The prevalence and predictors of discharge opioid overprescribing in opioid-naïve patients after breast, gynecologic, and head and neck cancer surgery: a prospective cohort study.

PURPOSE: The management of pain following cancer-related surgeries involves the use of opioid analgesics. Nevertheless, there is little evidence characterizing the utility and prescription patterns of opioids after these procedures. Our primary aim was to identify patients from three types of cancer surgery who were overprescribed with opioids. The secondary aim was to determine the potential predictors of overprescribing in the same period. METHODS: We conducted the study at a single cancer referral hospital. Opioid-naïve patients with breast, gynecologic, or head and neck cancer were studied. Patients were considered opioid-naïve if they had a history of opioid use ≤ 30 mg oral morphine equivalent daily dose for less than seven days in the preceding three months before surgery. We recruited eligible participants by convenience sampling on the wards until at least 102 patients were included in the final analysis. After discharge, we followed up on the participants on day 7 via telephone using a structured proforma including questions to identify the last date and amount of opioid dose taken. The equivalent days of opioid use were calculated by their 24-hr use before discharge and the number of doses prescribed for discharge. Our primary outcome was the prevalence of overprescribing in the three surgical specialties defined as the number of patients taking less than 50% of discharge opioids within the first seven days after discharge. We examined the predictors on incidents of overprescribing using multivariable Poisson regression as the secondary outcome. RESULTS: We recruited 119 patients, and 107 patients were included in the final analysis. There were 59/107 (55%) patients found to be overprescribed with opioids. At discharge, they exhibited lower mean numerical rating scale pain scores, lower mean pain severity scores, higher equivalent days of opioids prescribed, and not used opioids in the last 24 hr before discharge. The incidence of overprescribing was 2.4 times greater for patients prescribed with opioids without 24-hr opioid use (relative risk [RR], 2.38; 95% confidence interval [CI], 1.30 to 4.35; P = 0.005). Similarly, the incidence of overprescribing was 1.7 times greater for patients who had opioids 24 hr before discharge and were supplied with opioids for five equivalent days or more at the time of discharge (RR, 1.67; 95% CI, 1.09 to 2.56; P = 0.02). CONCLUSION: Our study shows that the majority of recruited patients undergoing breast, gynecologic, or head and neck cancer surgery were overprescribed opioids. Individualized assessments on patients' 24-hr opioid requirements before discharge and supplying for less than five days are important considerations to reduce overprescribing in opioid-naïve patients after cancer surgery.

