Precision off-the-shelf natural killer cell therapies for oncology with logic-gated gene circuits.

Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis (5-year survival rate of 30.5% in the United States). Designing cell therapies to target AML is challenging because no single tumor-associated antigen (TAA) is highly expressed on all cancer subpopulations. Furthermore, TAAs are also expressed on healthy cells, leading to toxicity risk. To address these targeting challenges, we engineer natural killer (NK) cells with a multi-input gene circuit consisting of chimeric antigen receptors (CARs) controlled by OR and NOT logic gates. The OR gate kills a range of AML cells from leukemic stem cells to blasts using a bivalent CAR targeting FLT3 and/or CD33. The NOT gate protects healthy hematopoietic stem cells (HSCs) using an inhibitory CAR targeting endomucin, a protective antigen unique to healthy HSCs. NK cells with the combined OR-NOT gene circuit kill multiple AML subtypes and protect primary HSCs, and the circuit also works in vivo.

Immersive virtual reality simulation training for cesarean section: a randomized controlled trial.

BACKGROUND: Caesarean section (CS) is a complex surgical procedure that involves many steps and requires careful precision. Virtual reality (VR) simulation has emerged as a promising tool for medical education and training, providing a realistic and immersive environment for learners to practice clinical skills and decision-making. This study aimed to evaluate the educational effectiveness of a VR simulation program in training the management of patients with premature rupture of membranes (PROM) and CS. MATERIALS AND METHODS: A two-arm parallel randomized controlled trial was conducted with 105 eligible participants randomly assigned to the VR group ( n =53) or the control group ( n =52) in a 1:1 ratio. The VR group received VR simulation training focused on PROM management and CS practice, while the control group watched a video presentation with narrative of clinical scenario and recording of CS. Both groups completed questionnaires assessing their prior experiences with VR, experience in managing patients with PROM and performing CS, as well as their confidence levels. These questionnaires were administered before and after the intervention, along with a mini-test quiz. RESULTS: Baseline characteristics and previous experiences were comparable between the two groups. After the intervention, the VR group had higher confidence scores in all four aspects, including managing patients with PROM, performing CS as an operator, and understanding the indications and complications of CS, compared to the control group. The VR group also achieved significantly higher scores on the mini-test quiz [median (interquartile range), 42 (37-48) in the VR group; 36 (32-40) in the control group, P <0.001]. CONCLUSION: VR simulation program can be an effective educational tool for improving participants' knowledge and confidence in managing patients with PROM and performing CS.

Effects of Post Traumatic Growth on Successful Aging in Breast Cancer Survivors in South Korea: The Mediating Effect of Resilience and Intolerance of Uncertainty.

This study aimed to identify post-traumatic growth and successful aging and the mediating effects of resilience and intolerance of uncertainty in breast cancer survivors. This study employed a descriptive survey approach. Data were collected from 143 breast cancer survivors between 27 January and 10 December 2021, at a cancer center in Gyeongsangnam-do, South Korea. SPSS/WIN 25.0 and PROCESS Macro version 3.5 were used for data analysis. Descriptive statistics were analyzed with SPSS. PROCESS was used to conduct a mediation analysis and the significance of the mediating effect was evaluated using 95% confidence intervals. Successful aging was significantly associated with post-traumatic growth, resilience, and the intolerance of uncertainty. The impact of post-traumatic growth on successful aging was mediated by resilience in breast cancer survivors. Resilience should be considered when developing nursing interventions to enhance post-traumatic growth and promote successful aging in breast cancer survivors.

Effective data quality management for electronic medical record data using SMART DATA.

