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Atopic dermatitis (AD) is one of major skin inflammatory diseases characterized by excessive Th2-mediated immune responses. Recent evidence provides that interlukin-13 (IL-13) plays the role of a key Th2 cytokine that drives the inflammation underlining AD. Due to adverse effects of commercially available synthetic drugs, the need for treatments based on natural products is gaining much attention. Sargassum horneri is an edible brown algae known for beneficial bioactivities including anti-inflammation. We investigated if polyphenol-rich S. horneri extracts (SHE) could suppress AD-like skin lesions in NC/Nga mice and if that involved inhibition of the infiltration of Th2-mediated cytokine IL-13. We observed markedly increased infiltration of IL-13 positive cells in AD-like skin lesions of mice but SHE treatments decreased it. Also, the dermal expression of IL-13 was sufficient to cause inflammatory responses in mice skin resembling human AD. SHE suppressed the dermal infiltration of inflammatory cells where IL-13 plays a crucial role in skin tissues and in the recruitment of inflammatory cells. Furthermore, it was confirmed that SHE reduced T cell, dendritic cell, and macrophage populations in spleen. Moreover, SHE decreased the collagen deposition in skin and ear dermis resulting in reduced fibrosis that occurs in AD due to excessive collagen. Taken together, our results reveal that SHE suppressed the infiltration of inflammatory cells into skin dermis by decreasing the infiltration of IL-13 positive cells. Therefore, SHE could be taken as a useful therapeutic agent to alleviate AD.

Neurological complications attributed to coronavirus disease-19 (COVID-19) infection have been reported including acute disseminated encephalomyelitis, Guillain-Barré syndrome, and so on. Herein, we report a 49-year-old woman presented with acute encephalopathy and paraplegia simultaneously after COVID-19 infection. Brain magnetic resonance imaging (MRI) showed symmetric hyperintense basal ganglia lesions on T2-weighted imaging. Cerebrospinal fluid pleocytosis, motor axonal neuropathy and enhancement of conus medullaris nerve roots on spine MRI were observed. We treated her with high-dose corticosteroid and intravenous immunoglobulin.

The Geostationary Environment Monitoring Spectrometer (GEMS) onboard the Geostationary Korea Multi-Purpose Satellite-2B (GEO-KOMPSAT-2B) satellite observes the hourly volcanic SO2 over Asia. In this study, the various physical characteristics of volcanic plumes have been investigated based on hourly volcanic SO2 measurements. The transport direction, path and speed, and altitude of volcanic SO2 plume emitted from Nishinoshima in Japan, Etna in Italy, and Dukono located in Halmahera, Indonesia were calculated. The SO2 plume from Nishinoshima, Japan, moved westward at a maximum speed of 57 km/h on August 4, 2020. The SO2 plume generated from Etna was observed to move over China using both GEMS and TROPOMI, and moved at an altitude of 11–14 km and a speed of 162–190 km/h. In the case of the SO2 plume from the Dukono volcano flowed into an average of 3.6 Mg of SO2 per hour to the cities of nearby islands. GEMS can be utilized for an improvement in the prediction accuracy of SO2 plume transport using a chemical transport model due to the availability of hourly volcanic SO2 height information. In addition, hourly observations of SO2 concentrations are expected to protect SO2 exposure through rapid forecasting for people in cities around the volcano.

