TRIM24 Cooperates with Ras Mutation to Drive Glioma Progression through snoRNA Recruitment of PHAX and DNA-PKcs.

The factors driving glioma progression remain poorly understood. Here, the epigenetic regulator TRIM24 is identified as a driver of glioma progression, where TRIM24 overexpression promotes HRasV12 anaplastic astrocytoma (AA) progression into epithelioid GBM (Ep-GBM)-like tumors. Co-transfection of TRIM24 with HRasV12 also induces Ep-GBM-like transformation of human neural stem cells (hNSCs) with tumor protein p53 gene (TP53) knockdown. Furthermore, TRIM24 is highly expressed in clinical Ep-GBM specimens. Using single-cell RNA-sequencing (scRNA-Seq), the authors show that TRIM24 overexpression impacts both intratumoral heterogeneity and the tumor microenvironment. Mechanically, HRasV12 activates phosphorylated adaptor for RNA export (PHAX) and upregulates U3 small nucleolar RNAs (U3 snoRNAs) to recruit Ku-dependent DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Overexpressed TRIM24 is also recruited by PHAX to U3 snoRNAs, thereby facilitating DNA-PKcs phosphorylation of TRIM24 at S767/768 residues. Phosphorylated TRIM24 induces epigenome and transcription factor network reprogramming and promotes Ep-GBM-like transformation. Targeting DNA-PKcs with the small molecule inhibitor NU7441 synergizes with temozolomide to reduce Ep-GBM tumorigenicity and prolong animal survival. These findings provide new insights into the epigenetic regulation of Ep-GBM-like transformation and suggest a potential therapeutic strategy for patients with Ep-GBM.

Oregano Essential Oil in Livestock and Veterinary Medicine.

With a growing global concern over food safety and animal welfare issues, the livestock and veterinary industries are undergoing unprecedented changes. These changes have not only brought challenges within each industry, but also brought unprecedented opportunities for development. In this context, the search for natural and safe products that can effectively replace traditional veterinary drugs has become an important research direction in the fields of animal husbandry and veterinary medicine. Oregano essential oil (OEO), as a natural extract, is gradually emerging in the fields of animal husbandry and veterinary medicine with its unique antibacterial, antioxidant, and multiple other biological activities. OEO not only has a wide antibacterial spectrum, effectively fighting against a variety of pathogenic microorganisms, but also, because of its natural properties, helps us to avoid traditional veterinary drugs that may bring drug residues or cause drug resistance problems. This indicates OEO has great application potential in animal disease treatment, animal growth promotion, and animal welfare improvement. At present, the application of OEO in the fields of animal husbandry and veterinary medicine has achieved preliminary results. Studies have shown that adding OEO to animal feed can significantly improve the growth performance and health status of animals and reduce the occurrence of disease. At the same time, pharmacokinetic studies in animals show that the absorption, distribution, metabolism, and excretion processes of OEO in animals shows good bioavailability. In summary, oregano essential oil (OEO), as a substitute for natural veterinary drugs with broad application prospects, is gradually becoming a research hotspot in the field of animal husbandry and veterinary medicine. In the future, we look forward to further tapping the potential of OEO through more research and practice and making greater contributions to the sustainable development of the livestock and veterinary industries.

LINC00115 promotes chemoresistant breast cancer stem-like cell stemness and metastasis through SETDB1/PLK3/HIF1α signaling.

BACKGROUND: Cancer stem-like cell is a key barrier for therapeutic resistance and metastasis in various cancers, including breast cancer, yet the underlying mechanisms are still elusive. Through a genome-wide lncRNA expression profiling, we identified that LINC00115 is robustly upregulated in chemoresistant breast cancer stem-like cells (BCSCs). METHODS: LncRNA microarray assay was performed to document abundance changes of lncRNAs in paclitaxel (PTX)-resistant MDA-MB-231 BCSC (ALDH+) and non-BCSC (ALDH-). RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to determine the binding proteins of LINC00115. The clinical significance of the LINC00115 pathway was examined in TNBC metastatic lymph node tissues. The biological function of LINC00115 was investigated through gain- and loss-of-function studies. The molecular mechanism was explored through RNA sequencing, mass spectrometry, and the CRISPR/Cas9-knockout system. The therapeutic potential of LINC00115 was examined through xenograft animal models. RESULTS: LINC00115 functions as a scaffold lncRNA to link SETDB1 and PLK3, leading to enhanced SETDB1 methylation of PLK3 at both K106 and K200 in drug-resistant BCSC. PLK3 methylation decreases PLK3 phosphorylation of HIF1α and thereby increases HIF1α stability. HIF1α, in turn, upregulates ALKBH5 to reduce m6A modification of LINC00115, resulting in attenuated degradation of YTHDF2-dependent m6A-modified RNA and enhanced LINC00115 stability. Thus, this positive feedback loop provokes BCSC phenotypes and enhances chemoresistance and metastasis in triple-negative breast cancer. SETDB1 inhibitor TTD-IN with LINC00115 ASO sensitizes PTX-resistant cell response to chemotherapy in a xenograft animal model. Correlative expression of LINC00115, methylation PLK3, SETDB1, and HIF1α are prognostic for clinical triple-negative breast cancers. CONCLUSIONS: Our findings uncover LINC00115 as a critical regulator of BCSC and highlight targeting LINC00115 and SETDB1 as a potential therapeutic strategy for chemotherapeutic resistant breast cancer.

