Knowledge and Attitudes Toward Obstructive Sleep Apnea Among Korean Pulmonologists: A Nationwide Survey.

BACKGROUND: Obstructive sleep apnea (OSA) significantly impacts cardiovascular, metabolic, and respiratory health. In Korea, OSA patients are treated by specialists in internal medicine, otolaryngology, neurology, and psychiatry, but the participation rate of pulmonologists in OSA management is relatively low compared to other specialties. This study investigated the knowledge and attitudes about OSA among Korean pulmonologists. MATERIALS AND METHODS: An online survey was conducted, targeting respiratory specialists listed in the Korean Academy of Tuberculosis and Respiratory Diseases directory. The survey used the validated "Obstructive Sleep Apnea Knowledge and Attitudes" (OSAKA) questionnaire, which consists of questions about knowledge and attitudes on OSA. To maximize participation, email invitations were sent three times to the target audience. RESULTS: Out of 634 queried pulmonologists, 127 (20%) responded to the survey. The mean age of respondents was 45.4 ± 8.6 years. The respondents' years of specialty acquisition ranged from the 1980s to the 2010s. Additionally, 74 (58.3%) held a doctor's degree, and 96 (75.6%) worked in hospitals with a sleep center. Furthermore, 71 (55.9%) of the pulmonologists reported having experience with OSA patients. Pulmonologists with experience managing OSA patients had significantly higher knowledge and attitude scores compared to those without such experience. Interestingly, older respondents and those who completed their pulmonology training earlier had higher attitude scores. In addition, the knowledge score significantly correlated with responses to the five items of the attitude questionnaire. CONCLUSION: This study provides valuable insights into the knowledge and attitudes of Korean pulmonologists regarding OSA. The findings indicate that their knowledge levels are comparable to or better than those in previous studies. These results underscore the need for targeted educational programs and practical training, especially for younger pulmonologists, to enhance their proficiency in managing OSA and to encourage a more active role in its treatment.

Inhibitory effects of compounds isolated from Geranium wilfordii on IL-4 production and ß-hexosaminidase release in RBL-2H3 cells.

This study aimed to investigate the anti-allergic activity of compounds isolated from Geranium wilfordii Maxim. and to suggest potential therapeutic agents for allergies. Nine compounds were isolated from an ethanolic G. wilfordii extract using chromatographic methods and identified chemically and by spectroscopic analysis. These compounds were identified using reported literature data as brevifolin carboxylic acid (1), chlorogenic acid (2), corilagin (3), ellagic acid (4), geraniol (5), kaempferol 3-O-dirhamnoside (6), kaempferol 3-O-neohesperidoside (7), protocatechuic acid (8), and gallic acid (9). All nine identified compounds were assessed for including IL-4 mRNA expression and ß-hexosaminidase release in RBL-2H3 cells stimulated with PMA/ionomycin or IgE + DNP-BSA. IL-4 gene expression assay showed that corilagin (3) potently inhibited IL-4 production, and ß-hexosaminidase release assay showed that protocatechuic acid (8) markedly reduced histamine release. The study shows that of the nine compounds isolated from G. wilfordii, corilagin (3), and protocatechuic acid (8) are potential treatments for allergy-related diseases.

Protective effects of Y-27632 against cisplatin-induced ototoxicity: A zebrafish model Y-27632 and cisplatin-induced ototoxicity.

Cisplatin is an effective chemotherapy agent against various solid malignancies; however, it is associated with irreversible bilateral sensorineural hearing loss, emphasizing the need for drug development to prevent this complication, with the current options being very limited. Rho-associated coiled-coil-containing protein kinase (ROCK) is a serine-threonine protein kinase involved in various cellular processes, including apoptosis regulation. In this study, we used a transgenic zebrafish model (Brn3C: EGFP) in which hair cells within neuromasts are observed in green under fluorescent microscopy without the need for staining. Zebrafish larvae were exposed to cisplatin alone or in combination with various concentrations of Y-27632, a potent ROCK inhibitor. Hair cell counts, apoptosis assessments using the terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling assay, FM1-43FX labeling assay and behavioral analyses (startle response and rheotaxis) were performed to evaluate the protective effects of Y-27632 against cisplatin-induced ototoxicity. Cisplatin treatment reduced the number of hair cells in neuromasts, induced apoptosis, and impaired zebrafish larval behaviors. Y-27632 demonstrated a dose-dependent protective effect against cisplatin-induced hair cell loss and apoptosis. These findings suggest that Y-27632, as a ROCK inhibitor, mitigates cisplatin-induced hair cell loss and associated ototoxicity in zebrafish.