In this study, nanocomplexes composed of glycyrrhizic acid (GA) derived from the root of the licorice plant (

The initiation of antiviral treatment in chronic hepatitis B (CHB) patients with compensated cirrhosis and low-level viremia (LLV; HBV DNA 15-2,000 IU/mL) remains controversial. We sought to compare the long-term outcomes of these untreated patients according to their viremic status.627 CHB untreated patients with compensated cirrhosis were analyzed retrospectively. The risk of hepatocellular carcinoma (HCC) and liver-related clinical events, including hepatic decompensation, were compared between patients with LLV and undetectable HBV DNA. Patients who received antiviral treatment were censored at the time of treatment initiation.The mean age of the patients was 54.7 years, 64.4 % of whom were male. During the study period, 59 patients developed HCC (20 and 39 in the undetectable and LLV groups, respectively) with an annual incidence of 2.44/100 person-years (PYs). Multivariable analysis revealed that the LLV group was associated with a significantly higher risk of HCC (adjusted hazard ratio [HR]: 2.36, p=0.002) than the undetectable group. In the 204 propensity-score (PS) matched cohort, the LLV group had a 2.16-fold greater risk of HCC than the undetectable group (p=0.014). Liver-related clinical events occurred in 121 patients with an annual incidence of 5.25/100 PYs. Despite not reaching statistical significance, the LLV group tended to have a higher risk of liver-related events in the PS-matched cohort (HR: 1.14, p=0.50).Compared with patients with undetectable HBV DNA, those with compensated cirrhosis and LLV had a significantly higher risk of HCC. Antiviral treatment should be advised for these patients.

In the fight against cancer, immunotherapies are one of the largest growing therapeutics in development. Immunotherapeutics are designed to boost or harness the power of the immune system to prevent, control, or eliminate cancer; while many immune therapies have been found to be safe others have induced severe toxicities. For instance, even compounds that target the same molecule/antigen can have dramatically differing safety profiles. Current preclinical models evaluating these therapies are underequipped to assess the safety of these compounds: in vitro assays fail to predict systemic responses and traditional animal models often fail to correlate with human responses. To better meet the needs of assessing preclinical toxicity we developed a PBMC-humanized mouse model to test a variety of therapeutics, including both monoclonal and bispecific antibodies and induce human cytokine release responses which can manifest within hours or days later resulting in tissue damage and lethality of the mice. To date we have tested a variety of therapeutics, including Blinatumomab, Rituximab, EGFRxCD3 BiTE, CAR-T, and others in our platform while evaluating the ability of the therapeutic to induce human cytokines, bodyweight loss, clinical symptom assessment, and survival in the context of toxicity alone or along with the evaluation with efficacy. We found that many of the therapeutics tested in our platform showed similarities to clinical data in humans. For example, urelumab and utomilumab are both fully humanized monoclonal antibodies against 4-1BB (CD137). However, during clinical trials, urelumab was shown to induce severe liver toxicities while utomilumab was well tolerated. In our huPBMC mouse model, we likewise showed that huPBMC mice dosed with 10 mpk of urelumab experienced body weight loss, showed liver necrosis, and met the clinical criteria for early euthanasia compared to mice treated with 10 mpk utomilumab and PBS treated controls. Serum levels of enzymes associated with liver damage: AST, ALT and GLDH were significantly higher in urelumab treated mice and terminal serum cytokine analysis revealed similarities with those found to be increased in urelumab clinical trials, including elevated IFNγ, IP-10, MIG, and MIP-1α and MIP-1β. Further, HuPBMC mice are also capable of detecting variability among donors. We have screened well over 60 human PBMC donors in huPBMC mice treated with OKT3 and αCD28 and while we always see an increase in cytokines such as IFNγ - the range of induction varies greatly among donors. Further, we see PBMC-donor variability in body weight loss and survival rate after OKT3 and αCD28 treatments. We demonstrate that the PBMC humanized mouse model shows clinical relevance. The use of these models for preclinical safety assessments has the potential to become an important part of novel immunotherapeutic development for patient safety and reducing drug development costs. Citation Format: Destanie Rose, Won Lee, Guoxiang Yang, Jiwon Yang, Mingshan Cheng, Wenqian He, Bernard Buetow, Allison Vitsky, Maggie Liu, Bart Jessen, James Keck. The use of PBMC humanized mice to test the efficacy and safety of antibody and cell-based cancer immunotherapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB349.

Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a revolutionary therapeutic to fight cancer. However, side effects such as cytokine-release syndrome and neurotoxicity often accompany and remain unpredictable. While autologous CAR-Ts are FDA-approved, allogeneic CAR-Ts are in active development in pursuit of “off-the-shelf” availability and reduced manufacturing costs. However, the same concern for adverse events applies. Importantly, how the immune characteristics of the patient may predispose towards toxicity is not well modeled. Further, it is unclear how autologous versus allogeneic products interact with the patient immune system. Toxicity does not correlate with in vitro characterization of the CAR-Ts, adding unpredictability to the toxicity and efficacy. These highlight the need for in vivo mouse models to explore biological variation, predictive biomarkers, and therapeutic intervention. Therefore, we developed a humanized mouse model using NSG™-MHC Class I/II double knock-out (DKO) mice engrafted with human PBMCs to access individual variability in CAR-T-induced toxicity and efficacy. DKO mice are optimal for assessing human cytokine induction from CAR-Ts as they show delayed onset of GvHD and low baseline cytokine levels. To test donor variation in autologous CAR-T toxicity, we humanized mice and treated with autologous CD19 CAR-Ts containing the CD28 costimulatory domain and CD3z chain from two human PBMC donors (Donor A and B). CAR-T successfully eliminated human B cells from both PBMC donors in vivo. We observed drastic body weight loss and 83% of Donor A mice (engrafted with 17M PBMCs) reached the humane endpoint. In contrast, Donor B mice did not experience body weight loss. CAR-T induced human cytokines such as IFN-ꝩ, IL-2, IL-4, IL-6, IL-10, TNFα, MIG, MIP-1a, and IP-10, recapturing clinical data. To test donor variation in allogeneic CAR-T toxicity, we engrafted mice with 10M PBMCs from 6 healthy donors and treated with allogeneic CAR-Ts from Donor A or B. Allogenic efficacy was greater in Donor B CAR- than Donor A CAR-Ts. Donor-specific variability was observed; mice humanized with one of the six donors, experienced significant body weight loss only from the Donor B CAR-Ts but not from Donor A CAR-Ts. Principal component analysis of cytokine data revealed that Donor B CAR-Ts induced more distinguished cytokine responses than Donor A CAR-Ts, driven by IFN-ꝩ and IL-10. Lastly, the data indicates that the CAR-T cells show poor expansion in allogeneic treatment, corresponding to the current literature. PBMC-humanized mice provide an in vivo platform to assess the toxicity and efficacy of autologous and allogeneic CAR-T treatment. This platform can be used to preclinically assess cytokine induction from the interaction between the patient immune system and allogeneic CAR-Ts from healthy donors. Citation Format: Won Lee, Destanie Rose, Katelyn Burleigh, Blair Armstrong, Heather Gustafson, Rebecca Gardner, James G. Keck, Jiwon Yang. Assessing individual variability in efficacy and toxicity of autologous and allogeneic chimeric antigen receptor T-cell immunotherapy using a PBMC-humanized mouse model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4096.

In this study, we examined cellular responses to acute and chronic IRA irradiation at mild and natural levels of exposure in two types of human fibroblasts, each isolated from a different donor, at physiological temperature (34°C).Two types of human dermal fibroblasts (derived from a 20- and 50-year-old women, respectively) were exposed to different repeat numbers of IRA exposure (3, 6, 10, and 14 times; 42 mW/cmWe demonstrated that chronic IRA irradiation-induced severe cellular damage, including prolonged cell proliferation, increased intracellular ROS levels, activated cellular apoptosis, and elongated cell morphology, whereas acute IRA irradiation had negligible effects at 34°C. In addition, it was evident that the degree of cellular damage due to IRA irradiation differed according to the type of fibroblasts.Considering the severe cellular damage induced by chronic IRA irradiation without heat, continuous exposure of skin to IRA irradiation during daily life may be harmful enough to induce photoaging.