Underreporting of non-study cigarette use by study participants confounds the interpretation of results from ambulatory clinical trial of reduced nicotine cigarettes.

BACKGROUND: As part of its comprehensive plan to significantly reduce the harm from tobacco products, the US Food and Drug Administration is establishing a product standard to lower nicotine in conventional cigarettes to make them "minimally addictive or non-addictive". Many clinical studies have investigated the potential impact of such a standard on smoking behavior and exposure to cigarette constituents. These ambulatory studies required participants who smoke to switch to reduced nicotine study cigarettes. In contrast to clinical trials on pharmaceuticals or medical devices, participants had ready access to non-study conventional nicotine cigarettes and high rates of non-study cigarette use were consistently reported. The magnitude of non-compliance, which could impact the interpretation of the study results, was not adequately assessed in these trials. METHODS: We conducted a secondary analysis of data from a large, randomized trial of reduced nicotine cigarettes with 840 participants to estimate the magnitude of non-compliance, i.e., the average number of non-study cigarettes smoked per day by study participants assigned to reduced nicotine cigarettes. Individual participants' non-study cigarette use was estimated based on his/her urinary total nicotine equivalent level, the nicotine content of the study cigarette assigned and the self-reported number of cigarettes smoked, using a previously published method. RESULTS: Our analysis showed that (1) there is a large variation in the number of non-study cigarettes smoked by participants within each group (coefficient of variation 90-232%); (2) participants in reduced nicotine cigarette groups underreported their mean number of non-study cigarettes smoked per day by 85-91%; and (3) the biochemical-based estimates indicate no reduction in the mean number of total cigarettes smoked per day for any group assigned to reduced nicotine cigarettes after accounting for non-study cigarettes. CONCLUSIONS: High levels of non-compliance, in both the rate and magnitude of non-study cigarette use, are common in ambulatory reduced nicotine cigarette trials where participants have access to conventional nicotine non-study cigarettes. The potential impact of high non-compliance on study outcomes should be considered when interpreting the results from such ambulatory studies.

Ultra-compact electro-optic phase modulator based on a lithium niobate topological slow light waveguide.

Electro-optic modulators (EOMs) are essential devices of optical communications and quantum computing systems. In particular, ultra-compact EOMs are necessary for highly integrated photonic chips. Thin film lithium niobate materials are a promising platform for designing highly efficient EOMs. However, EOMs based on conventional waveguide structures are at a millimeter scale and challenging to scale down further, greatly hindering the capability of on-chip integration. Here, we design an EOM based on lithium niobate valley photonic crystal (VPC) structures for the first time. Due to the high effective refractive index introduced by the strong slow light effect, the EOM can achieve an ultra-compact size of 4 µm×14 µm with a half-wave voltage of 1.4 V. The EOM has a high transmittance of 0.87 in the 1068 nm because of the unique spin-valley locking effect in VPC structures. The design is fully compatible with current nanofabrication technology and immune to fabrication defects. Therefore, it opens a new possibility in designing lithium niobate electro-optic modulators and will find broad applications in optical communication and quantum photonic devices.

Dual oxidase 2 (duox 2) participates in the intestinal antibacterial innate immune responses of Procambarus clarkii by regulating ROS levels.

