Search

This study aimed to find appropriate nickel‐titanium instruments for lingual canals in mandibular first premolars with two canals. Forty‐two extracted mandibular first premolars with lingual canals (Vertucci type V) verified by micro‐CT scanning were selected. The teeth were randomly divided into three groups, and their lingual canals were instrumented by M3, HyFlex CM and XP‐endo Shaper, respectively. After instrumentation, the canal morphology was scanned again by micro‐CT. The canal morphologies of pre‐ and post‐instrumentation were reconstructed and aligned. Morphological changes of the lingual canals were evaluated. No instrument breakages occurred during the procedure of root canal instrumentation. HyFlex CM and XP‐endo Shaper performed better than M3 files in preparation of lingual canals (Vertucci type V) of mandibular first premolars in terms of apical transportation and unprepared surface area. [ABSTRACT FROM AUTHOR]

Pure red mixed halide CsPbBr3−xIx perovskite nanocrystals (NCs) exhibit a high photoluminescence quantum yield (PLQY) and narrow full width at half maximum (FWHM), but there are phase stability issues that hinder their application in displays. In this work, we propose pure red CsPbBr0.96I2.04/SiO2 core/shell NCs by using (3-aminopropyl)triethoxysilane as the surface ligand and silicon source via a hot-injection and in situ hydrolytic process. The CsPbBr0.96I2.04/SiO2 NCs not only show excellent optical properties with a near-unity PLQY but also exhibit high stability against moisture, blue light, and heat. Pure red CsPbBr0.96I2.04/SiO2 NC inks were prepared by dispersing CsPbBr0.96I2.04/SiO2 NCs into a mixed solvent of toluene and dodecane and used to inkjet print NC color conversion films (NC-CCFs) with excellent luminescence uniformity and high stability. Finally, white-emitting Mini-LEDs were fabricated by combining pure red CsPbBr0.96I2.04/SiO2 NC-CCFs with green CsPbBr3/SiO2 NC-CCFs and blue Mini-LED chips, showing a high external quantum efficiency (EQE) of 24.8% and an ultrawide color gamut of 132.58% NTSC and 99.2% Rec. 2020 standards. This demonstrates the potential of pure red CsPbBr0.96I2.04/SiO2 NCs for Mini-LED backlights. [ABSTRACT FROM AUTHOR]

Currently, more and more growers are transitioning to the use of over-the-row machine harvesters for harvesting fresh market blueberries. This study assessed the microbial load of fresh blueberries harvested by different methods. Samples (n = 336) of 'Draper' and 'Liberty' northern highbush blueberries, which were harvested using a conventional over-the-row machine harvester, a modified machine harvester prototype, ungloved but sanitized hands, and hands wearing sterile gloves were collected from a blueberry farm near Lynden, WA, in the Pacific Northwest at 9 am, 12 noon, and 3 pm on four different harvest days during the 2019 harvest season. Eight replicates of each sample were collected at each sampling point and evaluated for the populations of total aerobes (TA), total yeasts and molds (YM), and total coliforms (TC), as well as for the incidence of fecal coliforms and enterococci. The harvest method was a significant factor (p < 0.05) influencing the TA and TC counts, the harvest time was a significant factor influencing the YM counts, while the blueberry cultivar was an insignificant (p > 0.05) factor for all three indicator microorganisms. These results suggest that effective harvester cleaning methods should be developed to prevent fresh blueberry contamination by microorganisms. This research will likely benefit blueberry and other fresh fruit producers. [ABSTRACT FROM AUTHOR]

