Targeting isoforms of RON kinase (MST1R) drives antitumor efficacy.

Recepteur d'origine nantais (RON, MST1R) is a single-span transmembrane receptor tyrosine kinase (RTK) aberrantly expressed in numerous cancers, including various solid tumors. How naturally occurring splicing isoforms of RON, especially those which are constitutively activated, affect tumorigenesis and therapeutic response, is largely unknown. Here, we identified that presence of activated RON could be a possible factor for the development of resistance against anti-EGFR (cetuximab) therapy in colorectal cancer patient tissues. Also, we elucidated the roles of three splicing variants of RON, RON Δ155, Δ160, and Δ165 as tumor drivers in cancer cell lines. Subsequently, we designed an inhibitor of RON, WM-S1-030, to suppress phosphorylation thereby inhibiting the activation of the three RON variants as well as the wild type. Specifically, WM-S1-030 treatment led to potent regression of tumor growth in solid tumors expressing the RON variants Δ155, Δ160, and Δ165. Two mechanisms for the RON oncogenic activity depending on KRAS genotype was evaluated in our study which include activation of EGFR and Src, in a trimeric complex, and stabilization of the beta-catenin. In terms of the immunotherapy, WM-S1-030 elicited notable antitumor immunity in anti-PD-1 resistant cell derived mouse model, likely via repression of M1/M2 polarization of macrophages. These findings suggest that WM-S1-030 could be developed as a new treatment option for cancer patients expressing these three RON variants.

Recommendations for SARS-CoV-2 testing and organ procurement from deceased donors in the Republic of Korea.

We present a summary of the evidence on testing for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and organ procurement from deceased donors and provide recommendations based on current clinical data and the guidelines from major transplant organizations. Because of the limited historical experience with coronavirus disease 2019 (COVID-19), certain recommendations in this document are based on theoretical rationales rather than clinical data. The recommendations in this manuscript may be subject to revision as subsequent clinical studies provide definitive evidence regarding COVID-19 in organ procurement.

Reflex and Spontaneous Movements in Pediatric Patients with Brain Death.

BACKGROUND: Reflex and spontaneous movements are not uncommon in brain death patients. However, most studies have been conducted in adults, while reports in infants and children are rare. Thus, we aimed to evaluate the frequency and characteristics of these movements in pediatric patients declared as brain death. METHODS: Records of pediatric patients who were diagnosed as brain death from 15 hospitals in the Yeongnam region, South Korea, between January 2013 and September 2016 were analyzed. All body movements in patients who met the criteria for brain death as established by the Korea Medical Association were assessed by medical doctors and trained organ transplant coordinators. The frequency and characteristics of these movements were identified. Additionally, the demographic and clinical factors of the brain death patients with and without these movements were compared. RESULTS: A total of 31 patients who met the criteria for brain death were enrolled. Seven patients (22.6%) showed either reflex or spontaneous movements; six of them (85.7%) showed reflex movements only, and one patient (14.3%) showed both types of movements. The most common types of reflex movements were the flexor/extensor plantar response and isolated finger jerk. Four of seven patients (57.1%) showed a single movement pattern, while three (42.9%) showed two different movement patterns. CONCLUSION: It is essential for physicians who perform pediatric brain death examinations to recognize the frequency and characteristics of reflex and spontaneous movements, and this article may help in the accurate and prompt diagnosis of brain death.

Reusing hepatic grafts in Korea: a case report.

The shortage of donor organs has compelled transplant centers to use organs from non-standard donors. The Korean Network for Organ Sharing data showed that there were 5,804 potential recipients on the waiting list, and only 1,579 patients underwent liver transplant in 2019. Reuse of a graft that has been transplanted previously to other recipients could be an option in this situation. However, given the susceptibility of hepatic grafts to ischemic damage, their reuse must be considered extremely carefully. In this retrospective, observational study, we investigated the outcomes of six cases of hepatic graft reuse in Korea since the year 2000, from information gathered from patient medical records from ten transplant centers. Only three of the six reused hepatic grafts functioned well. Among the three successful transplants, two had minimal ischemic damage owing to a longer interval between the first and second transplants, and because they were obtained from living donors. Two of the five cadaveric transplants were successful. The outcome of reusing hepatic grafts in Korea has not been ideal. However, in patients with limited choices, it can be carefully considered, provided the graft is thoroughly checked for ischemic damage and the recipient status is ascertained.