Dual oxidase (Duox) a member of the nicotinamide adenine dinucleotide phosphate oxidase (NOX) family can induce the production of reactive oxygen species (ROS). In vertebrates, the duox gene was indicated to be associated with the mucosal immunity. The roles of the duox gene in invertebrates were mainly studied in insects for the function of maintaining intestinal flora balance. In recent years, some studies have reported that Duox is involved in regulating the production of ROS and plays an important role in defending against the intestinal pathogen infection. However, the molecular mechanism has not been fully illuminated. In this study, a duox 2 involved in the production of H2O2 was identified for the first time in P. clarkii. Mature Pc-Duox 2 is a 7-transmembrane protein molecule that includes PHD, FAD, and NAD domains. Pc-duox 2 was mainly expressed in hemocytes and intestinal tissue. Its expression levels were obviously upregulated after intramuscular or oral infection with V. harveyi. In the RNAi assay, the upregulated trends of H2O2 and total ROS levels in crayfish intestine were significantly suppressed when Pc-duox 2 was knocked down. Compared with the slightly affected SOD activity, the upregulated CAT activity was suppressed more obviously in the crayfish intestine. Furthermore, Pc-duox 2 had an important effect on the maintenance of the structural stability of crayfish the intestine. Further research revealed that the knockdown of Pc-duox 2 could cause an obvious suppression in the upregulated levels of Toll signalling pathway-related genes, including Pc-toll 1, Pc-toll 3, Pc-dorsal, Pc-ALF 5, Pc-crustin 1, and Pc-lysozyme. Ultimately, these changes triggered the accelerated death of crayfish. Overall, we speculated that Pc-duox 2 played an important role in antibacterial innate immunity in the crayfish intestine by regulating the total ROS level.

Targeting TRIM24 promotes neuroblastoma differentiation and decreases tumorigenicity via LSD1/CoREST complex.

PURPOSE: High-risk neuroblastoma (NB) still has an unfavorable prognosis and inducing NB differentiation is a potential strategy in clinical treatment, yet underlying mechanisms are still elusive. Here we identify TRIM24 as an important regulator of NB differentiation. METHODS: Multiple datasets and clinical specimens were analyzed to define the role of TRIM24 in NB. The effects of TRIM24 on differentiation and growth of NB were determined by cell morphology, spheres formation, soft agar assay, and subcutaneous xenograft in nude mice. RNA-Seq and qRT-PCR were used to identify genes and pathways involved. Mass spectrometry and co-immunoprecipitation were used to explore the interaction of proteins. RESULTS: Trim24 is highly expressed in spontaneous NB in TH-MYCN transgenic mice and clinical NB specimens. It is associated with poor NB differentiation and unfavorable prognostic. Knockout of TRIM24 in neuroblastoma cells promotes cell differentiation, reduces cell stemness, and inhibits colony formation in soft agar and subcutaneous xenograft tumor growth in nude mice. Mechanistically, TRIM24 knockout alters genes and pathways related to neural differentiation and development by suppressing LSD1/CoREST complex formation. Besides, TRIM24 knockout activates the retinoic acid pathway. Targeting TRIM24 in combination with retinoic acid (RA) synergistically promotes NB cell differentiation and inhibits cell viability. CONCLUSION: Our findings demonstrate that TRIM24 is critical for NB differentiation and suggest that TRIM24 is a promising therapeutic target in combination with RA in NB differentiation therapy.

Molecular cloning and functional characterization of peroxiredoxin 4 (prx 4) in freshwater crayfish, Procambarus clarkii.

Peroxiredoxin (Prx), which is a newly discovered member of the antioxidant protein family, performs important biological functions in intracellular signal transduction. In the present study, a peroxiredoxin 4 gene was cloned from crayfish for the first time and named Pc-prx 4. According to the amino acid sequence signature, Pc-Prx 4 was identified as the typical 2-Cys Prx molecule, which possessed two conserved cysteines (Cys98 and Cys219). Time-course expression patterns post V. harveyi infection revealed that Pc-prx 4 was likely related to crayfish innate immune defense responses. In particular, the highest fold upregulation of the Pc-prx 4 mRNA transcript reached approximately 170 post V. harveyi infection in the crayfish hepatopancreas. The results of the mixed functional oxidase assay showed that rPc-Prx 4△ could resist the damaging effect of reactive oxygen species generated from the thiol/Fe3+/O2- reaction system to some extent. In addition, the results of the RNAi assay revealed that the crayfish survival rate was obviously increased post injection of V. harveyi when Pc-prx 4 was knocked down. Further study revealed that both hemolymph melanization and PO activity were strengthened to different degrees in the RNAi assay. Therefore, we speculated that the increase in the crayfish survival rate was likely due to the increase in hemolymph melanization. The obviously reinforced hemolymph melanization was directly caused by the upregulation of hemolymph PO activity, which was induced by the knockdown of Pc-prx 4. However, further studies are still indispensable for illuminating the molecular mechanism of Pc-prx 4 in the crayfish innate immune defense system.