OBJECTIVES: In the medical field, we face many challenges, including the high cost of data collection and processing, difficult standards issues, and complex preprocessing techniques. It is necessary to establish an objective and systematic data quality management system that ensures data reliability, mitigates risks caused by incorrect data, reduces data management costs, and increases data utilization. We introduce the concept of SMART data in a data quality management system and conducted a case study using real-world data on colorectal cancer. METHODS: We defined the data quality management system from three aspects (Construction - Operation - Utilization) based on the life cycle of medical data. Based on this, we proposed the "SMART DATA" concept and tested it on colorectal cancer data, which is actual real-world data. RESULTS: We define "SMART DATA" as systematized, high-quality data collected based on the life cycle of data construction, operation, and utilization through quality control activities for medical data. In this study, we selected a scenario using data on colorectal cancer patients from a single medical institution provided by the Clinical Oncology Network (CONNECT). As SMART DATA, we curated 1,724 learning data and 27 Clinically Critical Set (CCS) data for colorectal cancer prediction. These datasets contributed to the development and fine-tuning of the colorectal cancer prediction model, and it was determined that CCS cases had unique characteristics and patterns that warranted additional clinical review and consideration in the context of colorectal cancer prediction. CONCLUSIONS: In this study, we conducted primary research to develop a medical data quality management system. This will standardize medical data extraction and quality control methods and increase the utilization of medical data. Ultimately, we aim to provide an opportunity to develop a medical data quality management methodology and contribute to the establishment of a medical data quality management system.

The Illustration of Altered Glucose Dependency in Drug-Resistant Cancer Cells.

A chemotherapeutic approach is crucial in malignancy management, which is often challenging due to the development of chemoresistance. Over time, chemo-resistant cancer cells rapidly repopulate and metastasize, increasing the recurrence rate in cancer patients. Targeting these destined cancer cells is more troublesome for clinicians, as they share biology and molecular cross-talks with normal cells. However, the recent insights into the metabolic profiles of chemo-resistant cancer cells surprisingly illustrated the activation of distinct pathways compared with chemo-sensitive or primary cancer cells. These distinct metabolic dynamics are vital and contribute to the shift from chemo-sensitivity to chemo-resistance in cancer. This review will discuss the important metabolic alterations in cancer cells that lead to drug resistance.

Stress induces behavioral abnormalities by increasing expression of phagocytic receptor MERTK in astrocytes to promote synapse phagocytosis.

Childhood neglect and/or abuse can induce mental health conditions with unknown mechanisms. Here, we identified stress hormones as strong inducers of astrocyte-mediated synapse phagocytosis. Using in vitro, in vivo, and human brain organoid experiments, we showed that stress hormones increased the expression of the Mertk phagocytic receptor in astrocytes through glucocorticoid receptor (GR). In post-natal mice, exposure to early social deprivation (ESD) specifically activated the GR-MERTK pathway in astrocytes, but not in microglia. The excitatory post-synaptic density in cortical regions was reduced in ESD mice, and there was an increase in the astrocytic engulfment of these synapses. The loss of excitatory synapses, abnormal neuronal network activities, and behavioral abnormalities in ESD mice were largely prevented by ablating GR or MERTK in astrocytes. Our work reveals the critical roles of astrocytic GR-MERTK activation in evoking stress-induced abnormal behaviors in mice, suggesting GR-MERTK signaling as a therapeutic target for stress-induced mental health conditions.

Canine amniotic membrane-derived mesenchymal stem cells ameliorate atopic dermatitis through regeneration and immunomodulation.

Mesenchymal stem cells (MSCs) are a promising tool for treating immune disorders. However, the immunomodulatory effects of canine MSCs compared with other commercialized biologics for treating immune disorders have not been well studied. In this study we investigated the characteristics and immunomodulatory effects of canine amnion membrane (cAM)-MSCs. We examined gene expression of immune modulation and T lymphocytes from activated canine peripheral blood mononuclear cell (PBMC) proliferation. As a result, we confirmed that cAM-MSCs upregulated immune modulation genes (TGF-ß1, IDO1 and PTGES2) and suppressed the proliferation capacity of T cells. Moreover, we confirmed the therapeutic effect of cAM-MSCs compared with oclacitinib (OCL), the most commonly used Janus kinase (JAK) inhibitor, as a treatment for canine atopic dermatitis (AD) using a mouse AD model. As a result, we confirmed that cAM-MSCs with PBS treatment groups (passage 4, 6 and 8) compared with PBS only (PBS) though scores of dermatologic signs, tissue pathologic changes and inflammatory cytokines were significantly reduced. In particular, cAM-MSCs were more effective than OCL in the recovery of wound dysfunction, regulation of mast cell activity and expression level of immune modulation protein. Interestingly, subcutaneous injection of cAM-MSCs induced weight recovery, but oral administration of oclacitinib induced weight loss as a side effect. In conclusion, this study suggests that cAM-MSCs can be developed as a safe canine treatment for atopic dermatitis without side effects through effective regeneration and immunomodulation.