Outcomes of reused transplanted kidneys using cases from the Korean Network for Organ Sharing database.

Due to organ shortages, the reuse of transplanted organs may be a good option for potential organ recipients. However, reports on the reuse of transplanted organs are rare. We retrospectively investigated cases of kidney donation since 2000 using the Korean Network for Organ Sharing database. Three cases of retransplanted kidneys were identified between 2000 and 2019. Of these three cases of kidney reuse, two involved reuse after a living-donor kidney transplant, and one case involved reuse after a deceased-donor kidney transplant. Another patient required a graftectomy due to bacterial infection immediately after transplantation. In two cases, the transplants were successful, and the kidneys have been functioning well for over 7 years. We believe that this case report highlights the opportunities for organ reuse among potential organ recipients and alleviates concerns about reused transplanted kidneys.

Factors Affecting the Time Taken to Determine Brain Death in Patients with Impending Brain Death.

BACKGROUND AND PURPOSE: The increased demand for donor organs has made it crucial to keep the organs of patients with impending brain death (PWIBDs) suitable for transplantation during the process of determining brain death. This study aimed to identify the time taken to determine brain death (TT-BD) in PWIBDs and the associated influencing factors. METHODS: This study analyzed data collected by the Korean Organ Donation Agency from 15 hospitals in the Yeongnam region of South Korea. There were 414 PWIBDs eligible for inclusion in this study. The data consisted of the TT-BD for PWIBDs and the potential variables influencing the TT-BD. RESULTS: The mean age of the 414 PWIBDs was 48.9 years, and 120 of them were female (29.0%). The mean TT-BD was 8.5 days. The presence of spontaneous movements (SMs) and craniotomy significantly affected the TT-BD. The mean TT-BDs were 13.9 and 8.2 days in the PWIBDs with and without SMs, respectively, and 9.8 and 8.0 days in the PWIBDs with and without craniotomy, respectively. CONCLUSIONS: The SMs in PWIBDs and a craniotomy performed immediately before starting the process of determining brain death seem to be related to lengthening the TT-BD.

Reflex and Spontaneous Movements in Adult Patients during the Process of Determining Brain Death in Korea.

BACKGROUND: Brain death is a clinical diagnosis that implies irreversible loss of function of the entire brain, including the brainstem and both hemispheres. Based on previous reports, it is not rare for reflex and spontaneous movements to occur in patients during the process of determining brain death. However, reports of the frequency and common types of these movements vary from study to study. Thus, we evaluated adult patients with impending brain death in Korea to determine the frequency and characteristics of reflex and spontaneous movements. METHODS: Brain dead patients who were admitted to 15 hospitals in the Yeongnam region (Southeast) of Korea were recruited prospectively from January 2013 to September 2016. All patients met the criteria for brain death as established by the Korea Medical Association. All body movements occurred during the process of diagnosing brain death and were assessed by physicians and trained organ transplant coordinators. The frequency and characteristics of these movements were identified and the demographic and clinical factors of impending brain dead patients with and without these movements were compared. RESULTS: A total of 436 patients who met the criteria for brain death were enrolled during the study period. Of these patients, 74 (17.0%) exhibited either reflex or spontaneous movements. Of this subset, 45 (60.8%) exhibited reflex movements only, 18 (24.3%) exhibited spontaneous movements only, and 11 (14.9%) exhibited both reflex and spontaneous movements. The most common reflex movements were the flexor/extensor plantar response and spinal myoclonus. Of the 74 patients, 52 (70.3%) exhibited one movement of the same pattern and 22 (29.7%) exhibited two or more different movement patterns. In addition, 45 (60.8%) exhibited these movements only on a limited area of the body with the leg being most common (n = 26, 57.8%). Patients with hypoxic brain damage and a higher systolic blood pressure exhibited significantly more reflex or spontaneous movements. CONCLUSION: Movements associated with brain dead patients are not rare and thus an awareness of these movements is important to brain death diagnosis. Physicians who perform brain death examinations should understand the frequency and characteristics of these movements to reduce delays in determining brain death.

Risk assessment of zinc oxide, a cosmetic ingredient used as a UV filter of sunscreens.