The Geostationary Environment Monitoring Spectrometer (GEMS) onboard the Geostationary Korea Multi-Purpose Satellite-2B (GEO-KOMPSAT-2B) satellite was launched in February 2020 and observes the hourly volcanic SO2 in geostationary orbit. We For the first time show the hourly changes in volcanic SO2 distributions emitted and transported from several volcanoes over Asia. The various physical characteristics of volcanic plumes have been investigated based on hourly volcanic SO2 measurements. We estimated transport direction, path and speed, and altitude of volcanic SO2 plume emitted from Nishinoshima in Japan, Etna in Italy, Taal volcano in the Philippines and Dukono located in Halmahera, Indonesia. Before the eruption, Taal volcanic SO2 plumes, which were found to present within PBL, were transported mostly less than 100 km in various azimuth directions. Gradual increase in SO2 column densities was observed for about two months before a volcanic eruption from Taal. It implies that it might be possible to warn a volcanic eruption in advance which is subject to further investigation. GEMS can be further utilized for an improvement in prediction accuracy of SO2 plume transport using chemical transport model due to the availability of hourly volcanic SO2 height information.

Nitrogen dioxide (NO2) is generally emitted from the anthropogenic source such as fossil fuel combustion and natural sources such as lightning, forest fires, and soil emission. These NO2 have adverse effects on human health and are known to affect regional climate as a short lived climate forcer. In addition, it is a precursor of aerosol nitrate and plays a key role the photochemistry of tropospheric Ozone. Up to date, NO2 observation has been possible only once a day using low earth orbit satellite sensors such as GOME, SCIAMACHY, GEMS-2, OMI, OMPS, and TROPOMI. However, hourly NO2 monitoring is expected to provide better understanding of atmospheric chemistries and climate effects related with NOx in regional and global scales. From February, 2020, it is possible, for the first time, to observe the diurnal NO2 variations using Geostationary Environment Monitoring Spectrometer (GEMS). Here, we present first results of diurnal changes in total and tropospheric NO2 columns observed over Asia with high temporal and spatial resolutions using the GEMS operational NO2 algorithm. NIER of Ministry of Environment in South Korea plans to release the GEMS NO2 data in real-time. The GEMS operational NO2 algorithm based on DOAS technique and LUT based NO2 AMF to retrieve the total NO2 columns. We, in addition, retrieve the GEMS tropospheric NO2 columns by subtracting stratospheric NO2 columns from the total NO2 columns. The stratospheric NO2 columns are calculated from scaling stratospheric NO2 from SLIMCAT model using the real GEMS observation data over Pacific ocean. In this present study, we introduce diurnal characteristics at various major cities including, ports, and industrial regions. We also evaluate the performance of the GEMS NO2 retrieval algorithm by comparing GEMS NO2 columns and those observed from ground based Pandora at Seosan in South Korea and MAX-DOAS at Xianghe in China. The comparisons also are made between the total and tropospheric GEMS NO2 data and that of TROPOMI. The validation results show good agreements of GEMS data against those from others.