DNA Hypermethylation Inhibits the CD82 Metastasis Suppressor Gene in Gastric Cancer.

BACKGROUND/AIM: Gastric cancer, with its high global incidence and mortality rates, poses a significant challenge due to the rapid decline in patient survival upon metastasis. Understanding and combating metastasis are crucial in improving outcomes. The metastasis suppressor gene CD82 has demonstrated efficacy in inhibiting metastasis across various carcinomas but is frequently down-regulated. However, its role and regulatory mechanisms in gastric cancer remain elusive. MATERIALS AND METHODS: Utilizing public data, we assessed patient survival in relation to CD82 expression. CD82 expression in gastric cancer cell lines was evaluated via western blotting, and its impact on cell mobility was assessed through wound healing and Transwell assays. The demethylation of CD82 was induced using 5-aza-deoxycytidine, while methylation levels were detected via methylation-specific PCR. RESULTS: Low CD82 expression correlated with poor prognosis in patients, and down-regulation and over-expression of CD82 significantly affected cell mobility. Treatment with 5-aza-deoxycytidine restored CD82 expression in low-expressing cell lines, highlighting its methylation-dependent regulation. CONCLUSION: CD82 serves as a pivotal regulator of cell mobility in gastric cancer by suppressing metastasis. Its expression is attenuated in gastric cancer cells through promoter hypermethylation.

Neural Wiskott-Aldrich syndrome protein (N-WASP) promotes distant metastasis in pancreatic ductal adenocarcinoma via activation of LOXL2.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies. A specific mechanism of its metastasis has not been established. In this study, we investigated whether Neural Wiskott-Aldrich syndrome protein (N-WASP) plays a role in distant metastasis of PDAC. We found that N-WASP is markedly expressed in clinical patients with PDAC. Clinical analysis showed a notably more distant metastatic pattern in the N-WASP-high group compared to the N-WASP-low group. N-WASP was noted to be a novel mediator of epithelial-mesenchymal transition (EMT) via gene expression profile studies. Knockdown of N-WASP in pancreatic cancer cells significantly inhibited cell invasion, migration, and EMT. We also observed positive association of lysyl oxidase-like 2 (LOXL2) and focal adhesion kinase (FAK) with the N-WASP-mediated response, wherein EMT and invadopodia function were modulated. Both N-WASP and LOXL2 depletion significantly reduced the incidence of liver and lung metastatic lesions in orthotopic mouse models of pancreatic cancer. These results elucidate a novel role for N-WASP signaling associated with LOXL2 in EMT and invadopodia function, with respect to regulation of intercellular communication in tumor cells for promoting pancreatic cancer metastasis. These findings may aid in the development of therapeutic strategies against pancreatic cancer.

Antiadhesive Hyaluronic Acid-Based Wound Dressings Promote Wound Healing by Preventing Re-Injury: An In Vivo Investigation.

Wound dressings are widely used to protect wounds and promote healing. The water absorption and antifriction properties of dressings are important for regulating the moisture balance and reducing secondary damages during dressing changes. Herein, we developed a hyaluronic acid (HA)-based foam dressing prepared via the lyophilization of photocrosslinked HA hydrogels with high water absorption and antiadhesion properties. To fabricate the HA-based foam dressing (HA foam), the hydroxyl groups of the HA were modified with methacrylate groups, enabling rapid photocuring. The resulting photocured HA solution was freeze-dried to form a porous structure, enhancing its exudate absorption capacity. Compared with conventional biopolymer-based foam dressings, this HA foam exhibited superior water absorption and antifriction properties. To assess the wound-healing potential of HA foam, animal experiments involving SD rats were conducted. Full-thickness defects measuring 2 × 2 cm2 were created on the skin of 36 rats, divided into four groups with 9 individuals each. The groups were treated with gauze, HA foam, CollaDerm®, and CollaHeal® Plus, respectively. The rats were closely monitored for a period of 24 days. In vivo testing demonstrated that the HA foam facilitated wound healing without causing inflammatory reactions and minimized secondary damages during dressing changes. This research presents a promising biocompatible foam wound dressing based on modified HA, which offers enhanced wound-healing capabilities and improved patient comfort and addresses the challenges associated with conventional dressings.

Efficient Combination Chemo-Sonodynamic Cancer Therapy Using Mitochondria-Targeting Sonosensitizer-Loaded Polysorbate-Based Micelles.