This study aims to compare the biological characteristics of human dental pulp stem cells (hDPSCs) isolated from different-aged populations and examine the effects of Biodentine on proliferation and odonto/osteogenic differentiation of hDPSCs isolated from the elderly in vitro. hDPSCs were isolated from three different-aged populations: group A (≤18 years old), group B (19–59 years old), and group C (≥60 years old). The adhesion, proliferation, odonto/osteogenesis, and senescence were compared. The optimal concentration of aqueous Biodentine extract was determined by CCK-8 assay, alkaline phosphatase (ALP), and alizarin red staining (ARS). The effect of Biodentine on odonto/osteogenic gene and protein expression of hDPSCs in each group was evaluated by quantitative real-time PCR (QRT-PCR) and Western blot. hDPSCs were successfully isolated from three different-aged populations. Flow cytometry revealed that all isolated hDPSCs were positive for CD73 (>90%), CD90 (>90%), CD146 (<30%), and negative for CD45 (<1%). There existed an age-related decline in proliferation, odonto/osteogenic gene expression, and S-phase fraction (p < 0.05), an increase in senescence genes and p21 and p16 expression, and time needed for cell adhesion. Biodentine promoted hDPSC proliferation and mineralization in each group, particularly at a concentration of 0.2 mg/mL. Biodentine markedly enhanced odonto/osteogenesis-related gene and protein expression in each group (p < 0.05). hDPSCs can be obtained from populations of all ages. Though there is an age-related decline in their biological properties, hDPSCs from the elderly still maintain certain proliferation and multidirectional differentiation abilities. Biodentine can significantly promote the proliferation and odonto/osteogenic differentiation of hDPSCs isolated from the elderly over 60 years old, which could be considered a pulp capping material for vital pulp therapy in the elderly. Nevertheless, the efficacy of Biodentine in clinical application has to be further studied. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Electromagnetic navigation bronchoscopy (ENB)-guided microwave ablation is a minimally invasive technology for treating pulmonary lesions. This study analysed the short-term safety and efficacy of ENB-guided microwave ablation in multiple pulmonary nodules (MPNs). METHODS This retrospective study reports a single-centre experience with ENB-guided microwave ablation for MPNs. Clinical, surgical and pathological data were obtained for patients who underwent ENB-guided microwave ablation from 23 December 2019 to 23 June 2021. The primary end points were technical safety and efficiency. RESULTS The study assessed 65 patients who underwent ENB-guided microwave ablation, 57 of whom simultaneously underwent video-assisted thoracic surgery. In total, 216 nodules were treated. Of 96 nodules treated by ENB-guided microwave ablation, 94 nodules had ground-glass opacity. Ablation efficiency was confirmed by hybrid cone-beam computed tomography. Of 120 nodules surgically removed, 106 nodules had ground-glass opacity. The mean nodule size was 7.9 mm in ablated nodules and 10.2 mm in resected nodules. Distance between nodules and pleura or fissure was 17.45 mm in ablated nodules and 7.29 mm in resected nodules. The overall malignancy rate was 47.7% (103/216); the complication rate was low (65 patients). At short-term follow-up, the post-ablation target zone shrank by 1 week and stabilized after 4–6 months. No local recurrence or enlargement of other pulmonary nodules was noted. CONCLUSIONS To treat MPNs, ENB-guided microwave ablation is safe and efficient. The combination of this treatment and video-assisted thoracic surgery is a potential application, which can preserve as much pulmonary function as possible and treat MPNs to the maximum extent. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Open in new tab Download slide OBJECTIVES Oesophagogastric anastomosis is a core part of oesophagectomy, and anastomotic leakage is among its main concerns. We used the oversewing technique to reinforce the anastomosis created with a circular stapler. This study investigated the use of oversewing to reduce the incidence of anastomotic leakage without increasing morbidity. METHODS This study enrolled 1734 patients who underwent oesophagectomy for oesophageal cancer between April 2012 and December 2019. Using propensity score-matched analysis, the clinical results of postoperative complications were compared between anastomotic-oversewn and -unsewn oesophagectomies. RESULTS Of the 1734 patients, 661 were included in the anastomotic-unsewn group and 661 in the anastomotic-oversewn group after propensity score matching. The clinical characteristics did not differ between the 2 groups, but the frequency of anastomotic leakage was significantly higher in the anastomotic-unsewn group than in the anastomotic-oversewn group (10.3% vs 4.7%, P  < 0.001). Multivariable logistic analysis showed oversewn anastomosis and smoking history as the independent factors associated with anastomotic leakage (odds ratios, 0.399 and 2.383; P  < 0.001 and P  = 0.012, respectively). On the sub-group analysis, the relative risk for anastomotic leakage was significantly higher with unsewn than with oversewn anastomosis in patients <65 years old, those with American Association of Anesthesiologists score II, those who had middle segment oesophageal cancer and those who have undergone the McKeown approach and cervical anastomosis. CONCLUSIONS Anastomosis oversewing technique may be a practical method to reduce anastomotic leakage, especially in younger patients and those who have undergone the McKeown approach and cervical anastomosis. [ABSTRACT FROM AUTHOR]