RéSUMé: OBJECTIF: La prise en charge de la douleur à la suite d'interventions chirurgicales liées au cancer passe par l'utilisation d'analgésiques opioïdes. Néanmoins, il existe peu de données probantes caractérisant l'utilité et les habitudes de prescription des opioïdes après ces interventions. Notre objectif principal était d'identifier les patient·es de trois types de chirurgie du cancer auxquel·les des opioïdes avaient été surprescrits. L'objectif secondaire était de déterminer les prédicteurs potentiels de surprescription au cours de la même période. MéTHODE: Nous avons mené cette étude dans un seul hôpital de référence pour le cancer. La patientèle naïve aux opioïdes atteinte de cancer du sein, gynécologique ou de la tête et du cou a été étudiée. Les patient·es étaient considéré·es comme naïfs ou naïves aux opioïdes si leurs antécédents d'utilisation d'opioïdes étaient inférieurs ou égaux à une dose quotidienne équivalente à 30 mg de morphine orale pendant moins de sept jours au cours des trois mois précédant la chirurgie. Nous avons recruté les participant·es éligibles par échantillonnage de commodité dans les services jusqu'à ce qu'au moins 102 personnes soient incluses dans l'analyse finale. Après le congé, nous avons fait un suivi téléphonique auprès des participant·es le 7e jour à l'aide d'un formulaire structuré comprenant des questions visant à identifier la dernière date et la dose d'opioïdes prise. Les jours équivalents de consommation d'opioïdes ont été calculés en fonction de leur utilisation dans les 24 heures précédant le congé et du nombre de doses prescrites pour le congé. Notre critère d'évaluation principal était la prévalence de la surprescription dans les trois spécialités chirurgicales, définie comme le nombre de patient·es prenant moins de 50 % des opioïdes reçus au congé dans les sept premiers jours suivant le congé. Nous avons examiné les prédicteurs d'incidents de surprescription en utilisant la régression de Poisson multivariée comme critère d'évaluation secondaire. RéSULTATS: Nous avons recruté 119 patient·es, et 107 patient·es ont été inclus·es dans l'analyse finale. Une surprescription d'opioïdes a été observée pour 59 patient·es sur 107 (55 %). À leur congé, ces personnes présentaient des scores de douleur moyens plus faibles sur l'échelle d'évaluation numérique, des scores moyens de gravité de la douleur plus faibles, des jours équivalents d'opioïdes prescrits plus élevés et n'avaient pas utilisé d'opioïdes dans les 24 heures précédant le congé. L'incidence de surprescription était 2,4 fois plus élevée chez les patient·es à qui l'on avait prescrit des opioïdes sans utilisation d'opioïdes dans les 24 heures (risque relatif [RR], 2,38; intervalle de confiance [IC] à 95 %, 1,30 à 4,35; P = 0,005). De même, l'incidence de surprescription était 1,7 fois plus élevée chez les patient·es qui avaient reçu des opioïdes 24 heures avant le congé et qui avaient reçu des opioïdes pendant cinq jours équivalents ou plus au moment du congé (RR, 1,67; IC 95 %, 1,09 à 2,56; P = 0,02). CONCLUSION: Notre étude montre qu'il y a eu surprescription d'opioïdes pour la majorité des patient·es recruté·es bénéficiant d'une chirurgie de cancer du sein, gynécologique ou de la tête et du cou. Des évaluations individualisées des besoins en opioïdes des patient·es dans les 24 heures avant leur congé et une administration pendant moins de cinq jours sont des considérations importantes pour réduire la surprescription chez les personnes naïves aux opioïdes après une chirurgie oncologique.

Cancer Incidence Among Residents Near Coal-Fired Power Plants Based on the Korean National Health Insurance System Data.

BACKGROUND: Cancer is a leading cause of death worldwide, posing a significant threat to human health and life expectancy. Numerous existing studies explored the correlation between coal-fired power plants and cancer development. Currently, Chungcheongnam-do Province hosts 29 coal-fired power plants, constituting half of the total 58 plants across South Korea. METHODS: This study assessed the cancer incidence by proximity to coal-fired power plants in Chungcheongnam-do Province, Korea. In this study, the exposed group comprised individuals residing within a 2-km radius of the coal-fired power plants, whereas the control group comprised individuals who had no prior residency within the 2-km radius of such plants or elsewhere in the province. Standardized incidence ratios were calculated using the cancer incidence cases retrieved from the National Health Insurance System data from 2007 to 2017. RESULTS: The study found that exposed men had a 1.11 (95% confidence interval [CI], 1.09-1.21) times higher risk of developing all cancer types and a 1.15 (95% CI, 1.09-1.22) times higher risk of developing cancers excluding thyroid cancer compared with control men. Exposed women had a 1.05 (95% CI, 1.00-1.14) times higher risk of developing all cancer types and a 1.06 (95% CI, 0.98-1.13) times higher risk of developing cancers excluding thyroid cancer than did control women. The colorectal, liver, prostate, and bladder cancer incidence rates were significantly higher in exposed men than that in all control groups. The incidence of esophageal, stomach, liver, and lung cancers were significantly higher in exposed women compared with all control groups. CONCLUSION: The residents near coal-fired power plants had a higher risk of developing cancer than did those living in other areas. In the future, long-term follow-up investigations in residents living in the vicinity of power plants are warranted.

Predicting immune checkpoint therapy response in three independent metastatic melanoma cohorts.