Design of wavelength division multiplexing devices based on tunable edge states of valley photonic crystals.

Wavelength division multiplexing (WDM) devices are key photonic integrated circuit (PIC) elements. Conventional WDM devices based on silicon waveguides and photonic crystals have limited transmittance due to the high loss introduced by the strong backward scattering from defects. In addition, it is challenging to reduce the footprint of those devices. Here we theoretically demonstrate a WDM device in the telecommunication range based on all-dielectric silicon topological valley photonic crystal (VPC) structures. We tune its effective refractive index by tuning the physical parameters of the lattice in the silicon substrate, which can continuously tune the operating wavelength range of the topological edge states, which allows the designing of WDM devices with different channels. The WDM device has two channels (1475 nm-1530 nm and 1583 nm-1637 nm), with contrast ratios of 29.6 dB and 35.3 dB, respectively. We demonstrated highly efficient devices for multiplexing and demultiplexing in a WDM system. The principle of manipulating the working bandwidth of the topological edge states can be generally applied in designing different integratable photonic devices. Thus, it will find broad applications.

Thermal tunable silicon valley photonic crystal ring resonators at the telecommunication wavelength.

Tunable ring resonators are essential devices in integrated circuits. Compared to conventional ring resonators, valley photonic crystal (VPC) ring resonators have a compact design and high quality factor (Q-factor), attracting broad attention. However, tunable VPC ring resonators haven't been demonstrated. Here we theoretically demonstrate the first tunable VPC ring resonator in the telecommunication wavelength region, the resonance peaks of which are tuned by controlling the temperature based on the thermal-optic effect of silicon. The design is ultracompact (12.05 µm by 10.44 µm), with a high Q-factor of 1281.00. By tuning the temperature from 100 K to 750 K, the phase modulation can reach 7.70 π, and the adjustment efficiency is 0.062 nm/K. Since thermal tuning has been broadly applied in silicon photonics, our design can be readily applied in integrated photonic circuits and will find broad applications. Furthermore, our work opens new possibilities and deepens the understanding of designing novel tunable VPC photonic devices.

Learning to Overcome Noise in Weak Caption Supervision for Object Detection.

We propose the first mechanism to train object detection models from weak supervision in the form of captions at the image level. Language-based supervision for detection is appealing and inexpensive: many blogs with images and descriptive text written by human users exist. However, there is significant noise in this supervision: captions do not mention all objects that are shown, and may mention extraneous concepts. We first propose a technique to determine which image-caption pairs provide suitable signal for supervision. We further propose several complementary mechanisms to extract image-level pseudo labels for training from the caption. Finally, we train an iterative weakly-supervised object detection model from these image-level pseudo labels. We use captions from four datasets (COCO, Flickr30K, MIRFlickr1M, and Conceptual Captions) whose level of noise varies. We evaluate our approach on two object detection datasets. Weighting the labels extracted from different captions provides a boost over treating all captions equally. Further, our primary proposed technique for inferring pseudo labels for training at the image level, outperforms alternative techniques under a wide variety of settings. Both techniques generalize to datasets beyond the one they were trained on.

Filtering characteristics of 1D photonic crystal with Gaussian film thickness perturbation.

Conventional theoretical and numerical studies on photonic crystal, which often does not consider the film thickness error during the experimental preparation process, will meet a large deviation between the experiment and the simulation. The filtering characteristics of one-dimensional (1D) photonic crystals with random film thickness errors (modeled as the Gaussian distribution) are systematically investigated by statistical method and numerical simulations. By studying the influence of the deviation of film thickness and the period number on the filter characteristics, it shows that the forbidden bandwidth is reduced to 80.27% of the intrinsic energy band when the film thickness deviation is σ=0.25a. Furthermore, we found that introduction of a slight disturbance of the film thickness (σ=0.01a) to photonic crystal will broaden the forbidden bandwidth to 100.49%. The proposed photonic crystal model with film thickness deviation can reduce the error between experiment and theory, which can be used for designing broadband photonic bandgaps. These structures have potential applications such as light-matter interactions, ultra-small filters, and photonic chips.

Integrated nanophotonic optical diodes designed by genetic algorithms.