Sonodynamic therapy (SDT), utilizing ultrasound (US) and sonosensitizers, holds immense potential as a noninvasive and targeted treatment for a variety of deep-seated tumors. However, the clinical translation of SDT is hampered by several key limitations in sonosensitizers, especially their low aqueous stability and poor cellular uptake. In this study, non-ionic polysorbate (Tween 80, T80) was adopted to formulate effective nanocarriers for the safe and efficient delivery of sonosensitizers to cancer cells. Mitochondria-targeting triphenylphosphonium (TPP)-conjugated chlorin e6 (Ce6) sonosensitizer was loaded into T80-based micelles for efficient SDT. Pro-oxidant piperlongumine (PL) was co-encapsulated with TPP-conjugated Ce6 (T-Ce6) in T80 micelles to enable combination chemo-SDT. T80 micelles substantially enhanced the cellular internalization of T-Ce6. As a result, T80 micelles loaded with T-Ce6 and PL [T80(T-Ce6/PL)] significantly elevated intracellular reactive oxygen species (ROS) generation in MCF-7 human breast cancer cells upon US exposure. Moreover, T-Ce6 exhibited selective accumulation within the mitochondria, leading to efficient cell death under US irradiation. Importantly, T80(T-Ce6/PL) micelles caused cancer-specific cell death by selectively triggering apoptosis in cancer cells through PL. This study demonstrated the feasibility of using T80(T-Ce6/PL) micelles for efficient and cancer-specific combination chemo-SDT.

Enhancing Loop-Mediated Isothermal Amplification through Nonpowered Nanoelectric Preconcentration.

The global threat posed by the COVID-19 pandemic has catalyzed the development of point-of-care (POC) molecular diagnostics. While loop-mediated isothermal amplification (LAMP) stands out as a promising technique among FDA-approved methods, it is occasionally susceptible to a high risk of false positives due to nonspecific amplification of a primer dimer. In this work, we report an enhancing LAMP technique in terms of assay sensitivity and reliability through streamlined integration with a nonpowered nanoelectric preconcentration (NPP). The NPP, serving as a sample preparation tool, enriched the virus concentration in samples prior to the subsequent LAMP assay. This enrichment enabled not only to achieve more sensitive assay but also to shorten the assay time for all tested clinical samples by ∼10 min compared to the conventional LAMP. The shortened assay time suppresses the occurrence of nonspecific amplification by not providing the necessary incubation time, effectively suppressing misidentification by false positives. Utilizing this technique, we also developed a prototype of the POC NPP-LAMP kit. This kit offers a streamlined diagnostic process for nontrained individuals, from the sample enrichment, transfer of the enriched sample to LAMP assays, which facilitates on-site/on-demand diagnosis of SARS-CoV-2. This development holds the potential to contribute toward preventing not only the current outbreak but also future occurrences of pandemic viruses.

Impacts of regular physical activity on hospitalisation in chronic obstructive pulmonary disease: a nationwide population-based study.

INTRODUCTION: Studies that comprehensively evaluate the association between physical activity (PA) levels, particularly by quantifying PA intensity, and healthcare use requiring emergency department (ED) visit or hospitalisation in patients with chronic obstructive pulmonary disease (COPD) are limited in Korea. METHODS: The risk of all-cause and respiratory ED visit or hospitalisation according to the presence or absence of COPD and the level of PA was evaluated in a retrospective nationwide cohort comprising 3308 subjects with COPD (COPD cohort) and 293 358 subjects without COPD (non-COPD cohort) from 2009 to 2017. RESULTS: The COPD group exhibited a higher relative risk of all-cause and respiratory ED visit or hospitalisation across all levels of PA compared with the highly active control group (≥1500 metabolic equivalents (METs)-min/week). Specifically, the highest risk was observed in the sedentary group (adjusted HR (aHR) (95% CI) = 1.70 (1.59 to 1.81) for all-cause ED visit or hospitalisation, 5.45 (4.86 to 6.12) for respiratory ED visit or hospitalisation). A 500 MET-min/week increase in PA was associated with reductions in all-cause and respiratory ED visit or hospitalisation in the COPD cohort (aHR (95% CI) = 0.92 (0.88 to 0.96) for all-cause, 0.87 (0.82 to 0.93) for respiratory cause). CONCLUSIONS: Compared with the presumed healthiest cohort, the control group with PA>1500 METs-min/week, the COPD group with reduced PA has a higher risk of ED visit or hospitalisation.