Introduction: While Immune checkpoint inhibition (ICI) therapy shows significant efficacy in metastatic melanoma, only about 50% respond, lacking reliable predictive methods. We introduce a panel of six proteins aimed at predicting response to ICI therapy. Methods: Evaluating previously reported proteins in two untreated melanoma cohorts, we used a published predictive model (EaSIeR score) to identify potential proteins distinguishing responders and non-responders. Results: Six proteins initially identified in the ICI cohort correlated with predicted response in the untreated cohort. Additionally, three proteins correlated with patient survival, both at the protein, and at the transcript levels, in an independent immunotherapy treated cohort. Discussion: Our study identifies predictive biomarkers across three melanoma cohorts, suggesting their use in therapeutic decision-making.

Tacrolimus-loaded chitosan-based nanoparticles as an efficient topical therapeutic for the effective treatment of atopic dermatitis symptoms.

Atopic dermatitis (AD) is a chronic cutaneous disease with a complex underlying mechanism, and it cannot be completely cured. Thus, most treatment strategies for AD aim at relieving the symptoms. Although corticosteroids are topically applied to alleviate AD, adverse side effects frequently lead to the withdrawal of AD therapy. Tacrolimus (TAC), a calcineurin inhibitor, has been used to treat AD, but its high molecular weight and insolubility in water hinder its skin permeability. Herein, we developed and optimized TAC-loaded chitosan-based nanoparticles (TAC@CNPs) to improve the skin permeability of TAC by breaking the tight junctions in the skin. The prepared nanoparticles were highly loadable and efficient and exhibited appropriate characteristics for percutaneous drug delivery. TAC@CNP was stable for 4 weeks under physiological conditions. CNP released TAC in a controlled manner, with enhanced skin penetration observed. In vitro experiments showed that CNP was non-toxic to keratinocyte (HaCaT) cells, and TAC@CNP dispersed in an aqueous solution was as anti-proliferative as TAC solubilized in a good organic solvent. Importantly, an in vivo AD mouse model revealed that topical TAC@CNP containing ~1/10 of the dose of TAC found in commercially used Protopic® Ointment exhibited similar anti-inflammatory activity to that of the commercial product. TAC@CNP represents a potential therapeutic strategy for the management of AD.

4-O-Methylascochlorin Synergistically Enhances 5-Fluorouracil-Induced Apoptosis by Inhibiting the Wnt/ß-Catenin Signaling Pathway in Colorectal Cancer Cells.

4-O-Methyl-ascochlorin (MAC), a derivative of the prenyl-phenol antibiotic ascochlorin extracted from the fungus Ascochyta viciae, shows anticarcinogenic effects on various cancer cells. 5-Fluorouracil (5-FU) is used to treat colorectal cancer (CRC); however, its efficacy must be enhanced. In this study, we investigated the molecular mechanisms by which MAC acts synergistically with 5-FU to inhibit cell proliferation and induce apoptosis in CRC cells. MAC enhanced the cytotoxic effects of 5-FU by suppressing the Akt/mTOR/p70S6K and Wnt/ß-catenin signaling pathways. It also reduced the viability of 5-FU-resistant (5-FU-R) cells. Furthermore, expression of anti-apoptosis-related proteins and cancer stem-like cell (CSC) markers by 5-FU-R cells decreased in response to MAC. Similar to MAC, the knockdown of CTNNB1 induced apoptosis and reduced expression of mRNA encoding CRC markers in 5-FU-R cells. In summary, these results suggest that MAC and other ß-catenin modulators may be useful in overcoming the 5-FU resistance of CRC cells.

Predicting immune checkpoint therapy response in three independent metastatic melanoma cohorts.

While Immune checkpoint inhibition (ICI) therapy shows significant efficacy in metastatic melanoma, only about 50% respond, lacking reliable predictive methods. We introduce a panel of six proteins aimed at predicting response to ICI therapy. Evaluating previously reported proteins in two untreated melanoma cohorts, we used a published predictive model (EaSIeR score) to identify potential proteins distinguishing responders and non-responders. Six proteins initially identified in the ICI cohort correlated with predicted response in the untreated cohort. Additionally, three proteins correlated with patient survival, both at the protein, and at the transcript levels, in an independent immunotherapy treated cohort. Our study identifies predictive biomarkers across three melanoma cohorts, suggesting their use in therapeutic decision-making.

