Highly efficient microbial inactivation enabled by tunneling charges injected through two-dimensional electronics.

Airborne pathogens retain prolonged infectious activity once attached to the indoor environment, posing a pervasive threat to public health. Conventional air filters suffer from ineffective inactivation of the physics-separated microorganisms, and the chemical-based antimicrobial materials face challenges of poor stability/efficiency and inefficient viral inactivation. We, therefore, developed a rapid, reliable antimicrobial method against the attached indoor bacteria/viruses using a large-scale tunneling charge-motivated disinfection device fabricated by directly dispersing monolayer graphene on insulators. Free charges can be stably immobilized under the monolayer graphene through the tunneling effect. The stored charges can motivate continuous electron loss of attached microorganisms for accelerated disinfection, overcoming the diffusion limitation of chemical disinfectants. Complete (>99.99%) and broad-spectrum disinfection was achieved <1 min of attachment to the scaled-up device (25 square centimeters), reliably for 72 hours at high temperature (60°C) and humidity (90%). This method can be readily applied to high-touch surfaces in indoor environments for pathogen control.

RNA-Seq of an LPS-Induced Inflammation Model Reveals Transcriptional Profile Patterns of Inflammatory Processes.

The LPS-induced inflammation model is widely used for studying inflammatory processes due to its cost-effectiveness, reproducibility, and faithful representation of key hallmarks. While researchers often validate this model using clinical cytokine markers, a comprehensive understanding of gene regulatory mechanisms requires extending investigation beyond these hallmarks. Our study leveraged multiple whole-blood bulk RNA-seq datasets to rigorously compare the transcriptional profiles of the well-established LPS-induced inflammation model with those of several human diseases characterized by systemic inflammation. Beyond conventional inflammation-associated systems, we explored additional systems indirectly associated with inflammatory responses (i.e., ISR, RAAS, and UPR) using a customized core inflammatory gene list. Our cross-condition-validation approach spanned four distinct conditions: systemic lupus erythematosus (SLE) patients, dengue infection, candidemia infection, and staphylococcus aureus exposure. This analysis approach, utilizing the core gene list aimed to assess the model's suitability for understanding the gene regulatory mechanisms underlying inflammatory processes triggered by diverse factors. Our analysis resulted in elevated expressions of innate immune-associated genes, coinciding with suppressed expressions of adaptive immune-associated genes. Also, upregulation of genes associated with cellular stresses and mitochondrial innate immune responses underscored oxidative stress as a central driver of the corresponding inflammatory processes in both the LPS-induced and other inflammatory contexts.

Radio frequency hyperthermia system for skin tightening effect by filled waveguide aperture antenna with compact metamaterials.

Radio frequency (RF) hyperthermia focuses on raising the target area temperature to a value exceeding 45°C. Collagen is stimulated when the temperature rises to 45°C at the dermal layer, resulting in skin tightening. However, most studies on RF hyperthermia have focused on tumor ablation or using electrodes to radiate an electromagnetic field, which is highly inefficient. This study proposed a non-invasive RF hyperthermia skin-tightening system with a compact metamaterial-filled waveguide aperture antenna. The proposed RF system increased the temperature by 11.6°C and 35.3°C with 20 and 80 W of 2.45 GHz RF power, respectively, within 60 s and exhibited a very focused effective area. Furthermore, a metamaterial was proposed to reduce the size of the waveguide aperture antenna and focus the electromagnetic field in the near-field region. The proposed metamaterial-filled waveguide aperture antenna was compact, measuring 10 mm × 17.4 mm, with a peak gain of 2.2 dB at 2.45 GHz. The measured hyperthermia performance indicated that the proposed RF system exhibited better power- and time-efficient hyperthermia performance than other RF hyperthermia systems in the cosmetic skin lifting commercial market. The proposed RF hyperthermia systems will be applied into a new generation of beauty cosmetic devices.

Retrospective analysis on prognosis of oral cancer patients according to surgical approaches for effective cancer ablation: swing approach versus visor approach.