Objective: Cushing disease is a potentially fatal endocrine disorder caused by adrenocorticotropin (ACTH)‐secreting microadenomas in the pituitary gland. Accurate detection and localization of the adenomas is the key to clinical treatment. This study analysed the value of contrast‐enhanced Sampling Perfection with Application‐optimized Contrasts using different flip angle Evolutions (SPACE) sequence in magnetic resonance imaging (MRI) assessment of ACTH‐secreting pituitary microadenomas. Design and Patients: We carried out a retrospective study in which 45 patients with ACTH‐secreting pituitary microadenomas were enrolled. Dynamic contrast‐enhanced (DCE) coronal T1‐SE sequence was performed. A contrast‐enhanced coronal SPACE sequence was added immediately after DCE MRI finished. Two independent observers assessed the tumour existence and location, then the results were compared with surgical findings. Results: Twenty‐four lesions (53.3%) were detected by the DCE T1‐SE sequence alone, while 35 lesions (80.0%) were detected with the addition of contrast‐enhanced SPACE sequence. The sensitivity (58.5% vs. 85.3%; p <.05) and best diagnostic accuracy (62.0% vs. 84.4%; p <.05) were significantly better for addition with SPACE sequence than DCE‐SE images alone in detection of ACTH‐secreting pituitary microadenomas. For lesions <5 mm, the detected numbers were 4 (16.6%) versus 10 (27.8%) by DCE T1‐SE sequence and combined DCE T1‐SE with SPACE sequence. Conclusions: A combination of contrast‐enhanced SPACE with DCE T1‐SE sequence could improve the detection of ACTH‐secreting pituitary microadenomas. Contrast‐enhanced SPACE sequence could be a supplementary sequence for imaging of ACTH‐secreting pituitary adenomas when T1‐SE sequence provides negative or equivocal findings. [ABSTRACT FROM AUTHOR]

Background: With the popularity of lung cancer screening and advances in imaging technology, more and more synchronous multiple primary lung adenocarcinomas (SMPLA) are being diagnosed clinically, however, the clinical characteristics and prognosis of SMPLA with different EGFR mutations remains unclear. We aimed to explore clinical features and surgical outcomes of these patients to aid in the diagnosis and treatment of SMPLA. Methods: Medical records of patients with different EGFR mutations who have been diagnosed as SMPLA and underwent surgical resection from March 2015 to December 2019 were retrospectively analyzed. Clinical characteristics, surgical outcomes, recurrence-free survival (RFS) and overall survival (OS) were investigated. Results: A total of 70 patients (68.6% female and 77.1% non-somkers) were included. Total of 161 lesions in all patients, 84.4% were ground-glass opacity (GGO) lesions. EGFR mutations were detected in 108 lesions, most of which were L858R (35.4%) and 19Del (20.5%). The mutation rate of mixed GGO is significantly higher than that of pure GGO and solid nodules (SN); the mutation rate of invasive adenocarcinoma is significantly higher than that of other histology subtypes; the mutation rate of lesions >20 mm was significantly higher than that of ≤20 mm. However, there is no significant difference in the mutation rate of specific driver gene between different radiological features, pathological characteristics and sizes. After a median follow-up time of 29 months, the 3-year OS and RFS were 94.4% and 86.0%, respectively. Conclusions: A high discordance of EGFR mutations were identified between tumors in patients with SMPLA. Synchronous multiple lung adenocarcinomas with predominantly multiple GGO should be considered as SMPLA, and surgery may be aggressively performed for these patients due to a good prognosis. [ABSTRACT FROM AUTHOR]