Measuring Optokinetic Reflex and Vestibulo-Ocular Reflex in Unilateral Vestibular Organ Damage Model of Zebrafish.

One-sided vestibular disorders are common in clinical practice; however, their models have not been fully established. We investigated the effect of unilateral or bilateral deficits in the vestibular organs on the vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) of zebrafish using in-house equipment. For physical dislodgement of the otoliths in the utricles of zebrafish larvae, one or both utricles were separated from the surrounding tissue using glass capillaries. The video data from VOR and OKR tests with the larvae was collected and processed using digital signal processing techniques such as fast Fourier transform and low-pass filters. The results showed that unilateral and bilateral damage to the vestibular system significantly reduced VOR and OKR. In contrast, no significant difference was observed between unilateral and bilateral damage. This study confirmed that VOR and OKR were significantly reduced in zebrafish with unilateral and bilateral vestibular damage. Follow-up studies on unilateral vestibular disorders can be conducted using this tool.

Cloning and Expression Analysis of Bioluminescence Genes in Omphalotus guepiniiformis Reveal Stress-Dependent Regulation of Bioluminescence.

Bioluminescence is a type of chemiluminescence that arises from a luciferase-catalyzed oxidation reaction of luciferin. Molecular biology and comparative genomics have recently elucidated the genes involved in fungal bioluminescence and the evolutionary history of their clusters. However, most studies on fungal bioluminescence have been limited to observing the changes in light intensity under various conditions. To understand the molecular basis of bioluminescent responses in Omphalotus guepiniiformis under different environmental conditions, we cloned and sequenced the genes of hispidin synthase, hispidin-3-hydroxylase, and luciferase enzymes, which are pivotal in the fungal bioluminescence pathway. Each gene showed high sequence similarity to that of other luminous fungal species. Furthermore, we investigated their transcriptional changes in response to abiotic stresses. Wound stress enhanced the bioluminescence intensity by increasing the expression of bioluminescence pathway genes, while temperature stress suppressed the bioluminescence intensity via the non-transcriptional pathway. Our data suggested that O. guepiniiformis regulates bioluminescence to respond differentially to specific environmental stresses. To our knowledge, this is the first study on fungal bioluminescence at the gene expression level. Further studies are required to address the biological and ecological meaning of different bioluminescence responses in changing environments, and O. quepiniiformis could be a potential model species.

Molecular and Treatment Characteristics of SMARCB1 or SMARCA4-Deficient Undifferentiated Tumor: Retrospective Case Series.

SMARCB1 or SMARCA4-deficient sinonasal carcinoma or thoracic undifferentiated tumor has aggressive nature with a poor prognosis. Patients with this disease were diagnosed by immunohistochemistry or next-generation sequencing. Those who were able to receive a surgery tended to be cured, while the others treated with chemotherapy, radiation therapy, or immune checkpoint inhibitor were often insensitive to these therapies. However, one having CD274 (PD-L1) amplification showed the response to immune checkpoint inhibitor and a good prognosis. We believed that this report could provide promising information for determining the optimal treatment option.

Location-Matching Adaptive Testing for Polytomous Technology-Enhanced Items.

The article presents adaptive testing strategies for polytomously scored technology-enhanced innovative items. We investigate item selection methods that match examinee's ability levels in location and explore ways to leverage test-taking speeds during item selection. Existing approaches to selecting polytomous items are mostly based on information measures and tend to experience an item pool usage problem. In this study, we introduce location indices for polytomous items and show that location-matched item selection significantly improves the usage problem and achieves more diverse item sampling. We also contemplate matching items' time intensities so that testing times can be regulated across the examinees. Numerical experiment from Monte Carlo simulation suggests that location-matched item selection achieves significantly better and more balanced item pool usage. Leveraging working speed in item selection distinctly reduced the average testing times as well as variation across the examinees. Both the procedures incurred marginal measurement cost (e.g., precision and efficiency) and yet showed significant improvement in the administrative outcomes. The experiment in two test settings also suggested that the procedures can lead to different administrative gains depending on the test design.

Analysis of the association between vestibular schwannoma and hearing status using a newly developed radiomics technique.