BACKGROUND: For the surgical treatment of oral cancer, it is sometimes necessary to expand intraoral access within the oral cavity. The "swing approach" that involves lip splitting of the mandible and temporary mandibular osteotomy and the "visor approach" that does not split the lower lip and mandible are mainly used. This study analyzed postoperative outcomes such as complications, recurrence rate, and survival rate by these two approaches. The goal of this study is to evaluate the surgical outcomes of patients using these two approaches, to propose effective perioperative management for oral cancer surgery, and to compare the prognosis of oral cancer patients. MATERIALS AND METHODS: From 2005 to 2020, 29 patients who underwent surgery at the Department of Oral and Maxillofacial Surgery of Pusan National University Dental Hospital for oral cancer lesions occurred in the mandible, floor of mouth, and tongue were selected for the study. Based on the surgical approach used, a chart review was conducted on various prognostic clinical factors such as the patients' sex and age, primary site, TNM stage, histopathologic grade, recurrence and metastasis, postoperative survival rate, adjuvant chemo-radiation therapy, satisfaction with aesthetics/function/swallowing, length of hospital stay, tracheostomy and its duration, and neck dissection and its type. Statistical analysis was conducted using SPSS 25.0 (SPSS Inc., Chicago, IL) through Fisher's exact t-test. RESULT: There was no statistically significant difference between two groups in terms of clinical and pathological findings, such as survival rate, the need for adjuvant therapies, and the local recurrence rate. Although better outcomes were observed in terms of function, aesthetics, and postoperative complications in the group with visor approach, there was still no statistically significant difference between two groups. However, the duration of hospital stay was shorter in the visor approach group. CONCLUSION: There was no statistically significant difference in clinical prognostic factors between the swing approach and the visor approach. Therefore, when choosing between the two approaches for the ablation of oral cancer, it is considered to select the surgical priority approach that can be easy access based on the size and location of the lesion. The visor approach had advantages of aesthetics and healing period.

Association of Increased Lateral Femoral Condylar Ratio With Lateral Meniscus Posterior Root Tear in Noncontact ACL Injury.

Background: In the setting of anterior cruciate ligament (ACL) injury, lateral meniscus posterior root tears (LMPRTs) are less readily diagnosed on preoperative magnetic resonance imaging (MRI). Therefore, to predict LMPRTs in ACL injuries, it is necessary to understand the risk factors associated with them. Purpose/Hypothesis: The purpose of this study was to investigate the association of lateral femoral condylar ratio (LFCR) with LMPRTs in ACL injuries. It was hypothesized that an increased LFCR would be associated with LMPRTs in noncontact ACL injuries. Study Design: Cohort study; Level of evidence, 3. Methods: Enrolled were consecutive patients who underwent primary acute (<6 weeks from injury) ACL reconstruction after noncontact injury and had LMPRT confirmed on preoperative MRI and arthroscopically (combined group; n = 62) as well as patients who underwent isolated acute ACL reconstruction (isolated group; n = 80) who were matched to the combined group by age, height, and body mass index (BMI). All patients underwent surgery between January 1999 and November 2021. LFCR and posterior tibial slope (PTS) were measured and compared between the isolated and combined groups. The area under the receiver operating characteristic curve (AUC) was calculated to determine the cutoff for detecting increased risk of LMPRTs. Results: The demographic characteristics of the 2 groups did not differ significantly, nor did the PTS. The LFCR was a significant factor (odds ratio [OR], 1.23; P = .001) associated with LMPRT. Patient age, height, BMI, and PTS were not associated with LMPRT. The AUC (0.66; 95% CI, 0.57-0.75) for LFCR had a sensitivity of 39% and specificity of 90% to predict LMPRT. The calculated cutoff associated with an increased risk for LMPRT when compared with the isolated group was 67.0% (OR, 4.98; 95% CI, 2.10-11.79). Conclusion: Increased LFCR was associated with the presence of LMPRTs in patients with acute ACL injuries. The LFCR may provide surgeons with additional information regarding the risk of having a concomitant LMPRT when planning ACL reconstructions.