Autophagy mediates an amplification loop during ferroptosis.

Ferroptosis, a programmed cell death, has been identified and associated with cancer and various other diseases. Ferroptosis is defined as a reactive oxygen species (ROS)-dependent cell death related to iron accumulation and lipid peroxidation, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. However, accumulating evidence has revealed a link between autophagy and ferroptosis at the molecular level and has suggested that autophagy is involved in regulating the accumulation of iron-dependent lipid peroxidation and ROS during ferroptosis. Understanding the roles and pathophysiological processes of autophagy during ferroptosis may provide effective strategies for the treatment of ferroptosis-related diseases. In this review, we summarize the current knowledge regarding the regulatory mechanisms underlying ferroptosis, including iron and lipid metabolism, and its association with the autophagy pathway. In addition, we discuss the contribution of autophagy to ferroptosis and elucidate the role of autophagy as a ferroptosis enhancer during ROS-dependent ferroptosis.

Targeting HMG-CoA synthase 2 suppresses tamoxifen-resistant breast cancer growth by augmenting mitochondrial oxidative stress-mediated cell death.

AIMS: In this study, we aimed to investigate previously unrecognized lipid metabolic perturbations in tamoxifen-resistant breast cancer (BC) by conducting comprehensive metabolomics and transcriptomics analysis. We identified the role of 3-hydroxy-3-methylglutary-coenzyme-A-synthase 2 (HMGCS2), a key enzyme responsible for ketogenesis, in tamoxifen-resistant BC growth. MAIN METHODS: Comprehensive metabolomics (CE-TOFMS, LC-TOFMS) and transcriptiomics analysis were performed to characterize metabolic pathways in tamoxifen-resistant BC cells. The upregulation of HMGCS2 were verified thorugh immunohistochemistry (IHC) in clinical samples obtained from patients with recurrent BC. HMGCS2 inhibitor was discovered through surface plasmon resonance analysis, enzyme assay, and additional molecular docking studies. The effect of HMGCS2 suppression on tumor growth was studied thorugh BC xenograft model, and intratumoral lipid metabolites were analyzed via MALDI-TOFMS imaging. KEY FINDINGS: We revealed that the level of HMGCS2 was highly elevated in both tamoxifen-resistant T47D sublines (T47D/TR) and clinical refractory tumor specimens from patients with ER+ breast cancer, who had been treated with adjuvant tamoxifen. Suppression of HMGCS2 in T47D/TR resulted in the accumulation of mitochondrial reactive oxygen species (mtROS) and apoptotic cell death. Further, we identified alphitolic acid, a triterpenoid natural product, as a novel HMGCS2-specific inhibitor that elevated mtROS levels and drastically retarded the growth of T47D/TR in in vitro and in vivo experiments. SIGNIFICANCE: Enhanced ketogenesis with upregulation of HMGCS2 is a potential metabolic vulnerability of tamoxifen-resistant BC that offers a new therapeutic opportunity for treating patients with ER+ BC that are refractory to tamoxifen treatment.