Thymoma is closely associated with myasthenia gravis (MG). However, due to the heterogeneity of thymoma and the intricate pathogenesis of MG, it remains unclear why some patients with thymoma develop MG and others do not. In this study, we conducted a comparative phenotype analysis of thymocytes in type B thymomas in patients with MG (MG (+) thymomas) and without MG (MG (-) thymomas) via fluorescence-activated cell sorting (FACS). Our results show that the developmental stages defined by the expression of CD3, CD4, and CD8 were largely maintained in both MG (+) and MG (-) thymomas, with CD4 + CD8 + cells constituting the majority of thymocytes in type B thymoma, and no significant difference between this cell population was observed in MG (+) and MG (-) thymomas.We discovered that CD4 + CD8 + thymocytes in MG (+) thymomas expressed low levels of αβ TCR and high levels of IL-7 receptor α (IL-7Rα), whereas in MG (-) thymomas, CD4 + CD8 + thymocytes exhibited the opposite pattern of αβ TCR and IL-7Rα expression. These results suggest that the positive and negative selection processes of CD4 + CD8 + thymocytes might differ between MG (+) thymomas and MG (-) thymomas. The expression of the Helios transcription factor is induced during negative selection and marks a group of T cells that have undergone negative selection and are likely to be deleted due to strong TCR binding with self-peptides/MHC ligands. We observed that the percentage of Helios-positive CD4SP T cells was greater in MG (-) than in MG (+) thymomas. Thus, the differentially regulated selection process of CD4 + CD8 + thymocytes, which involves TCR and IL-7/IL-7Rα signaling, is associated with the presence of MG in type B thymomas.

Background: Accurate localization of multi-focal ground-glass opacities (GGOs) is crucial for successful video-assisted thoracoscopic surgery (VATS). Electromagnetic navigation bronchoscopy (ENB) provides a minimally invasive and dependable approach for precise localization. This study assessed the accuracy and safety of ENB-guided localization in cases involving multi-focal GGOs., Methods: This retrospective study presents a single-center investigation into ENB-guided localization, utilizing methylene blue, for multi-focal GGOs assisting VATS. Clinical, surgical, and pathological data were collected from patients who underwent ENB-guided localization between 23 December 2019 and 31 August 2022., Results: The study examined 57 patients with multi-focal GGOs who underwent ENB-guided localization and VATS. A total of 150 GGOs were treated, with ENB-guided localization taking a median time of 65 min. Following localization, all patients proceeded to VATS, with a median duration of 170 min. The median lesion size measured 7.8 mm, with a 5-mm distance between GGO and pleura or fissure. When the distance between GGO and pleura/fissure exceeded 1 cm, an additional location point was introduced below the pleura or fissure based on GGO location. No complications related to localization were observed. The overall malignancy rate stood at 66%. Location precision was confirmed by measuring the marker-to-GGO lesion distance, resulting in a 94% (141/150) accuracy rate for GGO localization., Conclusion: ENB-guided methylene blue injection is a safe and precise method to treat multi-focal GGOs, potentially minimizing operation time and simplifying lesion detection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zeng, Yang, Wei, Wang, Wang, Ye, Fu, Cai and Wang.)