Immune Cells Are Differentially Affected by SARS-CoV-2 Viral Loads in K18-hACE2 Mice.

Viral load and the duration of viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important determinants of the transmission of coronavirus disease 2019. In this study, we examined the effects of viral doses on the lung and spleen of K18-hACE2 transgenic mice by temporal histological and transcriptional analyses. Approximately, 1×105 plaque-forming units (PFU) of SARS-CoV-2 induced strong host responses in the lungs from 2 days post inoculation (dpi) which did not recover until the mice died, whereas responses to the virus were obvious at 5 days, recovering to the basal state by 14 dpi at 1×102 PFU. Further, flow cytometry showed that number of CD8+ T cells continuously increased in 1×102 PFU-virus-infected lungs from 2 dpi, but not in 1×105 PFU-virus-infected lungs. In spleens, responses to the virus were prominent from 2 dpi, and number of B cells was significantly decreased at 1×105 PFU; however, 1×102 PFU of virus induced very weak responses from 2 dpi which recovered by 10 dpi. Although the defense responses returned to normal and the mice survived, lung histology showed evidence of fibrosis, suggesting sequelae of SARS-CoV-2 infection. Our findings indicate that specific effectors of the immune response in the lung and spleen were either increased or depleted in response to doses of SARS-CoV-2. This study demonstrated that the response of local and systemic immune effectors to a viral infection varies with viral dose, which either exacerbates the severity of the infection or accelerates its elimination.

Human ST3Gal II and ST6GalNAc IV genes increase human serum-mediated cytotoxicity to xenogeneic cells.

Carbohydrate-antigens widely existed on glycoproteins and glycosphingolipids of all mammalian cells play a crucial role in self-defense and immunity. Xeno-reactive antibodies included in natural human sera play a protecting role in an acute phase-rejection of xenotransplantation. In this study, we investigated the effect of an alteration of glycosylation-pattern, caused by human sialyltransferases such as hST3Gal II or hST6GalNAc IV, on human serum mediated cytotoxicity in pig kidney PK15 cells. From LDH cytotoxicity assay, cytotoxicity to human serum was significantly increased in hST3Gal II and hST6GalNAc IV-transfected PK15 cells, as compared to the control. In the hST6Gal I-carrying cells, the cytotoxicity to human serum was rather decreased. Moreover, flow cytometry analysis revealed that an alteration of pig glycosylation-pattern by hST3Gal II or hST6GalNAc IV influences on a binding of human IgM or IgG, respectively, in pig kidney cells, regardless of Gal antigen alteration. Finally, we found that hST6GalNAc IV contributed to increase of terminal disialylated tetrasaccharide structure, disialyl T antigen, as evidenced by increase of the MAL II lectin binding capacity in the hST6GalNAc IV-transfected PK15 cells, compared with control. Therefore, our results suggest that carbohydrate antigens, such as disialyl T antigen, newly synthesized by the ST3Gal II- and ST6GalNAc IV are potentially believed to be new xeno-reactive elements.

3D finite element analysis of stress distribution on the shape of resected root-end or with/without bone graft of a maxillary premolar during endodontic microsurgery.

Background/purpose: Apical root resection pattern affects the stress distribution behavior in the apical region of the resected tooth. The purpose of the study was to compare the biomechanical responses of resected teeth between endodontic microsurgery (horizontal resection) and targeted endodontic microsurgery (round resection). Materials and methods: Five different models were developed. The basic model without resection (NR) was regarded as the control model, and the others involved: horizontal resection without bone grafting (HN), horizontal resection with bone grafting (HG), round resection without bone grafting (RN), and round resection with bone grafting (RG) models. A static load of 100 N was applied to the buccal and palatal cusps of all the teeth in a 30° oblique direction. The maximum von-Mises stress and tooth displacement values were analyzed and compared. Results: Both the HN and RN models exhibited lower stress distribution values on bone compared with the NR (control) model. Regarding maximum stress distribution at the root apex, the stress value of the RN model was slightly higher compared to the HN model, whereas the RG model displayed a slightly lower stress value in comparison with the HG model. For maximum tooth displacement value, there were no significant differences between the HN and RN models, as well as the HG and RG models. Conclusion: The round resection pattern had comparable stress distribution behaviors at the root apex and tooth displacement values with the horizontal resection pattern. Targeted endodontic microsurgery might provide better biomechanical response of the resected tooth after root-end resection.