PURPOSE: Vestibular schwannoma is a benign tumor originating from Schwann cells surrounding the eighth cranial nerve and can cause hearing loss, tinnitus, balance problems, and facial nerve disorders. Because of the slow growth of the tumor, predicting the hearing function of patients with vestibular schwannoma's is important to obtain information that would be useful for deciding the treatment modality. This study aimed to analyze the association between magnetic resonance imaging features and hearing status using a new radiomics technique. METHODS: We retrospectively analyzed 115 magnetic resonance images and hearing results from 73 patients with vestibular schwannoma. A total of 70 radiomics features from each tumor volume were calculated using T1-weighted magnetic resonance imaging. Radiomics features were classified as histogram-based, shape-based, texture-based, and filter-based. The least absolute shrinkage and selection operator method was used to select the radiomics features among the 70 features that best predicted the hearing test. To ensure the stability of the selected features, the least absolute shrinkage and selection operator method was repeated 10 times. Finally, features set five or more times were selected as radiomics signatures. RESULTS: The radiomics signatures selected using the least absolute shrinkage and selection operator method were: minimum, variance, maximum 3D diameter, size zone variance, log skewness, skewness slope, and kurtosis slope. In random forest, the mean performance was 0.66 (0.63-0.77), and the most important feature was Log skewness. CONCLUSIONS: Newly developed radiomics features are associated with hearing status in patients with vestibular schwannoma and could provide information when deciding the treatment modality.

Incidence and risk factors of COVID-19 in a tertiary hospital and the effectiveness of booster vaccination among health care workers: A retrospective cohort study, January 2020 to June 2022.

BACKGROUND: Health care workers (HCWs) face a higher risk of infection and may transmit pathogens to patients during a pandemic. This study aims to evaluate infection-control measures by analyzing the incidence and risk factors of COVID-19 and estimating vaccine effectiveness (VE) at a tertiary hospital in Seoul, Republic of Korea. METHODS: This study included 2,516 HCWs from January 1, 2020, to June 30, 2022. Data were analyzed to determine the incidence density and cumulative incidence; the results were compared by the age- and gender-specific standardized incidence ratios (SIR). VE was estimated with multivariate Cox proportional-hazard models as 1-adjusted hazard ratio × 100%. RESULTS: SIR indicated a lower COVID-19 risk in the hospital population than in the general Korean population (SIR, 0.81; 95% confidence interval [CI]: 0.76-0.87). Multivariate Cox analysis indicated that, compared to doctors, nonmedical service supporters and other HCWs (excluding doctors and nurses) were high-risk groups (adjusted hazard ratio [95% CI], 1.72 [1.04-2.83] and 1.76 [1.20-2.58], respectively). Compared to the outpatient unit, the emergency department was a high-risk department (1.70 [1.16-2.50]). The VE of the booster dose was 55.47%, compared to no or incomplete vaccination (95% CI: 22.63-74.37). CONCLUSIONS: Besides encouraging HCWs vaccination, effective infection-control measures should target high-risk groups and departments.

Exploring Embryo-Ototoxic Effects: Insights into Deodorant-Induced Hair Cell Damage in Zebrafish.

Our study investigated the embryo-ototoxic effects of deodorant2 (DA2) on zebrafish embryos, which serve as valuable model organisms due to genetic and physiological similarities to humans. We focused on understanding DA2's impact on zebrafish hair cells, which are vital for sensory perception and balance regulation. DA2, provided by the Ministry of Environment, Republic of Korea, was used at 460 µg/mL in dimethyl sulfoxide (DMSO), with a 0.43% DMSO solvent control group. Three experiments, each using 10 zebrafish specimens from each group, showed an initial 13% hair cell count reduction in the DA2-exposed group. Subsequent experiments demonstrated reductions of 37% and 22%, each with one mortality case. Statistical analysis revealed a significant 24% hair cell count reduction in the DA2-exposed group. We also assessed DA2's impact on zebrafish behavior. Although not statistically significant, differences in distances traveled (0.33-0.39, 95% confidence interval: -0.46-1.1, p = 0.2033) and latencies (-0.016-0.018, 95% confidence interval: -0.052-0.021, p = 0.1917) hinted at negative effects. These results highlight DA2's ototoxic properties affecting zebrafish auditory systems and behavior. Further investigation into DA2's effects on aquatic organisms and potential mitigation strategies are essential. These findings contribute to understanding DA2's safety profile, benefiting aquatic ecosystems and human health assessments.

Flow with an intelligent tutor: A latent variable modeling approach to tracking flow during artificial tutoring.