This study aims to compare the biological characteristics of human dental pulp stem cells (hDPSCs) isolated from different-aged populations and examine the effects of Biodentine on proliferation and odonto/osteogenic differentiation of hDPSCs isolated from the elderly in vitro. hDPSCs were isolated from three different-aged populations: group A (≤18 years old), group B (19−59 years old), and group C (≥60 years old). The adhesion, proliferation, odonto/osteogenesis, and senescence were compared. The optimal concentration of aqueous Biodentine extract was determined by CCK-8 assay, alkaline phosphatase (ALP), and alizarin red staining (ARS). The effect of Biodentine on odonto/osteogenic gene and protein expression of hDPSCs in each group was evaluated by quantitative real-time PCR (QRT-PCR) and Western blot. hDPSCs were successfully isolated from three different-aged populations. Flow cytometry revealed that all isolated hDPSCs were positive for CD73 (>90%), CD90 (>90%), CD146 (<30%), and negative for CD45 (<1%). There existed an age-related decline in proliferation, odonto/osteogenic gene expression, and S-phase fraction (p < 0.05), an increase in senescence genes and p21 and p16 expression, and time needed for cell adhesion. Biodentine promoted hDPSC proliferation and mineralization in each group, particularly at a concentration of 0.2 mg/mL. Biodentine markedly enhanced odonto/osteogenesis-related gene and protein expression in each group (p < 0.05). hDPSCs can be obtained from populations of all ages. Though there is an age-related decline in their biological properties, hDPSCs from the elderly still maintain certain proliferation and multidirectional differentiation abilities. Biodentine can significantly promote the proliferation and odonto/osteogenic differentiation of hDPSCs isolated from the elderly over 60 years old, which could be considered a pulp capping material for vital pulp therapy in the elderly. Nevertheless, the efficacy of Biodentine in clinical application has to be further studied.

Background: Tumor cells outcompete T cells for methionine via overexpressing SLC43A2, causing T cells exhaustion. We explored the influence of SLC43A2 on tumor immune microenvironment (TIME), immune-related genes (IRGs) and the prognosis of liver hepatocellular carcinoma (LIHC) patients. Methods: The TCGA-LIHC dataset ( n = 374) and the ICGC-LIRI-JP-LIHC ( n = 231) datasets were used as training and validation cohort, respectively. IRGs were obtained from ImmPort. Statistical analyses were performed using R (V 4.0.5). Online databases such as GEPIA, GSCALite, the Kaplan-Meier plotter, KEGG, TIMER2, and CMap were used for differential expression, immune infiltration, functional enrichment, survival, and drug-induced gene perturbation analysis. Results: SLC43A2 expression was higher in LIHC, correlated with worse survival, but could not predict prognosis of LIHC separately (AUC = 0.467). SLC43A2 positively correlated with immune exhaustion markers (all p < 0.001) and with increased infiltration of Tregs, macrophages and myeloid-derived suppressor cells (MDSC) (all p < 0.05). SLC43A2 may regulate 120 IRGs. A prognostic risk score model was developed using the TCGA-LIHC cohort and validated by the ICGC-LIRI-JP cohort. Arachidonic acid, SB-202190 and guanethidine were identified as possible immunomodulators pharmacologically targeting SLC43A2 in LIHC. Conclusion: SLC43A2 may create suppressive tumor microenvironment and regulate related IRGs, thus affecting the prognosis of LIHC. Arachidonic acid, SB-202190, and guanethidine may be worthy of further study as immunomodulators on SLC43A2., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liao, Weng, Chen, Hu, Yuan, Wang, He, Cai, Huang, Wang and Huang.)