PPIB/Cyclophilin B expression associates with tumor progression and unfavorable survival in patients with pulmonary adenocarcinoma.

Cyclophilin B (CypB), encoded by peptidylprolyl isomerase B (PPIB), is involved in cellular transcriptional regulation, immune responses, chemotaxis, and proliferation. Recent studies have shown that PPIB/CypB is associated with tumor progression and chemoresistance in various cancers. However, the clinicopathologic significance and mechanism of action of PPIB/CypB in non-small cell lung cancer (NSCLC) remain unclear. In this study, we used RNA in situ hybridization to examine PPIB expression in 431 NSCLC tissue microarrays consisting of 295 adenocarcinomas (ADCs) and 136 squamous cell carcinomas (SCCs). Additionally, Ki-67 expression was evaluated using immunohistochemistry. The role of PPIB/CypB was assessed in five human NSCLC cell lines. There was a significant correlation between PPIB/CypB expression and Ki-67 expression in ADC (Spearman correlation r=0.374, P<0.001) and a weak correlation in SCC (r=0.229, P=0.007). In ADCs, high PPIB expression (PPIBhigh) was associated with lymph node metastasis (P=0.023), advanced disease stage (P=0.014), disease recurrence (P=0.013), and patient mortality (P=0.015). Meanwhile, high Ki-67 expression (Ki-67high) was correlated with male sex, smoking history, high pT stage, lymph node metastasis, advanced stage, disease recurrence, and patient mortality in ADC (all P<0.001). However, there was no association between either marker or clinicopathological factors, except for old age and PPIBhigh (P=0.038) in SCC. Survival analyses revealed that the combined expression of PPIBhigh/Ki-67high was an independent prognosis factor for poor disease-free survival (HR 1.424, 95% CI 1.177-1.723, P<0.001) and overall survival (HR 1.266, 95% CI 1.036-1.548, P=0.021) in ADC, but not in SCC. Furthermore, PPIB/CypB promoted the proliferation, colony formation, and migration of NSCLC cells. We also observed the oncogenic properties of PPIB/CypB expression in human bronchial epithelial cells. In conclusion, PPIB/CypB contributes to tumor growth in NSCLC, and elevated PPIB/Ki-67 levels are linked to unfavorable survival, especially in ADC.

Identifying Ferroptosis Inducers, HDAC, and RTK Inhibitor Sensitivity in Melanoma Subtypes through Unbiased Drug Target Prediction.

The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem. Here we mine large scale MM proteogenomic data integrating it with MM cell line dependency screen, and drug sensitivity data to identify druggable targets and forecast treatment efficacy and resistance. Leveraging protein profiles from established MM subtypes and molecular structures of 82 cancer treatment drugs, we identified nine candidate hub proteins, mTOR, FYN, PIK3CB, EGFR, MAPK3, MAP4K1, MAP2K1, SRC and AKT1, across five distinct MM subtypes. These proteins serve as potential drug targets applicable to one or multiple MM subtypes. By analyzing transcriptomic data from 48 publicly accessible melanoma cell lines sourced from Achilles and CRISPR dependency screens, we forecasted 162 potentially targetable genes. We also identified genetic resistance in 260 genes across at least one melanoma subtype. In addition, we employed publicly available compound sensitivity data (Cancer Therapeutics Response Portal, CTRPv2) on the cell lines to assess the correlation of compound effectiveness within each subtype. We have identified 20 compounds exhibiting potential drug impact in at least one melanoma subtype. Remarkably, employing this unbiased approach, we have uncovered compounds targeting ferroptosis, that demonstrate a striking 30x fold difference in sensitivity among different subtypes. This implies that the proteogenomic classification of melanoma has the potential to predict sensitivity to ferroptosis compounds. Our results suggest innovative and novel therapeutic strategies by stratifying melanoma samples through proteomic profiling, offering a spectrum of novel therapeutic interventions and prospects for combination therapy. Highlights: (1) Proteogenomic subtype classification can define the landscape of genetic dependencies in melanoma (2) Nine proteins from molecular subtypes were identified as potential drug targets for specified MM patients (3) 20 compounds identified that show potential effectiveness in at least one melanoma subtype (4) Proteogenomics can predict specific ferroptosis inducers, HDAC, and RTK Inhibitor sensitivity in melanoma subtypes.