Increasing use of intelligent tutoring systems in education calls for analytic methods that can unravel students' learning behaviors. In this study, we explore a latent variable modeling approach for tracking learning flow during computer-interactive artificial tutoring. The study considers three models that give discrete profiles of a latent process: the (i) latent class model, (ii) latent transition model, and (iii) hidden Markov model. We illustrate application of each model using example log data from Cognitive Tutor Algebra I and suggest analytic procedures of drawing learning flow. Through experimental application, we show that the models can reveal substantive information about students' learning behaviors and have potential utility for describing the learning flow. The models differed in the assumptions and data constraints but yielded consistent findings on the flow states and interaction modalities. Based on our experiential analyses, we discuss strengths and limitations of the models and illuminate areas of future development.

Safety and efficacy of remimazolam compared with midazolam during bronchoscopy: a single-center, randomized controlled study.

Although remimazolam is an ultra-short-acting benzodiazepine with a shorter elimination half-life and faster recovery time than midazolam, studies evaluating its safety and efficacy during bronchoscopy are limited. This study aimed to compare the safety and efficacy of remimazolam with those of midazolam for bronchoscopy. This prospective randomized parallel-group study was conducted at a single institution. The primary outcome was the time from the end of the procedure to full alertness. Other procedural time parameters, satisfaction profiles, and adverse effects were thoroughly evaluated. The time taken to reach peak sedation and the time from the end of the procedure to full alertness was significantly shorter in the remimazolam group than in the midazolam group (median [interquartile range], 2 min [1-4] vs. 3 min [2-5], P = 0.006; and median, 2 min [1-5] vs. 5 min [1-12], P = 0.035, respectively). In patients with non-biopsy procedures (n = 79), participant satisfaction was significantly higher in the remimazolam group than in the midazolam group (median rated scale, 10 vs. 7, P = 0.042). Physician satisfaction and willingness to repeat the procedure were similar between groups. Although the incidence of adverse effects was similar between the groups and there was no significant difference, the midazolam group had a higher antidote administration rate than the remimazolam group (15.7% vs. 4.1%, P = 0.092). Remimazolam is effective and safe for achieving adequate sedation, with a shorter onset time and faster neuropsychiatric recovery than midazolam. It may be a new option for sedation during bronchoscopy.Trial registration: The trial registration number is NCT05994547, and the date of first registration is 16/08/2023.

Comprehensive single cell aging atlas of mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer.

Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. We investigate how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory, or cancer-associated genes. Aged stromal cells downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts. Among immune cells, distinct T cell subsets (Gzmk+, memory CD4+, γδ) and M2-like macrophages expand with age. Spatial transcriptomics reveal co-localization of aged immune and epithelial cells in situ. Lastly, transcriptional signatures of aging mammary cells are found in human breast tumors, suggesting mechanistic links between aging and cancer. Together, these data uncover that epithelial, immune, and stromal cells shift in proportions and cell identity, potentially impacting cell plasticity, aged microenvironment, and neoplasia risk.

Combination therapy of niclosamide with gemcitabine inhibited cell proliferation and apoptosis via Wnt/ß-catenin/c-Myc signaling pathway by inducing ß-catenin ubiquitination in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer with high morbidity and mortality rates worldwide. Owing to a lack of therapeutic options, the overall survival rate of patients with pancreatic cancer is low. Gemcitabine has been mainly used to treat patients with pancreatic cancer, but its efficacy is limited by chemoresistance. Therefore, a novel therapeutic agent for PDAC therapy is urgently needed. An anthelminthic drug, niclosamide, has already been researched in breast, lung, colon, and pancreatic cancer as an anti-cancer purpose by re-positioning its original purpose. However, combination therapy of gemcitabine and niclosamide was not informed yet. Here, we found that niclosamide co-administered with gemcitabine significantly inhibited tumorigenesis of pancreatic cancer compared to gemcitabine alone. Further, combining niclosamide and gemcitabine inhibited cell proliferation and induced apoptosis. Niclosamide induced cell cycle arrest at the G1 phase, and the levels of CDK4/6 and cyclin D1 were lowered after gemcitabine treatment. In addition, the combination of these chemical compounds more effectively increased the binding level of activated ß-catenin destruction complex and ß-catenin to enable phosphorylation, compared to gemcitabine alone. After phosphorylation, niclosamide - gemcitabine upregulated the ubiquitin level, which caused phosphorylated ß-catenin to undergo proteasomal degradation; the combination was more potent than gemcitabine alone. Finally, the combination more effectively suppressed tumor growth in vivo, compared to gemcitabine alone. Altogether, our results indicate that niclosamide synergistically enhances the antitumor effect of gemcitabine in pancreatic cancer, by inducing the degradation of ß-catenin with ubiquitination. Therefore, this drug combination can potentially be used in PDAC therapy.