Background: More and more ground glass opacity associated lung adenocarcinoma (GGO-LUAD) have been diagnosed in young patients nowadays. Our study aims to investigate the clinical features and surgical outcomes of young patients with GGO-LUAD., Methods: Patients aged ≤ 40 years who were diagnosed as lung adenocarcinoma and who underwent video assisted thoracoscopic surgery (VATS) were retrospectively reviewed from January 2017 to December 2018. According to radiological appearance of the patient's lesions, they were divided into a solid nodule (SN) group and GGO group. The pathological subtypes, surgical procedures and nodules size were analyzed, and the clinical features and prognosis were evaluated between these patients., Results: A total of 165 patients were included, of which 133 were in the GGO group and 32 in the SN group. Both the GGO group and the SN group had a higher proportion of females and non-smokers. Compared with patients (15.63%) in the SN group, there are more patients (27.8%) under the age of 30 in the GGO group. Pathological findings showed 83.5% of lesions were pre-invasive lesions in the GGO group, although 16.5% of lesions were invasive adenocarcinoma, whereas in the SN group, 96.9% were invasive adenocarcinoma. The GGO group had significantly better histological characteristics and prognosis than the SN group. Perioperative complications occurred in only 6 patients, including pneumonia in one patient, pneumothorax in two patients, and prolonged air leak in three patients. No other serious complications or deaths occurred. After a median follow-up time of 41.2 ± 7.2 months (32-56), the 3-year recurrence free survival (RFS) (100%) and overall survival (OS) (100%) of the GGO group were significantly higher than those (93.42% and 96.88%) in the SN group., Conclusions: Young patients with GGO-LUAD are mainly non-smokers and female. Most of these patients were early-stage with good prognosis after surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Qu, Tu, Cai, Ping and Fu.)

Background: The pathogenesis of Cushing's disease (CD) is still not adequately understood despite the identification of somatic driver mutations in USP8, BRAF, and USP48. In this multiomics study, we combined RNA sequencing (RNA-seq) with Sanger sequencing to depict transcriptional dysregulation under different gene mutation backgrounds. Furthermore, we evaluated the potential of achaete-scute complex homolog 1 (ASCL1), a pioneer transcription factor, as a novel therapeutic target for treatment of CD and its possible downstream pathway., Methods: RNA-seq was adopted to investigate the gene expression profile of CD, and Sanger sequencing was adopted to detect gene mutations. Bioinformatics analysis was used to depict transcriptional dysregulation under different gene mutation backgrounds. The function of ASCL1 in hormone secretion, cell proliferation, and apoptosis were studied in vitro. The effectiveness of an ASCL1 inhibitor was evaluated in primary CD cells, and the clinical relevance of ASCL1 was examined in 68 patients with CD. RNA-seq in AtT-20 cells on Ascl1 knockdown combined with published chromatin immunoprecipitation sequencing data and dual luciferase assays were used to explore downstream pathways., Results: ASCL1 was exclusively overexpressed in USP8-mutant and wild-type tumors. Ascl1 promoted adrenocorticotrophin hormone overproduction and tumorigenesis and directly regulated Pomc in AtT-20 cells. An ASCL1 inhibitor presented promising efficacy in both AtT-20 and primary CD cells. ASCL1 overexpression was associated with a larger tumor volume and higher adrenocorticotrophin secretion in patients with CD., Conclusion: Our findings help to clarify the pathogenesis of CD and suggest that ASCL1 is a potential therapeutic target the treatment of CD., Summary: The pathogenesis of Cushing's disease (CD) is still not adequately understood despite the identification of somatic driver mutations in USP8, BRAF, and USP48. Moreover, few effective medical therapies are currently available for the treatment of CD. Here, using a multiomics approach, we first report the aberrant overexpression of the transcription factor gene ASCL1 in USP8-mutant and wild-type tumors of CD. Ascl1 promoted adrenocorticotrophin hormone overproduction and tumorigenesis and directly regulated Pomc in mouse AtT-20 cells. Notably, an ASCL1 inhibitor presented promising efficacy in both AtT-20 and primary CD cells. Importantly, ASCL1 overexpression was associated with a larger tumor volume and higher adrenocorticotrophin secretion in patients with CD. Thus, our findings improve understanding of CD pathogenesis and suggest that ASCL1 is a potential therapeutic target the treatment of CD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Surgery-induced immunosuppression is associated with infectious complications and cancer recurrence. This study aimed to characterize the effects of perioperative multiple doses of glucocorticoids on the peripheral immune environment in patients with non-small cell lung cancer., Methods: In this retrospective study, surgical patients with lung cancer were included. Lymphocyte subsets, lymphocyte phenotypes, lymphocyte functions, and inflammatory cytokines were evaluated in the peripheral blood preoperatively, then at 1 day and 7 days postoperatively. Levels of immune cells and inflammatory factors were compared between those who did or did not receive glucocorticoids at all time points., Results: Multiple doses or high doses (15-20 mg dexamethasone equivalents) of glucocorticoids that were all given within 24 h were associated with decreased absolute numbers of T cells, CD4 + and CD8 + T cells, B cells, and impaired T cells function at 1 day postoperatively while a single intraoperative low dose (5 mg) of dexamethasone had little influence on the peripheral environment. IL-1β, IL-6, and TNF-α were also more affected by multiple doses of glucocorticoids., Conclusions: Among patients with lung cancer, perioperative multiple doses of glucocorticoids that are all given within a short time are associated with decreased immune cell counts and impaired T cells functions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Cai and Fu.)