A One-Year Randomized Controlled Clinical Trial of Three Types of Narrow-Diameter Implants for Fixed Partial Implant-Supported Prosthesis in the Mandibular Incisor Area.

Narrow-diameter implants (NDI) serve as a solution for treating limited bone volume in the anterior mandible. This study aimed to evaluate the one-year clinical outcomes of various NDIs in the mandibular incisor area after immediate loading in partially edentulous patients. This single-center, prospective, single-blinded, randomized controlled trial study included 21 patients, with 7 patients in each of the following groups: control (BLT NC SLActive®; Straumann), experimental group 1 (CMI IS-III Active® S-Narrow; Neobiotech), and experimental group 2 (CMI IS-III Active® Narrow; Neobiotech). Using full digital flow, two fixtures were placed in each patient and immediately provisionalized on the day of surgery. Evaluations encompassed periapical radiographs, implant stability quotient (ISQ), implant stability test (IST) readings, per-implant soft tissue health, patient satisfaction surveys, and esthetic score assessments. Definitive prostheses were delivered twelve weeks post-surgery (CRiS, number: KCT0007300). Following exclusions due to low stability values (n = 2), fixture failure (n = 5), and voluntary withdrawal (n = 1), the implant success rate for patients completing all clinical protocols stood at 100%. The resulting patient failure rates in the control, experimental group 1, and experimental group 2 were 50.0%, 42.9%, and 14.3%, respectively. There were no significant differences between the groups in terms of marginal bone loss, soft tissue health, patient satisfaction, and esthetic scores. Narrow implants showed superior clinical outcomes, followed by S-Narrow and Straumann implants. Calculated one-year survival rates at the implant level were 66.7% for the control group, 85.7% for experimental group 1, and 100% for experimental group 2. All three types of NDIs showed acceptable clinical and radiographic results during the year-long observation period.

Alterations in Plasma Cytokine Levels in Korean Children with Autism Spectrum Disorder.

PURPOSE: Numerous studies have supported the role of the immune dysfunction in the pathogenesis of autism spectrum disorder (ASD); however, to our knowledge, no study has been conducted on plasma cytokine levels in children with ASD in South Korea. In this study, we aimed to analyze the immunological characteristics of Korean children with ASD through plasma cytokine analysis. MATERIALS AND METHODS: Blood samples were collected from 94 ASD children (mean age 7.1; 81 males and 13 females) and 48 typically developing children (TDC) (mean age 7.3; 30 males and 18 females). Plasma was isolated from 1 mL of blood by clarifying with centrifugation at 8000 rpm at 4℃ for 10 min. Cytokines in plasma were measured with LEGENDplex HU Th cytokine panel (BioLegend, 741028) and LEGENDplex HU cytokine panel 2 (BioLegend, 740102). RESULTS: Among 25 cytokines, innate immune cytokine [interleukin (IL)-33] was significantly decreased in ASD children compared with TDC. In acute phase proteins, tumor necrosis factor α (TNF-α) was significantly increased, while IL-6, another inflammation marker, was decreased in ASD children compared with TDC. The cytokines from T cell subsets, including interferon (IFN)-γ, IL-5, IL-13, and IL-17f, were significantly decreased in ASD children compared to TDC. IL-10, a major anti-inflammatory cytokine, and IL-9, which modulates immune cell growth and proliferation, were also significantly decreased in ASD children compared to TDC. CONCLUSION: We confirmed that Korean children with ASD showed altered immune function and unique cytokine expression patterns distinct from TDC.