Over the past few years, chimeric antigen receptor T (CAR T)-cell therapy has emerged as a novel treatment option for certain hematologic malignancies. Several CAR T-cell therapies produced highly efficacious responses from patients with hematologic malignancies. However, wider adoption of CAR T-cell therapy is challenged due to the potential development of life-threatening toxicities including cytokine release syndrome (CRS). CRS symptoms can range from mild fever to life-threatening events, including death. Preclinical animal models to assess the efficacy and toxicity of CAR T-cell therapies have been lacking. Here, we developed a novel mouse model to assess the efficacy and toxicity of CAR T-cell therapy simultaneously. Two different PBMC humanized NSG™ variants were used. NSG-MHC Class I/II double knock-out strain is known to have a delayed onset of GvHD, and NSG-SGM3xIL15 strain shows a higher engraftment level of human NK and myeloid cells, in addition to human T cells. Mice were humanized using PBMCs and treated with autologous or allogeneic CAR T cells, and efficacy and toxicity were assessed. Compared to the control treatment, CD19 CAR T-cells caused a decrease in the human CD19+ cell population in the blood and spleen, and induced cytokine release. Both T-cell and myeloid cytokine releases, including IFNgamma, IL-10, RANTES, and MIP-1alpha, were induced in our animal models. The in vivo platform can also be used to determine individual PBMC/CAR T donor differences and show the extent of efficacy and toxicity of each PBMC donor treated with autologous and allogeneic CAR T-cell therapy. We further confirmed anticancer efficacy using luciferase-tagged human B-cell lymphoma Raji tumor cells, which express a high level of CD19. In summary, we have developed a novel in vivo model to test the efficacy and toxicity of both autologous and allogeneic CAR T-cell therapy simultaneously. Citation Format: Jiwon Yang, Won Lee, Jing Jiao, Danying Cai, Heather Gustafson, Rebecca Gardner, Mingshan Cheng, James G. Keck. A novel in vivo model to simultaneously assess efficacy and toxicity of chimeric antigen receptor T-cell immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2816.

Cancer has a higher incidence in the elderly and immunotherapy is widely applied to this population. However, the majority of preclinical studies assessing drug toxicity and efficacy have been done in young healthy mice. Immunosenescence is a state of aging-related gradual deterioration of the immune system in the elderly. Here, we established tumor models in aged mice that show immunosenescence for a better representation of cancer patients, and to examine the effects of aging and immunosenescence on cancer drug efficacy and toxicity. Young (7 weeks), mid-aged (54-58 weeks), and aged (76-78 weeks) C57BL/6J female mice were used for this study. Syngeneic tumor models were established using three different mouse cancer cell lines, B16-F10 melanoma, MC38 colon adenocarcinoma, and E0771 breast cancer. Age-related tumor growth kinetics varied based on tumor models. Specifically, aging did not affect tumor growth kinetics of B16-F10 tumors, while aged mice showed slowed growth of MC38 tumors and faster growth of E0771 tumors. To evaluate the maximum tolerated dose, young and aged mice were dosed with the standard of care cancer drugs (docetaxel, cisplatin, and doxorubicin) and body weight was monitored three times a week. Aged mice showed higher toxicity against standard care cancer drugs compared to young counterparts. Next, we performed efficacy study using checkpoint inhibitor. Young, mid-aged, and aged mice bearing MC-38 tumor were treated with isotype control or Anti-PD1 (8 mg/kg), intravenously, twice weekly for 3 weeks. Whole blood and tumor samples were collected for immune cell profiling. Comparisons of PD-1 response in the various age groups showed that anti-PD1 treatment showed significant suppression of tumor growth in all age groups with the MC38 tumors, with the greatest effect in aged mice. We also found that anti-PD1 treatment increased T cell infiltration into the tumor, and that regulatory T cells in the tumor are decreased in aged mice. In conclusion, we established syngeneic tumor models using aged mice, and found aged mice exhibit higher toxicity against drugs. The effect of aging on tumor growth kinetics varies depending on the models. Differences in immune cell infiltration in the tumor might be an underlying event that causes age-related differences in response to anti-PD1 treatment. The integration of aging in cancer research could potentially bridge the gap between preclinical studies and clinical outcomes. Citation Format: Jiwon Yang, Andrew Schile, Mingshan Cheng, James G. Keck. Age-related immunosenescence and cancer drug toxicity and efficacy in C57BL/6J syngeneic model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 135.