Integrable nanophotodiode devices have attracted much research interest in recent years because of their potential applications in all-optical computing and optical communication systems. We propose a new optical diode design scheme. We use genetic algorithms (GAs) to design an optical diode, which has a device footprint of only 2.5×2.5µm2. These devices designed by GA have the ability to achieve high-efficiency unidirectional transmission. Simulations show the forward transmission efficiency can reach higher than 65% for a Gaussian beam between the wavelengths of 1400 and 1600 nm, and the peak transmission efficiency reaches 75%. The transmission contrast at the design wavelength between 1500 and 1600 nm is higher than 90%, which meets the requirements of high unidirectionality, wide operational bandwidth, and small scale. The devices have more advantages for optical diodes compared with structures designed by photonic crystals and gratings. The application of this scheme provides a new idea for the design and research of all-optical diodes in the field of optical communication.

KAT6A, a novel regulator of ß-catenin, promotes tumorigenicity and chemoresistance in ovarian cancer by acetylating COP1.

Background: Ovarian cancer is a fatal gynecologic malignancy that is found worldwide and exhibits an insidious onset and a lack of early warning symptoms. Despite ongoing studies, the mechanistic basis of the aggressive phenotypes of ovarian cancer remains unclear. Lysine acetyltransferase 6A (KAT6A) is a MYST-type histone acetyltransferase (HAT) enzyme identified as an oncogene in breast cancer, glioblastoma and leukemia. However, the specific functions of KAT6A in ovarian cancer remain unclear. Methods: Immunohistochemistry (IHC) staining and western blotting were performed to characterize KAT6A protein expression in ovarian cancer tissues and cell lines. The biological functions of KAT6A in ovarian cancer were evaluated by cell proliferation, wound healing and transwell invasion assays in vitro. Tumorigenesis and metastasis assays were performed in nude mice to detect the role of KAT6A in vivo. Mass spectrometry and immunoprecipitation assays were performed to detect the KAT6A-COP1 interaction. An in vivo ubiquitination assay was performed to determine the regulation of ß-catenin by KAT6A. Results: In the present study, we revealed that KAT6A expression is upregulated in ovarian cancer and is associated with patient overall survival. Downregulation of KAT6A markedly inhibited the proliferation and migration abilities of ovarian cancer cells in vivo and in vitro. Additionally, the inhibition of KAT6A induced apoptosis and enhanced the sensitivity of ovarian cancer cells to cisplatin. Furthermore, KAT6A bound to and acetylated COP1 at K294. The acetylation of COP1 impaired COP1 function as an E3 ubiquitin ligase and led to the accumulation and enhanced activity of ß-catenin. Conclusions: Our findings suggest that the KAT6A/COP1/ß-catenin signaling axis plays a critical role in ovarian cancer progression and that targeting the KAT6A/COP1/ß-catenin signaling axis could be a novel strategy for treating ovarian cancer.

Interpreting the Rhetoric of Visual Advertisements.

Visual media have important persuasive power, but prior computer vision approaches have predominantly ignored the persuasive aspects of images. In this work, we propose a suite of data and techniques that enable progress on understanding the messages that visual advertisements convey. We make available a dataset of 64,832 image ads and 3,477 video ads, annotated with ten types of information: the topic and sentiment of the ad; whether it is funny, exciting, or effective; what action it prompts the viewer to do, and what arguments it provides for why this action should be taken; symbolic associations that the ad relies on; the metaphorical object transformations on which especially creative ads rely; and the climax in video ads. We develop methods that use multimodal cues, i.e., both visuals and slogans, for both the image and video domains. Our methods rely on finding poignant content spatially and temporally. We also examine the creative story construction in ads: for videos, we learn to predict when the climax occurs (if any), and how effective the story is; for images, we analyze how object transformations in ads metaphorically depict product properties.

Switchable broadband metamaterial absorber/reflector based on vanadium dioxide rings.

A new broadband tunable metamaterial absorber based on different radii of vanadium dioxide (VO2) rings loaded on the dielectric layer is designed. According to the insulator-to-metal phase transition characteristics of VO2 under thermal excitation, the dynamic adjustment of the absorption by the external temperature is achieved. The simulation results demonstrate that when VO2 is in its metal phase at high temperature, an absorption greater than 90% in the bandwidth range of 2.64-7 THz can be obtained and its relative bandwidth is reached to 90.5%. However, the absorption rate in the same frequency range is always lower than 2.3% when VO2 is in the insulator phase at low temperature, which means that the absorber can be used as a perfect reflector. The maximum tunable range of the proposed absorber can be realized from below 2.3% to nearly 100%. We further analyze and discuss the equivalent impedance and electric field distribution of the absorber and clarify the adjustment mechanism of the absorption performance of the VO2 ring. In addition, a multireflection interference theory is also investigated to quantitatively explain the physical absorption mechanism. Such a tunable broadband absorber based on temperature control has great potential to be applied to sensors, thermophotovoltaics, and wireless communication.