Tubulointerstitial nephritis antigen-like 1 from cancer-associated fibroblasts contribute to the progression of diffuse-type gastric cancers through the interaction with integrin ß1.

BACKGROUND: Tumor cells of diffuse-type gastric cancer (DGC) are discohesive and infiltrate into the stroma as single cells or small subgroups, so the stroma significantly impacts DGC progression. Cancer-associated fibroblasts (CAFs) are major components of the tumor stroma. Here, we identified CAF-specific secreted molecules and investigated the mechanism underlying CAF-induced DGC progression. METHODS: We conducted transcriptome analysis for paired normal fibroblast (NF)-CAF isolated from DGC patient tissues and proteomics for conditioned media (CM) of fibroblasts. The effects of fibroblasts on cancer cells were examined by transwell migration and soft agar assays, western blotting, and in vivo. We confirmed the effect of blocking tubulointerstitial nephritis antigen-like 1 (TINAGL1) in CAFs using siRNA or shRNA. We evaluated the expression of TINAGL1 protein in frozen tissues of DGC and paired normal stomach and mRNA in formalin-fixed, paraffin-embedded (FFPE) tissue using RNA in-situ hybridization (RNA-ISH). RESULTS: CAFs more highly expressed TINAGL1 than NFs. The co-culture of CAFs increased migration and tumorigenesis of DGC. Moreover, CAFs enhanced the phosphorylation of focal adhesion kinase (FAK) and mesenchymal marker expression in DGC cells. In an animal study, DGC tumors co-injected with CAFs showed aggressive phenotypes, including lymph node metastasis. However, increased phosphorylation of FAK and migration were reduced by blocking TINAGL1 in CAFs. In the tissues of DGC patients, TINAGL1 was higher in cancer than paired normal tissues and detected with collagen type I alpha 1 chain (COL1A1) in the same spot. Furthermore, high TINAGL1 expression was significantly correlated with poor prognosis in several public databases and our patient cohort diagnosed with DGC. CONCLUSIONS: These results indicate that TINAGL1 secreted by CAFs induces phosphorylation of FAK in DGC cells and promotes tumor progression. Thus, targeting TINAGL1 in CAFs can be a novel therapeutic strategy for DGC.

Akt enhances the vulnerability of cancer cells to VCP/p97 inhibition-mediated paraptosis.

Valosin-containing protein (VCP)/p97, an AAA+ ATPase critical for maintaining proteostasis, emerges as a promising target for cancer therapy. This study reveals that targeting VCP selectively eliminates breast cancer cells while sparing non-transformed cells by inducing paraptosis, a non-apoptotic cell death mechanism characterized by endoplasmic reticulum and mitochondria dilation. Intriguingly, oncogenic HRas sensitizes non-transformed cells to VCP inhibition-mediated paraptosis. The susceptibility of cancer cells to VCP inhibition is attributed to the non-attenuation and recovery of protein synthesis under proteotoxic stress. Mechanistically, mTORC2/Akt activation and eIF3d-dependent translation contribute to translational rebound and amplification of proteotoxic stress. Furthermore, the ATF4/DDIT4 axis augments VCP inhibition-mediated paraptosis by activating Akt. Given that hyperactive Akt counteracts chemotherapeutic-induced apoptosis, VCP inhibition presents a promising therapeutic avenue to exploit Akt-associated vulnerabilities in cancer cells by triggering paraptosis while safeguarding normal cells.

Intravascular papillary endothelial hyperplasia in the lungs of a wild Korean raccoon dog.