LC-MS/MS-based serum proteomics reveals a distinctive signature in a rheumatoid arthritis mouse model after treatment with mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are known to be able to modulate immune responses, possess tissue-protective properties, and exhibit healing capacities with therapeutic potential for various diseases. The ability of MSCs to secrete various cytokines and growth factors provides new insights into autoimmune-diseases such as rheumatoid arthritis (RA). RA is a systemic autoimmune disease that affects the lining of synovial joints, causing stiffness, pain, inflammation, and joint erosion. In recent years, MSCs-based therapies have been widely proposed as promising therapies in the treatment of RA. However, the mechanism involved in disease-specific therapeutic effects of MSCs on RA remains unclear. To clarify the mechanism involved in effects of MSCs on RA, proteomic profiling was performed using an RA mouse model before and after treatment with MSCs. In this study, treatment efficacy of human umbilical cord blood-mesenchymal stem cells (hUCB-MSCs) was confirmed using a type II collagen-induced arthritis (CIA) mouse model. Results of measuring incidence rates of arthritis and clinical arthritis index (CAI) revealed that mice administrated with hUCB-MSCs had a significant reduction in arthritis severity. Proteins that might affect disease progression and therapeutic efficacy of hUCB-MSC were identified through LC-MS/MS analysis using serum samples. In addition, L-1000 analysis was performed for hUCB-MSC culture medium. To analysis data obtained from LC-MS/MS and L-1000, tools such as ExDEGA, MEV, and DAVID GO were used. Results showed that various factors secreted from hUCB-MSCs might play roles in therapeutic effects of MSCs on RA, with platelet activation possibly playing a pivotal role. Results of this study also suggest that SERPINE1 and THBS1 among substances secreted by hUCB-MSC might be key factors that can inhibit platelet activation. This paper is expected to improve our understanding of mechanisms involved in treatment effects of stem cells on rheumatoid arthritis.

Recent progress of gene circuit designs in immune cell therapies.

The success of chimeric antigen receptor (CAR) T cell therapy against hematological cancers has convincingly demonstrated the potential of using genetically engineered cells as therapeutic agents. Although much progress has been achieved in cell therapy, more beneficial capabilities have yet to be fully explored. One of the unique advantages afforded by cell therapies is the possibility to implement genetic control circuits, which enables diverse signal sensing and logical processing for optimal response in the complex tumor microenvironment. In this perspective, we will first outline design considerations for cell therapy control circuits that address clinical demands. We will compare and contrast key design features in some of the latest control circuits developments and conclude by discussing potential future directions.

Time to surgery and survival in breast cancer.

BACKGROUND: This study aimed to investigate the effect of the time from diagnosis to breast cancer surgery on breast cancer patients' prognosis. METHODS: Of the 1900 patients diagnosed with invasive (stage 1-3) breast cancer who underwent surgery in KUH between 2012 and 2019, 279 patients were enrolled in this study. All patients, including those who received neoadjuvant chemotherapy, were classified as Model 1 subjects, and those who received immediate surgical treatment were classified as Model 2 subjects. We conducted a Cox regression analysis to identify prognostic factors of breast cancer associated with the time from diagnosis to surgery. RESULTS: The univariate results indicated a sharp drop in both groups' survival rates when the time to surgery was delayed for more than 8 weeks (Model 1 p = 0.000; Model 2 p = 0.001). In the multivariate analysis, the hazard ratio (HR) of Model 1increased (HR = 6.84, 95% CI 1.06-44.25) in response to a delay in surgery of more than 8 weeks. Smoking and the American Joint Committee on Cancer (AJCC) staging system had a negative effect on breast cancer prognosis, while hormone therapy had a positive effect. CONCLUSION: For all patients, a delay in breast cancer surgery of more than 8 weeks was inversely associated with survival.

Analysis of energy intakes, physical activities and metabolic syndrome according to the income level in Korean elderly people: Korean National Health and Nutrition Examination Survey 2016‒2018.