A bispecific T-cell engager (BiTE) enhances the antitumor capabilities of T-cells by directing them to recognize a tumor-specific antigen. Several BiTEs are currently in clinical trials, and there is one FDA-approved BiTE for cancer therapy at the moment. However, one of the biggest challenges BiTE is currently facing is cytokine release syndrome (CRS). While most patients have mild flu-like symptoms, some patients experience a severe inflammatory syndrome, which could ultimately cause multi-system organ failure and death. Thus, the key is to accurately predict the risk-benefit ratio of each individual before starting the treatment. Unfortunately, there is no reliable in vitro or in vivo model to predict the toxicity and efficacy of BiTE at the moment. Additionally, one of the most challenging factors for pre-clinical evaluation of BiTEs for toxicity and efficacy is the inherent differences among patients’ immune systems. Here, we developed an in vivo PBMC-humanized mouse model that can evaluate both toxicity and efficacy of BiTE and other immune-oncology therapeutics in each individual mouse. The platform was validated using an anti-CD28 superagonist (TGN1412), which none of the pre-clinical in vitro assays and in vivo studies, including non-human primates, executed before clinical trials were able to predict the observed clinical toxicities. This model uses luciferase-tagged human B-cell lymphoma Raji tumor cells to allow the measurement of tumor burden and response to treatment, along with toxicity simultaneously. In addition, we showed that this platform can determine individual PBMC donor differences, and potential adverse drug combinations and drug dose-response with efficacy and safety on individual PBMC donors. The model we developed can potentially be used as a predictive and reproducible platform to identify patient, cancer, and therapy combinations at risk for developing CRS. This model will also help to optimize the therapeutic drug dose range to improve the safety profile of BiTE and other immune-oncology drugs. We believe this platform will greatly benefit not only the scientific community but potentially cancer patients as well. Citation Format: Jiwon Yang, Jing Jiao, Kyle Draheim, Danying Cai, Michael A. Brehm, Leonard D. Shultz, Dale L. Greiner, Mingshan Cheng, James G. Keck. A novel, rapid, sensitive, and reproducible in vivo platform to assess efficacy and toxicity of bispecific antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2049.

e14602 Background: Immunotherapy is proven to be powerful and effective in treating cancer. One of the strategies for the therapy is to boost a patient’s immune system by stimulating tumor necrosis factor receptors via the activation of 4-1BB (CD137) costimulatory molecule. Urelumab was the first 4-1BB agonist investigated in clinical trials and showed clinical promise but doses were limited by severe liver toxicity. Preclinical assessment of toxicity failed to predict the clinical safety outcome. Methods: To address the critical needs of in vivo evaluation of toxicity in a preclinical setting, we have developed an animal model using PBMC humanized mice to assess the safety of immunotherapy. In this model, agents targeting human immune system including monoclonal and bispecific antibodies can induce an acute response of cytokine release within hours of treatment and with some therapies a systemic response can manifest in tissue damage and lethality of mice days later. Results: The potential clinical relevance of the PBMC humanized mouse model was demonstrated using 4-1BB agonists urelumab and utomilumab. The antibody-treated PBMC humanized mice were evaluated daily for clinical score and assessed for clinical chemistry and liver histopathology at study terminus. Animals dosed with urelumab at 10 mg/kg exhibited body weight loss and underwent early euthanasia, while animals dosed with utomilumab survived to scheduled euthanasia with minimum body weight loss. Urelumab showed marked liver toxicity relative to utomilumab and controls with more necrosis in the tissue and higher mean ALT, AST and GLDH activities, and the tolerability of urelumab was increased by lowering the dose to 1 mg/kg. The differences captured by the humanized mouse model presented a safety profile similar to the findings about urelumab and utomilumab from the clinical trials. Utomilumab was well tolerated at the dose that caused severe toxicity for urelumab in patients, and the toxicity of urelumab could be reduced by lowering the dose. Conclusions: Our data suggest that the PBMC humanized mouse model could identify human 4-1BB agonists that caused potentially severe liver toxicity. Preclinical safety assessment using humanized mouse models as used for these studies could be an important step in the course of the development of novel immunotherapy for the safety of patients as well as mitigating drug development cost.