A male Korean raccoon dog of unknown age was rescued and placed at the Daejeon Wildlife Rescue Center, Korea. Physical examination revealed severe emaciation and dehydration, as well as thick crusts and alopecia over most of the body. During medical care, the animal died and was submitted for postmortem examination. Firm, brown-red lesions of various sizes were observed on the surface of the lungs. In cross-sections of the lungs, pulmonary vessels were thickened and dilated, with white irregular papillary luminal projections. Histologically, pulmonary blood vessels were severely hyperplastic, characterized by thickened dilated walls and fibrous papillary projections covered with a single layer of endothelial cells (ECs). Hyperplastic fibrous connective tissue was confirmed by Masson trichrome staining. The ECs expressed CD31. We diagnosed the lesion as intravascular papillary endothelial hyperplasia, a unique non-neoplastic reactive process that has not been reported previously in pulmonary vessels of canids, equids, or felids, to our knowledge.

Targeting GAS6/AXL signaling improves the response to immunotherapy by restoring the anti-immunogenic tumor microenvironment in gastric cancer.

AIMS: Immunotherapy has shown remarkable effects on several malignancies; however, its impact on gastric cancers has been limited. Therefore, a novel strategy to overcome resistance to immunotherapy is required. In this study, we compared the gene expression profiles of two murine GC cell lines that exhibited different effects on tumor immunity. The functions of specific genes related to negative tumor immunity and the impact of a specific inhibitor were evaluated in syngeneic GC mouse models. MATERIALS AND METHODS: RT-PCR and Western blotting validated Gas6 and AXL expression in murine cell lines. RT-PCR compared YTN16 and YTN3 GC cell's impact on T cell activation. AXL, the receptor for GAS6 in YTN16, was validated by western blotting. Gas6 was inhibited in YTN16 cells using shRNA, and then the gene expression pattern, effects to T cell activation, and tumor growth were assessed. YTN16 cells were injected into mice and treated with CCB-3233, anti-PD-1 antibody, or both. Immunohistochemistry and flow cytometry evaluated tumor-infiltrating immune cells. KEY FINDINGS: YTN16 cells expressed more Gas6 and had reduced T cell activation compared to YTN3 cells. AXL activation was higher in YTN16. CCB-3233 reduced AXL phosphorylation. Knocking down Gas6 in YTN16 reduced immunosuppression-related genes and increased tumor-infiltrating T cells. Combined CCB-3233 and anti-PD-1 treatment reduced tumor growth and increased T-cell infiltration. Human GC data revealed a negative correlation between GAS6 and immune activation-related genes. SIGNIFICANCE: The GAS6/AXL pathway contributes to immunotherapy resistance in GC. Targeting this pathway may be a novel therapeutic strategy.

An on-demand bioresorbable neurostimulator.

Bioresorbable bioelectronics, with their natural degradation properties, hold significant potential to eliminate the need for surgical removal. Despite notable achievements, two major challenges hinder their practical application in medical settings. First, they necessitate sustainable energy solutions with biodegradable components via biosafe powering mechanisms. More importantly, reliability in their function is undermined by unpredictable device lifetimes due to the complex polymer degradation kinetics. Here, we propose an on-demand bioresorbable neurostimulator to address these issues, thus allowing for clinical operations to be manipulated using biosafe ultrasound sources. Our ultrasound-mediated transient mechanism enables (1) electrical stimulation through transcutaneous ultrasound-driven triboelectricity and (2) rapid device elimination using high-intensity ultrasound without adverse health effects. Furthermore, we perform neurophysiological analyses to show that our neurostimulator provides therapeutic benefits for both compression peripheral nerve injury and hereditary peripheral neuropathy. We anticipate that the on-demand bioresorbable neurostimulator will prove useful in the development of medical implants to treat peripheral neuropathy.

Reliability Analysis of PAUT Based on the Round-Robin Test for Pipe Welds with Thermal Fatigue Cracks.