Association between urinary arsenic concentration and genetic polymorphisms in Korean adults.

Arsenic (As) is a human carcinogen widely distributed in the environment. This study evaluated the association between the urinary As concentration and single nucleotide polymorphisms (SNPs) in Korean adults to determine the genetic factors related to As concentration. The study included 496 participants for the genome-wide association study (GWAS) and 1483 participants for the candidate gene approach study. Participants were 19 years and older. The concentrations of total As (Tot As) and total As metabolites (Tmet As, the sum of inorganic As and their metabolites; arsenite, arsenate, monomethylarsonic, and dimethylarsinic acid) in the urine were analyzed. The GWAS identified four SNPs (rs1432523, rs3776006, rs11171747, and rs807573) associated with urinary Tot As and four SNPs (rs117605537, rs3776006, rs11171747, and rs148103384) significantly associated with urinary Tmet As concentration (P < 1 × 10-4). The candidate gene study identified two SNPs (PRDX2 rs10427027 and GLRX rs3822751) in genes related to the reduction reaction associated with urinary Tot As and Tmet As. This study suggests that genetic factors may play a role in regulating As metabolism in the human body, affecting both exposure levels and its potential health risks in the general Korean population, even at low exposure levels. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00216-x.

Rg3-enriched red ginseng extracts enhance apoptosis in CoCl2-stimulated breast cancer cells by suppressing autophagy.

Background: Ginsenoside Rg3, a primary bioactive component of red ginseng, has anti-cancer effects. However, the effects of Rg3-enriched ginseng extract (Rg3RGE) on apoptosis and autophagy in breast cancer have not yet been investigated. In the present study, we explored the anti-tumor effects of Rg3RGE on breast cancer cells stimulated CoCl2, a mimetic of the chronic hypoxic response, and determined the operative mechanisms of action. Methods: The inhibitory mechanisms of Rg3RGE on breast cancer cells, such as apoptosis, autophagy and ROS levels, were detected both in vitro. To determine the anti-cancer effects of Rg3RGE in vivo, the cancer xenograft model was used. Results: Rg3RGE suppressed CoCl2-induced spheroid formation and cell viability in 3D culture of breast cancer cells. Rg3RGE promoted apoptosis by increasing cleaved caspase 3 and cleaved PARP and decreasing Bcl2 under the hypoxia mimetic conditions. Further, we identified that Rg3RGE promoted apoptosis by inhibiting lysosomal degradation of autophagosome contents in CoCl2-induced autophagy. We further identified that Rg3RGE-induced apoptotic cell death and autophagy inhibition was mediated by increased intracellular ROS levels. Similarly, in the in vivo xenograft model, Rg3RGE induced apoptosis and inhibited cell proliferation and autophagy. Conclusion: Rg3RGE-stimulated ROS production promotes apoptosis and inhibits protective autophagy under hypoxic conditions. Autophagosome accumulation is critical to the apoptotic effects of Rg3RGE. The in vivo findings also demonstrate that Rg3RGE inhibits breast cancer cell growth, suggesting that Rg3RGE has potential as potential as a putative breast cancer therapeutic.

Impact of Radiofrequency Exposure From Mobile Phones on the Risk of Developing Brain Tumors in Korean and Japanese Adolescents: A MOBI-Kids Case-control Study.