PURPOSE: To determine the correlations of differences in the income level with the presence of metabolic syndrome (MetS), energy intake, and physical activity across Korean elderly populations. METHODS: We obtained data from 2,139 elderly individuals (aged >65 years) based on the Korea National Health and Nutrition Examination Survey (KNHANES) (2016‒2018). We analyzed the levels of physical activity (PA) and energy intake using the survey data. Moreover, we analyzed the differences in energy intake and PA levels according to the income level and MetS. RESULTS: Compared with the non-MetS group, the MetS group displayed significantly higher levels of waist circumference (p=0.000), triglycerides (p=0.000), systolic blood pressure (p=0.000), diastolic blood pressure (p=0.016), and fasting blood glucose (p=0.000) for both high and low income levels. However, the level of high-density lipoprotein cholesterol was significantly lower in the MetS group than that in the non-MetS group (p=0.000). The level of smoking in non-MetS men was significantly higher than that in MetS men across all participants (p=0.047). Except carbohydrate intake, the total energy intake (p=0.022), fat intake (p=0.009), and protein intake (p=0.005) were significantly lower in the MetS group than those in the non-MetS group for high income levels. We obtained similar results for low income levels. The two-way analysis of variance (ANOVA) did not identify an interaction between the income level and the presence of MetS; however, the total energy, i.e., the level of total energy intake, was significantly lower in participants with low income levels than in those with high income levels. For high income levels, transport PA (p=0.002), vigorous recreational PA (p=0.001), moderate recreational PA (p=0.001), and total PA (p=0.000) were significantly lower in the MetS group than those in the non-MetS group. For low income levels, moderate occupational PA (p=0.012), transport PA (p=0.018), and total PA ((p=0.000) were significantly lower in the MetS group than those in the non-MetS group. The total PA, i.e., the level of energy consumption, was significantly lower in the elderly with low income levels than in those with high income levels. CONCLUSION: Regardless of the income level, the elderly with MetS exhibited low levels of energy intake and PA, compared with those without MetS. In addition, regardless of the presence of MetS, the elderly with low income levels exhibited lesser energy intake and PA. These findings implied the need for balanced nutrient intake and increased participation in PA as well as education and program development to prevent MetS in the elderly.

Immunomodulatory Effect of Epidermal Growth Factor Secreted by Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells on Atopic Dermatitis.

Background and Objectives: Human mesenchymal stem cells (MSCs) are emerging as a treatment for atopic dermatitis (AD), a chronic inflammatory skin disorder that affects a large number of people across the world. Treatment of AD using human umbilical cord blood-derived MSCs (hUCB-MSCs) has recently been studied. However, the mechanism underlying their effect needs to be studied continuously. Thus, the objective of this study was to investigate the immunomodulatory effect of epidermal growth factor (EGF) secreted by hUCB-MSCs on AD. Methods and Results: To explore the mechanism involved in the therapeutic effect of MSCs for AD, a secretome array was performed using culture medium of hUCB-MSCs. Among the list of genes common for epithelium development and skin diseases, we focused on the function of EGF. To elucidate the effect of EGF secreted by hUCB-MSCs, EGF was downregulated in hUCB-MSCs using EGF-targeting small interfering RNA. These cells were then co-cultured with keratinocytes, Th2 cells, and mast cells. Depletion of EGF disrupted immunomodulatory effects of hUCB-MSCs on these AD-related inflammatory cells. In a Dermatophagoides farinae-induced AD mouse model, subcutaneous injection of hUCB-MSCs ameliorated gross scoring, histopathologic damage, and mast cell infiltration. It also significantly reduced levels of inflammatory cytokines including interleukin (IL)-4, tumor necrosis factor (TNF)-α, thymus and activation-regulated chemokine (TARC), and IL-22, as well as IgE levels. These therapeutic effects were significantly attenuated at all evaluation points in mice injected with EGF-depleted hUCB-MSCs. Conclusions: EGF secreted by hUCB-MSCs can improve AD by regulating inflammatory responses of keratinocytes, Th2 cells, and mast cells.

Combined Mesenchymal Stem Cells and Cartilage Acellular Matrix Injection Therapy for Osteoarthritis in Goats.