Thermal fatigue cracks occurring in pipes in nuclear power plants pose a high degree of risk. Thermal fatigue cracks are generated when the thermal fatigue load caused by local temperature gradients is repeatedly applied. The flaws are mainly found in welds, owing to the effects of stress concentration caused by the material properties and geometric shapes of welds. Thermal fatigue pipes are classified as targets of risk-informed in-service inspection, for which ultrasonic testing, a volumetric non-destructive testing method, is applied. With the advancement of ultrasonic testing techniques, various studies have been conducted recently to apply the phased array ultrasonic testing (PAUT) method to the inspection of thermal fatigue cracks occurring on pipes. A quantitative reliability analysis of the PAUT method must be performed to apply the PAUT method to on-site thermal fatigue crack inspection. In this study, to evaluate the quantitative reliability of the PAUT method for thermal fatigue cracks, we fabricated crack specimens with the thermal fatigue mechanism applied to the pipe welds. We performed a round-robin test to collect PAUT data and determine the validity of the detection performance (probability of detection; POD) and the error in the sizing accuracy (root-mean-square error; RMSE) evaluation. The analysis results of the POD and sizing performance of the length and depth of thermal fatigue cracks were comparatively evaluated with the acceptance criteria of the American Society of Mechanical Engineers Code to confirm the effectiveness of applying the PAUT method.

Production of Feline Universal Erythrocytes with Methoxy Polyethylene Glycol.

Blood group mismatch in veterinary medicine is a significant problem in blood transfusion, sometimes leading to severe transfusion reactions and even patient death. Blood groups vary from species to species and there are three known blood groups in cats: A, B and AB. While A-type cats are most common, there is a shortage of feline B-type blood groups in cats. By using methoxy polyethylene glycol (mPEG) to protect antigenic epitopes on red blood cells (RBCs), we aimed to find the optimal conditions for the production of feline universal RBCs. The surfaces of feline A-type RBCs were treated with mPEG at various molecular weights and concentrations. Agglutination tests showed that the coating of feline A-type RBCs with mPEG of 20 kDa and 2 mM blocked hemagglutination to feline anti-A alloantibodies over 8 h. While no differences in RBC size and shape between intact and mPEG-treated RBCs were seen, coating RBCs with mPEG inhibited the binding of feline anti-A alloantibodies. Furthermore, the mPEG-treated RBCs did not cause spontaneous hemolysis or osmotic fragility, compared to control RBCs. According to a monocyte monolayer assay, mPEG treatment significantly reduced feline anti-A antibody-mediated phagocystosis of RBCs. These results confirm the potential of using activated mPEG on feline A-type RBC to create universal erythrocytes for transfusion to B-type cats.

Advances in Bioresorbable Triboelectric Nanogenerators.

With the growing demand for next-generation health care, the integration of electronic components into implantable medical devices (IMDs) has become a vital factor in achieving sophisticated healthcare functionalities such as electrophysiological monitoring and electroceuticals worldwide. However, these devices confront technological challenges concerning a noninvasive power supply and biosafe device removal. Addressing these challenges is crucial to ensure continuous operation and patient comfort and minimize the physical and economic burden on the patient and the healthcare system. This Review highlights the promising capabilities of bioresorbable triboelectric nanogenerators (B-TENGs) as temporary self-clearing power sources and self-powered IMDs. First, we present an overview of and progress in bioresorbable triboelectric energy harvesting devices, focusing on their working principles, materials development, and biodegradation mechanisms. Next, we examine the current state of on-demand transient implants and their biomedical applications. Finally, we address the current challenges and future perspectives of B-TENGs, aimed at expanding their technological scope and developing innovative solutions. This Review discusses advancements in materials science, chemistry, and microfabrication that can advance the scope of energy solutions available for IMDs. These innovations can potentially change the current health paradigm, contribute to enhanced longevity, and reshape the healthcare landscape soon.

Removal of an intraosseous hemangioma of the frontal bone through an anterior hairline incision: a case report.

