mice fed HFD without nor-NOHA. Arginase inhibition led to considerable increases in eNOS expression and NO levels and significant decreases in the levels of circulating ICAM-1. These findings were further confirmed by the results of siRNA-mediated knockdown of Arg in human umbilical vein endothelial cells. In conclusion, arginase inhibition can help restore dysregulated endothelial function by increasing the eNOS-dependent NO production in the endothelium, indicating that arginase could be a therapeutic target for correcting obesity-induced vascular endothelial dysfunction.

Comprehensive model for simultaneous monitoring of primary tumor to metastatic cancer utilizing Prkdc and Il2rg double knockout mice.

Liver cancer is the second leading cause of cancer-related deaths worldwide, motivating major scientific efforts to understand and treat this cancer type. Over 30% of patients with liver cancer progress to metastasis, which reduces the survival rate. Extensive studies on primary tumors have been conducted to improve the prognosis. However, there is a lack of appropriate and accessible models for studying the progression and metastasis of liver cancer. Moreover, conventional metastasis models do not reproduce metastasis as it occurs in patients. To address this lack of an appropriate model for the monitoring of cancer progression and evaluation of anticancer drugs, we established a spontaneous metastatic xenograft model using NSG mice subcutaneously transplanted with SK-Hep-1 cells. Compared to the conventional experimental metastasis model (intravenous transplantation), in which only lung metastasis was observed, the established spontaneous metastatic xenograft model was superior, as it showed both a primary tumor and metastatic patterns similar to those observed in human patients. Additionally, this model was successfully used to assess the antimetastatic efficacy of sorafenib. In conclusion, our results demonstrate that the established spontaneous metastatic xenograft model better reflects liver cancer metastasis and can be utilized to assess the efficacy of anticancer drugs for liver cancer.

Oligomeric amyloid-ß targeted contrast agent for MRI evaluation of Alzheimer's disease mouse models.

Background: Oligomeric amyloid beta (oAß) is a toxic factor that acts in the early stage of Alzheimer's disease (AD) and may initiate the pathologic cascade. Therefore, detecting oAß has a crucial role in the early diagnosis, monitoring, and treatment of AD. Purpose: The purpose of this study was to evaluate MRI signal changes in different mouse models and the time-dependent signal changes using our novel gadolinium (Gd)-dodecane tetraacetic acid (DOTA)- ob5 aptamer contrast agent. Methods: We developed an MRI contrast agent by conjugating Gd-DOTA-DNA aptamer called ob5 to evaluate its ability to detect oAß deposits in the brain using MRI. A total of 10 control mice, 9 3xTg AD mice, and 11 APP/PS/Tau AD mice were included in this study, with the age of each model being 16 or 36 weeks. A T1-weighted image was acquired at the time points before (0 min) and after injection of the contrast agent at 5, 10, 15, 20, and 25 min. The analyses were performed to compare MRI signal differences among the three groups and the time-dependent signal differences in different mouse models. Results: Both 3xTg AD and APP/PS/Tau AD mouse models had higher signal enhancement than control mice at all scan-time points after injection of our contrast media, especially in bilateral hippocampal areas. In particular, all Tg AD mouse models aged 16 weeks showed a higher contrast enhancement than those aged 36 weeks. For 3xTg AD and APP/PS/Tau AD groups, the signal enhancement was significantly different among the five time points (0 min, 5 min, 10 min, 15 min, 20 min, and 25 min) in multiple ROI areas, typically in the bilateral hippocampus, left thalamus, and left amygdala. Conclusion: The findings of this study suggest that the expression of the contrast agent in different AD models demonstrates its translational flexibility across different species. The signal enhancement peaked around 15-20 min after injection of the contrast agent. Therefore, our novel contrast agent targeting oAß has the potential ability to diagnose early AD and monitor the progression of AD.