Stimulator of interferon genes (STING) pathway activation predicts the effectiveness of targeting the PD-1/PD-L1 axis in lung cancer. Active IFN-γ signaling is a common feature in tumors that respond to PD-1/PD-L1 blockade. The connection between IFN-γ and STING signaling in cancer cells has not been documented. We showed that IFN-γ caused DNA damage and the accumulation of cytosolic dsDNA, leading to the activation of the cGAS- and IFI16-dependent STING pathway in lung adenocarcinoma cells. IFN-γ-induced iNOS expression and nitric oxide production were responsible for DNA damage and STING activation. Additional etoposide treatment enhanced IFN-γ-induced IFN-β and CCL5 expression. Tumor-infiltrating T cells stimulated with a combination of anti-CD3 and anti-PD-1 antibodies caused STING activation and increased IFN-β and CCL5 expression in lung adenocarcinoma. These effects were abrogated by the addition of an IFN-γ neutralizing antibody. Our results suggest that the activation of tumor-infiltrating T cells could alter the tumor microenvironment via the IFN-γ-mediated activation of STING signaling in cancer cells., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Interferon-gamma (IFN-γ) is a major effector molecule of immunity and a common feature of tumors responding to immunotherapy. Active IFN-γ signaling can directly trigger apoptosis and cell cycle arrest in human cancer cells. However, the mechanisms underlying these actions remain unclear. Here, we report that IFN-γ rapidly increases protein synthesis and causes the unfolded protein response (UPR), as evidenced by the increased expression of glucose-regulated protein 78, activating transcription factor-4, and c/EBP homologous protein (CHOP) in cells treated with IFN-γ. The JAK1/2-STAT1 and AKT-mTOR signaling pathways are required for IFN-γ-induced UPR. Endoplasmic reticulum (ER) stress promotes autophagy and restores homeostasis. Surprisingly, in IFN-γ-treated cells, autophagy was impaired at the step of autophagosome-lysosomal fusion and caused by a significant decline in the expression of lysosomal membrane protein-1 and -2 (LAMP-1/LAMP-2). The ER stress inhibitor 4-PBA restored LAMP expression in IFN-γ-treated cells. IFN-γ stimulation activated the protein kinase-like ER kinase (PERK)-eukaryotic initiation factor 2a subunit (eIF2α) axis and caused a reduction in global protein synthesis. The PERK inhibitor, GSK2606414, partially restored global protein synthesis and LAMP expression in cells treated with IFN-γ. We further investigated the functional consequences of IFN-γ-induced ER stress. We show that inhibition of ER stress significantly prevents IFN-γ-triggered apoptosis. CHOP knockdown abrogated IFN-γ-mediated apoptosis. Inhibition of ER stress also restored cyclin D1 expression in IFN-γ-treated cells. Thus, ER stress and the UPR caused by IFN-γ represent novel mechanisms underlying IFN-γ-mediated anticancer effects. This study expands our understanding of IFN-γ-mediated signaling and its cellular actions in tumor cells., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)