An intraosseous hemangioma of the frontal bone is typically removed via a coronal incision. This procedure, while effective, can be lengthy and may result in complications such as a prominent scar and hair loss. An alternative approach involves a direct incision in the forehead, which leaves a less noticeable scar and allows a quicker recovery. However, in this specific case, the patient declined both coronal surgery and surgery through a direct forehead incision due to cosmetic concerns. Therefore, we proposed an anterior hairline incision. A 35-year-old woman presented with a firm, non-mobile, palpable mass on her right forehead. Preoperative non-contrast computed tomography revealed a heterogeneous osteolytic lesion. We performed an excisional biopsy through the anterior hairline. Postoperative non-contrast computed tomography was conducted 2 and 6 months after surgery. The wound was clean and free of complications, and there was no local recurrence. Partial resection can reduce scarring for patients who are concerned about cosmetic outcomes. However, the potential for recurrence remains a significant concern. We present this case of an anterior hairline incision for a hemangioma located in the forehead, evaluated using serial computed tomography for both preoperative and postoperative imaging.

Bone Morphological Characteristics as Risk Factors for Anterior Cruciate Ligament Injury: Comparison Between Contact and Noncontact Injury.

Background: Altered bone morphologies are considered risk factors for noncontact anterior cruciate ligament (ACL) injuries. Purpose/Hypothesis: This study aimed to investigate bone morphological characteristics as risk factors for ACL tears in contact injuries and compare these factors with those for noncontact ACL injuries. We hypothesized that altered bone morphologies would also be risk factors for contact ACL injury. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Enrolled were patients who underwent primary ACL reconstructions between January 2000 and December 2021 within 6 weeks after injury. Patients in the ACL group were classified according to injury mechanism (contact vs noncontact). During the same period, a control group of patients matched by age, height, and body mass index to the ACL group was selected. The lateral femoral condylar ratio (LFCR), notch width index (NWI), and lateral posterior tibial slope (PTS) were measured. Measured parameters were compared between the control, contact, and noncontact groups using analysis of variance. Results: There were 86 patients in the control group, 102 patients in the contact ACL group, and 105 patients in the noncontact ACL group. The demographic characteristics of the 3 groups did not differ significantly. The contact group had significantly higher LFCRs and lower NWIs compared with the control group (P < .001 and P = .001, respectively). The noncontact group had significantly higher LFCRs and PTSs and lower NWIs compared with the control group (P = .031; P < .001; and P < .001, respectively). The noncontact group had significantly higher PTSs and lower NWIs compared with the contact group (P = .003 and P =.014, respectively). In the contact group, the LFCR, PTS, and NWI were significant risk factors for ACL tears (odds ratio [OR], 1.25 [P < .001]; OR, 1.16 [P = .008]; and OR, 1.27 [P = .001], respectively), and in the noncontact group, the PTS and NWI were significant risk factors for ACL tears (OR, 1.20 [P < .001]; OR, 1.59 [P < .001], respectively). Conclusion: Altered bone morphological characteristics of the knee were found to be risk factors for ACL tears in contact injuries as well as noncontact injuries. Altered morphology has a more significant effect in noncontact ACL injuries.

Micropipette tip intubation in rats as a replacement for conventional endotracheal tube intubation.

Endotracheal intubation is often necessary in the course of animal experiments, especially in craniofacial surgery. However, endotracheal intubation can be a major burden in this context. The authors performed simple and cost-saving method using a 200 µL yellow micropipette tip, and the success of this method was demonstrated by X-ray and autopsy. We used a total of 30 rats. After the rats were fixed with a plaster, the trachea and vocal cords were visualized with the tongue pulled back. Under direct visualization of the vocal cords, a curving micropipette tip was advanced into the trachea. This method can be learned quickly and applied successfully by general experimenters. We successfully intubated all 30 rats without any complications. The success rate of micropipette tip intubation was 100%. This procedure was performed by one experimenter within 2 to 3 minutes after induction of anesthesia. We demonstrated its superiority by X-ray and autopsy. Herein, we describe endotracheal intubation of rats using micropipette tips. To the best of our knowledge, this method is novel and represents the simplest and most efficient means of intubation in rats, providing an alternative to conventional endotracheal intubation.