BACKGROUND: Human umbilical cord blood-derived MSCs (hUCB-MSCs) have been studied in osteoarthritis (OA) and cartilage regeneration. Our previous study demonstrated that hUCB-MSCs combined with cartilage acellular matrix injection (CAM Inj.) represent potential therapeutic agents for structural improvement and anti-inflammatory effects in a rabbit model of OA. METHODS: Based on a previous study, this study has evaluated the safety and efficacy of hUCB-MSCs combined with CAM Inj. in an anterior cruciate ligament transection (ACLT) with medial meniscectomy (MMx) in a goat model. In this study, 27 goats were divided into 5 groups: normal (n = 3), OA (n = 6), OA + CAM Inj. (n = 6), OA + hUCB-MSCs (n = 6), and OA + hUCB-MSCs + CAM Inj. (n = 6). Lameness and radiographic parameters were assessed 6 months after administration, and macroscopic and histological evaluations of the goat articular cartilage were performed 6 months after intervention. RESULTS: The results showed significant improvement in lameness score only in the OA + hUCB-MSCs group at 5 months after treatment (*p < 0.05), whereas the K&L score showed significant improvement only in the OA + hUCB-MSCs + CAM Inj. group 6 months after intervention (*p < 0.05). In addition, the gross findings showed significance in OA + CAM Inj. and OA + hUCB-MSCs + CAM Inj. groups 6 months after treatment (*p < 0.05 and **p < 0.01). CONCLUSION: In conclusion, treatment with a combination of hUCB-MSCs and CAM Inj. reduced OA symptoms and induced effective cartilage tissue repair in a goat model. We suggest the combination of hUCB-MSCs and CAM Inj. as an alternative therapy for OA.

Long-term oral administration of an HNF4α agonist prevents weight gain and hepatic steatosis by promoting increased mitochondrial mass and function.

We report here that the potent HNF4α agonist N-trans-caffeoyltyramine (NCT) promotes weight loss by inducing an increase in mitochondrial mass and function, including fatty acid oxidation. Previously, we found in a short term trial in obese mice that NCT promoted reversal of hepatic steatosis through a mechanism involving the stimulation of lipophagy by dihydroceramides. NCT led to increased dihydroceramide levels by inhibiting dihydroceramide conversion to ceramides. Here, we were able to administer NCT orally, permitting longer term administration. Mice fed NCT mixed with high fat diet exhibited decreased weight. Examination of RNA-seq data revealed an increase in PPARGC1A, a central regulator of mitochondrial biogenesis. In addition to the decreased hepatic steatosis that we found previously, mice fed a high fat diet containing NCT mice weighed substantially less than control mice fed high fat diet alone. They had increased mitochondrial mass, exhibited increased fatty acid oxidation, and had an increased level of NAD. Markers of liver inflammation such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), which are important in the progression of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis were decreased by NCT. There was no evidence of any toxicity from NCT consumption. These results indicate that HNF4α is an important regulator of mitochondrial mass and function and support that use of HNF4α to treat disorders of fatty acid excess, potentially including obesity, NAFLD, and NASH.

Bioactive Lipids and Their Derivatives in Biomedical Applications.

Lipids, which along with carbohydrates and proteins are among the most important nutrients for the living organism, have a variety of biological functions that can be applied widely in biomedicine. A fatty acid, the most fundamental biological lipid, may be classified by length of its aliphatic chain, and the short-, medium-, and long-chain fatty acids and each have distinct biological activities with therapeutic relevance. For example, short-chain fatty acids have immune regulatory activities and could be useful against autoimmune disease; medium-chain fatty acids generate ketogenic metabolites and may be used to control seizure; and some metabolites oxidized from long-chain fatty acids could be used to treat metabolic disorders. Glycerolipids play important roles in pathological environments, such as those of cancers or metabolic disorders, and thus are regarded as a potential therapeutic target. Phospholipids represent the main building unit of the plasma membrane of cells, and play key roles in cellular signaling. Due to their physical properties, glycerophospholipids are frequently used as pharmaceutical ingredients, in addition to being potential novel drug targets for treating disease. Sphingolipids, which comprise another component of the plasma membrane, have their own distinct biological functions and have been investigated in nanotechnological applications such as drug delivery systems. Saccharolipids, which are derived from bacteria, have endotoxin effects that stimulate the immune system. Chemically modified saccharolipids might be useful for cancer immunotherapy or as vaccine adjuvants. This review will address the important biological function of several key lipids and offer critical insights into their potential therapeutic applications.

Effects of Al Precursors on the Characteristics of Indium-Aluminum Oxide Semiconductor Grown by Plasma-Enhanced Atomic Layer Deposition.