Zinc oxide (ZnO), an inorganic compound that appears as a white powder, is used frequently as an ingredient in sunscreens. The aim of this review was to examine the toxicology and risk assessment of ZnO based upon available published data. Recent studies on acute, sub-acute, and chronic toxicities of ZnO indicated that this compound is virtually non-toxic in animal models. However, it was reported that ZnO nanoparticles (NP) (particle size, 40 nm) induced significant changes in anemia-related hematologic parameters and mild to moderate pancreatitis in male and female Sprague-Dawley rats at 536.8 mg/kg/day in a 13-week oral toxicity study. ZnO displayed no carcinogenic potential, and skin penetration is low. No-observed-adverse-effect level (NOAEL) ZnO was determined to be 268.4 mg/kg/day in a 13-week oral toxicity study, and a maximum systemic exposure dose (SED) of ZnO was estimated to be 0.6 mg/kg/day based on topical application of sunscreen containing ZnO. Subsequently, the lowest margin of safety (MOS) was estimated to be 448.2, which indicates that the use of ZnO in sunscreen is safe. A risk assessment was undertaken considering other routes of exposure (inhalation or oral) and major product types (cream, lotion, spray, and propellant). Human data revealed that MOS values (7.37 for skin exposure from cream and lotion type; 8.64 for skin exposure of spray type; 12.87 for inhalation exposure of propellant type; 3.32 for oral exposure of sunscreen) are all within the safe range (MOS > 1). Risk assessment of ZnO indicates that this compound may be used safely in cosmetic products within the current regulatory limits of 25% in Korea.

Urinary metabolic profiling of volatile organic compounds in acute exposed volunteers after an oil spill in Republic of Korea.

The Herbei Spirit oil spill occurred in western Korea. A large number of people who participated in the cleanup tasks of the contaminated area were exposed to crude oil component. We developed a method to monitor volatile organic compound (VOC) metabolites in urine, and evaluate the acute exposure caused by the oil spill in exposed volunteer workers (n = 100, 20.7 +/- 2.1 years, mean +/- SD). Acidified urine samples were extracted by SPE, derivatized with trimethylsilyl, and analyzed using gas chromatography-mass spectrometry. Calibration curves were found to be linear from 3 to 1000 ng/mL (r(2) > 0.993). Accuracy was over 82.4%, and precision was less than 24.8%. Using this method, the VOC metabolites, except hippuric acid, were present at higher levels in the urine samples of volunteers after cleanup work. The levels of mandelic acid (MA) and trans,trans-muconic acid (t,t-MU) were increased significantly (p < 0.001). The exposure effect was greater in women than in men. The effect of smoking was analyzed in all exposed and non-exposed groups, with non-smokers showing increased MA and t,t-MU levels related to exposure. The present method was reliable to determine VOC metabolites in urine and could be useful for biomonitoring of acute exposure effects of VOCs.

Effects of Brx-019 (acetic acid 3,6a,9-triacetoxy-6,6a,7, 11b-tetrahydro-indeno [2,1-c] chromen-10-yl ester), a Brazilin derivative, on T cell-mediated immune responses in multiple low dose streptozotocin-induced diabetic C57BL/6 male mice.

Brx-019 (acetic acid 3,6a,9-triacetoxy-6, 6a,7,11b-tetrahydro-indeno [2,1-c] chromen-10-yl ester) was derived from brazilin (CAS 474-07-7) during a trial designed to search for immunomodulators with lower toxicity and more effective immunomodulating activities than brazilin. Brx-019 was selected as a potential immunomodulator based on its effects on Concanavalin A (Con A)-induced proliferation of splenocytes and the 3-[14,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Intraperitoneally administered Brx-019 significantly improved delayed type hypersensitivity and increased immunoglobulin M (IgM) plaque forming cells (PFCs) in multiple low dose streptozotocin-induced diabetic mice (MLDS-diabetic mice). This finding suggests that Brx-019 may increase suppressed humoral and cell-mediated immunity in type 1 diabetes. Brx-019 also significantly increased Con A- or alloantigen-induced proliferation of splenocytes, Con A-induced interleukin 2 (IL-2) production from splenocytes, and IL-2-induced proliferation of Con A-activated splenocytes in MLDS-diabetic mice. These results suggest that Brx-019 might improve immunity in diabetic mice by increasing IL-2 production in splenocytes and responsiveness of splenocytes to IL-2, which were suppressed in MLDS-diabetes.