Recent Advances in Triboelectric Nanogenerators: From Technological Progress to Commercial Applications.

Serious climate changes and energy-related environmental problems are currently critical issues in the world. In order to reduce carbon emissions and save our environment, renewable energy harvesting technologies will serve as a key solution in the near future. Among them, triboelectric nanogenerators (TENGs), which is one of the most promising mechanical energy harvesters by means of contact electrification phenomenon, are explosively developing due to abundant wasting mechanical energy sources and a number of superior advantages in a wide availability and selection of materials, relatively simple device configurations, and low-cost processing. Significant experimental and theoretical efforts have been achieved toward understanding fundamental behaviors and a wide range of demonstrations since its report in 2012. As a result, considerable technological advancement has been exhibited and it advances the timeline of achievement in the proposed roadmap. Now, the technology has reached the stage of prototype development with verification of performance beyond the lab scale environment toward its commercialization. In this review, distinguished authors in the world worked together to summarize the state of the art in theory, materials, devices, systems, circuits, and applications in TENG fields. The great research achievements of researchers in this field around the world over the past decade are expected to play a major role in coming to fruition of unexpectedly accelerated technological advances over the next decade.

Ultrasound-Driven Injectable and Fully Biodegradable Triboelectric Nanogenerators.

Implantable medical devices (IMDs) provide practical approaches to monitor physiological parameters, diagnose diseases, and aid treatment. However, device installation, maintenance, and long-term implantation increase the risk of infection with conventional IMDs. Therefore, medical devices with biocompatibility, controllability, and miniaturization are highly demandable. An ultrasound-driven, biodegradable, and injectable triboelectric nanogenerator (I-TENG) is demonstrated to reduce the risks of implant-related injuries and infections. The injection can be given by subcutaneous injection with a needle to minimize the implantation incision. The stable output of I-TENG is driven by ultrasound (20 kHz, 1 W cm-2 ), with a voltage of 356.8 mV and current of 1.02 µA during in vivo studies and an electric field of about 0.92 V mm-1 during ex vivo experiments. The cell scratch and proliferation assays showed that the delivered electric field effectively increased cell migration and proliferation, indicating a significant potential to accelerate healing with electricity.

Dual inhibition of thioredoxin reductase and proteasome is required for auranofin-induced paraptosis in breast cancer cells.

Auranofin (AF), a gold (I)-containing phosphine compound, is being investigated for oncological application as a repurposed drug. We show here that 4~5 µM AF induces paraptosis, a non-apoptotic cell death mode characterized by dilation of the endoplasmic reticulum (ER) and mitochondria, in breast cancer cells. Although the covalent inhibition of thioredoxin reductase (TrxR), an enzyme that critically controls intracellular redox homeostasis, is considered the primary mechanism of AF's anticancer activity, knockdown of TrxR1 did not induce paraptosis. Instead, both TrxR1 knockdown plus the proteasome inhibitor (PI), bortezomib (Bz), and 2 µM AF plus Bz induced paraptosis, thereby mimicking the effect of 5 µM AF. These results suggest that the paraptosis induced by 5 µM AF requires the inhibition of both TrxR1 and proteasome. We found that TrxR1 knockdown/Bz or subtoxic doses of AF and Bz induced paraptosis selectively in breast cancer cells, sparing non-transformed MCF10A cells, whereas 4~5 µM AF killed both cancer and MCF10A cells. GSH depletion was found to be more critical than ROS generation for the paraptosis induced by dual TrxR1/proteasome inhibition. In this process, the ATF4/CHAC1 (glutathione-specific gamma-glutamylcyclotransferase 1) axis leads to GSH degradation, contributing to proteotoxic stress possibly due to the accumulation of misfolded thiol-containing proteins. These results suggest that the paraptosis-inducing strategy of AF plus a PI may provide an effective therapeutic strategy against pro-apoptotic therapy-resistant cancers and reduce the potential side effects associated with high-dose AF.