BACKGROUND: This study aimed to examine the association between risk of brain tumors and radiofrequency (RF) exposure from mobile phones among young people in Korea and Japan. METHODS: This case-control study of brain tumors in young people was conducted in Korea and Japan under the framework of the international MOBI-Kids study. We included 118 patients diagnosed with brain tumors between 2011 and 2015 and 236 matched appendicitis controls aged 10-24 years. Information on mobile phone use was collected through face-to-face interviews. A detailed RF exposure algorithm, based on the MOBI-Kids algorithm and modified to account for the specificities of Japanese and Korean phones and networks, was used to calculate the odds ratios (ORs) for total cumulative specific energy using conditional logistic regression. RESULTS: The adjusted ORs in the highest tertile of cumulative call time at 1 year before the reference date were 1.61 (95% confidence interval [CI], 0.72-3.60) for all brain tumors and 0.70 (95% CI, 0.16-3.03) for gliomas, with no indication of a trend with exposure. The ORs for glioma specifically, were below 1 in the lowest exposure category. CONCLUSION: This study provided no evidence of a causal association between mobile phone use and risk of brain tumors as a whole or of glioma specifically. Further research will be required to evaluate the impact of newer technologies of communication in the future.

NDUFA12 as a Functional Target of the Anticancer Compound Ertredin in Human Hepatoma Cells As Revealed by Label-Free Chemical Proteomics.

Many attempts have been made to develop new agents that target EGFR mutants or regulate downstream factors in various cancers. Cell-based screening showed that a natural small molecule, Ertredin, inhibited the growth of EGFRvIII mutant cancer cells. Previous studies have shown that Ertredin effectively inhibits anchorage-independent 3D growth of sphere-forming cells transfected with EGFRvIII mutant cDNA. However, the underlying mechanism remains unclear. In this study, we investigated the target protein of Ertredin by combining drug affinity-responsive target stability (DARTS) assays with liquid chromatography-mass spectrometry using label-free Ertredin as a bait and HepG2 cell lysates as a proteome pool. NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 (NDUFA12) was identified as an Ertredin-binding protein that was responsible for its biological activity. The interaction between NDUFA12 and Ertredin was validated by DARTS and cellular thermal shift assays. In addition, the genetic knockdown of the identified target, NDUFA12, was shown to suppress cell proliferation. NDUFA12 was identified as a biologically relevant target protein of Ertredin that is responsible for its antitumor activity, and these results provide insights into the role of NDUFA12 as a downstream factor in EGFRvIII mutants.

A longitudinal molecular and cellular lung atlas of lethal SARS-CoV-2 infection in K18-hACE2 transgenic mice.

BACKGROUND: The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to approximately 500 million cases and 6 million deaths worldwide. Previous investigations into the pathophysiology of SARS-CoV-2 primarily focused on peripheral blood mononuclear cells from patients, lacking detailed mechanistic insights into the virus's impact on inflamed tissue. Existing animal models, such as hamster and ferret, do not faithfully replicate the severe SARS-CoV-2 infection seen in patients, underscoring the need for more relevant animal system-based research. METHODS: In this study, we employed single-cell RNA sequencing (scRNA-seq) with lung tissues from K18-hACE2 transgenic (TG) mice during SARS-CoV-2 infection. This approach allowed for a comprehensive examination of the molecular and cellular responses to the virus in lung tissue. FINDINGS: Upon SARS-CoV-2 infection, K18-hACE2 TG mice exhibited severe lung pathologies, including acute pneumonia, alveolar collapse, and immune cell infiltration. Through scRNA-seq, we identified 36 different types of cells dynamically orchestrating SARS-CoV-2-induced pathologies. Notably, SPP1+ macrophages in the myeloid compartment emerged as key drivers of severe lung inflammation and fibrosis in K18-hACE2 TG mice. Dynamic receptor-ligand interactions, involving various cell types such as immunological and bronchial cells, defined an enhanced TGFß signaling pathway linked to delayed tissue regeneration, severe lung injury, and fibrotic processes. INTERPRETATION: Our study provides a comprehensive understanding of SARS-CoV-2 pathogenesis in lung tissue, surpassing previous limitations in investigating inflamed tissues. The identified SPP1+ macrophages and the dysregulated TGFß signaling pathway offer potential targets for therapeutic intervention. Insights from this research may contribute to the development of innovative diagnostics and therapies for COVID-19. FUNDING: This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2020M3A9I2109027, 2021R1A2C2004501).