Atomic layer deposition (ALD) has attracted much attention, particularly for applications in nanoelectronics because of its atomic-level controllability and high-quality products. In this study, we developed a plasma-enhanced atomic layer deposition (PEALD) process to fabricate a homogeneous indium aluminum oxide (IAO) semiconductor film. Trimethylaluminum (TMA) and dimethylaluminum isopropoxide (DMAI) were used as Al precursors, which yielded different compositions. Density functional theory (DFT) calculations on the surface reactions between indium and aluminum precursors showed that while highly reactive TMA would etch In, DMAI with lower reactivity would allow indium to persist in the films, resulting in a more controlled doping of Al. The In/Al composition ratio could be further precisely controlled by adjusting the indium precursor dose time to sub-saturation. IAO based on DMAI was applied to fabricate thin-film transistors (TFTs), showing that Al can be a carrier suppressor of indium oxide. TFTs with PEALD IAO containing 3.8 atomic % Al showed a turn-on voltage of -0.4 ± 0.3 V, a subthreshold slope of 0.09 V/decade, and a field effect mobility of 18.9 cm2/(V s).

Pimecrolimus interferes the therapeutic efficacy of human mesenchymal stem cells in atopic dermatitis by regulating NFAT-COX2 signaling.

BACKGROUND: Human mesenchymal stem cells (hMSCs) therapy has recently been considered a promising treatment for atopic dermatitis (AD) due to their immunomodulation and tissue regeneration ability. In our previous studies, we demonstrated that hMSCs alleviate allergic inflammation in murine AD model by inhibiting the activation of mast cells and B cells. Also our phase I/IIa clinical trial showed clinical efficacy and safety of hMSCs in moderate-to-severe adult AD patients. However, hMSCs therapy against atopic dermatitis have had poor results in clinical field. Therefore, we investigated the reason behind this result. We hypothesized that drug-cell interaction could interfere with the therapeutic efficacy of stem cells, and investigated whether coadministration with pimecrolimus, one of the topical calcineurin inhibitors, could influence the therapeutic potential of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) in AD. METHODS: hUCB-MSCs were subcutaneously injected to AD-induced mice with or without pimecrolimus topical application. To examine whether pimecrolimus influenced the immunomodulatory activity of hUCB-MSCs, hUCB-MSCs were treated with pimecrolimus. RESULTS: Pimecrolimus disturbed the therapeutic effect of hUCB-MSCs when they were co-administered in murine AD model. Moreover, the inhibitory functions of hUCB-MSCs against type 2 helper T (Th2) cell differentiation and mast cell activation were also deteriorated by pimecrolimus treatment. Interestingly, we found that pimecrolimus decreased the production of PGE2, one of the most critical immunomodulatory factors in hUCB-MSCs. And we demonstrated that pimecrolimus downregulated COX2-PGE2 axis by inhibiting nuclear translocation of NFAT3. CONCLUSIONS: Coadministration of pimecrolimus with hMSCs could interfere with the therapeutic efficacy of hMSCs in atopic dermatitis, and this is the first study that figured out the interaction of hMSCs with other drugs in cell therapy of atopic dermatitis. Therefore, this study might give rise to improvement of the clinical application of hMSCs therapy and facilitate the widespread application of hMSCs in clinical field.

Liver fat storage is controlled by HNF4α through induction of lipophagy and is reversed by a potent HNF4α agonist.

We report the discovery of strong HNF4α agonists and their use to uncover a previously unknown pathway by which HNF4α controls the level of fat storage in the liver. This involves the induction of lipophagy by dihydroceramides, the synthesis and secretion of which is controlled by genes induced by HNF4α. The HNF4α activators are N-trans caffeoyltyramine (NCT) and N-trans feruloyltyramine (NFT), which are structurally related to the known drugs alverine and benfluorex, which we previously showed to be weak HNF4α activators. In vitro, NCT and NFT induced fat clearance from palmitate-loaded cells. In DIO mice, NCT led to recovery of hepatic HNF4α expression and reduction of steatosis. Mechanistically, increased dihydroceramide production and action downstream of HNF4α occurred through increased expression of HNF4α downstream genes, including SPNS2 and CYP26A1. NCT was completely nontoxic at the highest dose administered and so is a strong candidate for an NAFLD therapeutic.