Asymmetric transmission of light waves in a photonic crystal waveguide heterostructure with complete bandgaps.

Here, we theoretically present an on-chip nanophotonic asymmetric transmission device (ATD) based on the photonic crystal (PhC) waveguide structure with complete photonic bandgaps (CPBGs). The ATD comprises two-dimensional silica and germanium PhCs with CPBGs, within which line defects are introduced to create highly efficient waveguides to achieve high forward transmittance. In the meantime, the total internal reflection principle is applied to block the backward incidence, achieving asymmetric transmission. We optimize the design of the PhCs and the waveguide structure by scanning different structure parameters. The optimized ATD shows a high forward transmittance of 0.581 and contrast ratio of 0.989 at the wavelength of 1582 nm for TE mode. The results deepen the understanding and open up the new possibility in designing novel ATDs. The on-chip ATD will find broad applications in optical communications and quantum computing.

Monitoring ICU Mortality Risk with A Long Short-Term Memory Recurrent Neural Network.

In intensive care units (ICU), mortality prediction is a critical factor not only for effective medical intervention but also for allocation of clinical resources. Structured electronic health records (EHR) contain valuable information for assessing mortality risk in ICU patients, but current mortality prediction models usually require laborious human-engineered features. Furthermore, substantial missing data in EHR is a common problem for both the construction and implementation of a prediction model.Inspired by language-related models, we design a new framework for dynamic monitoring of patients' mortality risk. Our framework uses the bag-of-words representation for all relevant medical events based on most recent history as inputs. By design, it is robust to missing data in EHR and can be easily implemented as an instant scoring system to monitor the medical development of all ICU patients. Specifically, our model uses latent semantic analysis (LSA) to encode the patients' states into low-dimensional embeddings, which are further fed to long short-term memory networks for mortality risk prediction. Our results show that the deep learning based framework performs better than the existing severity scoring system, SAPS-II. We observe that bidirectional long short-term memory demonstrates superior performance, probably due to the successful capture of both forward and backward temporal dependencies.

Broadband and wide-angle light absorption of organic solar cells based on multiple-depths metal grating.

A silver grating containing three grooves with different depths in one period was proposed as the back electrode for improving light absorption in organic solar cells. We found that the broadband absorption enhancement of the active layer covering the visible and near-infrared bands can be obtained due to the excitation of surface plasmon resonance and the multiple resonances of cavity mode. The integrated absorption efficiency of the proposed structure under TM polarization between 350 nm to 900 nm is 57.4%, with consideration of the weight of AM 1.5G solar spectrum, and is increased by 13.4% with respect to the equivalent planar device. Besides, the wide-angle absorption in proposed structure can be observed in the range from 0 to 50 degrees. These findings are of great importance for rationally designing composite nanostructures of metal gratings-based absorbers for sensing and photon-detecting applications.

Digoxin sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine via inhibiting Nrf2 signaling pathway.

Chemoresistance is a major therapeutic obstacle in the treatment of human pancreatic ductal adenocarcinoma (PDAC). As an oxidative stress responsive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of cytoprotective genes. Nrf2 not only plays a critical role in chemoprevention, but also contributes to chemoresistance. In this study, we found that digoxin markedly reversed drug resistance of gemcitabine by inhibiting Nrf2 signaling in SW1990/Gem and Panc-1/Gem cells. Further research revealed that digoxin regulated Nrf2 at transcriptional level. In in vivo study, we found that digoxin and gemcitabine in combination inhibited tumor growth more substantially when compared with gemcitabine treatment alone in SW1990/Gem-shControl cells-derived xenografts. In the meantime, SW1990/Gem-shNrf2 cells-derived xenografts responded to gemcitabine and combination treatment similarly, suggesting that digoxin sensitized gemcitabine-resistant human pancreatic cancer to gemcitabine, which was Nrf2 dependent. These results demonstrated that digoxin might be used as a promising adjuvant sensitizer to reverse chemoresistance of gemcitabine-resistant pancreatic cancer to gemcitabine via inhibiting Nrf2 signaling.