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Hao Lin,1,* Bo Wei,1,* Guangsheng Li,1 Jinchang Zheng,1 Jiecong Sun,1 Jiaqi Chu,2 Rong Zeng,1 Yanru Niu21Department of Spinal Surgery, Affiliated Hospital of Guangdong Medical College, Zhanjiang, People’s Republic of China; 2Laboratory Institute of Minimally Invasive Orthopedic Surgery, Affiliated Hospital of Guangdong Medical College, Zhanjiang, People’s Republic of China *These authors contributed equally to this work Abstract: Apoptosis of osteoblasts triggered by high-dose glucocorticoids (GCs) has been identified as a major cause of osteoporosis. However, the underlying molecular mechanisms accounting for this action remain elusive, which has impeded the prevention and cure of this side effect. Sulforaphane (SFP) is a naturally occurring isothiocyanate that has huge health benefits for humans. In this study, by using osteoblastic MC3T3-E1 cells as a model, we demonstrate the protective effects of SFP against dexamethasone (Dex)-induced apoptosis and elucidate the underlying molecular mechanisms. The results show that SFP could effectively inhibit the Dex-induced growth inhibition and release of lactate dehydrogenase in MC3T3-E1 cells. Treatment with Dex induced caspase-dependent apoptosis in MC3T3-E1 cells, as evidenced by an increase in the Sub-G1 phase, chromatin condensation, and deoxyribonucleic acid fragmentation, which were significantly suppressed by coincubation with SFP. Mitochondria-mediated apoptosis pathway contributed importantly to Dex-induced apoptosis, as revealed by the activation of caspase-3/-9 and subsequent cleavage of poly adenosine diphosphate ribose polymerase, which was also effectively blocked by SFP. Moreover, treatments of Dex strongly induced overproduction of reactive oxygen species and inhibited the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and the downstream effectors HO1 and NQO1. However, cotreatment with SFP effectively reversed this action of Dex. Furthermore, silencing of Nrf2 by small interfering ribonucleic acid significantly blocked the cytoprotective effects of SFP against Dex-induced apoptosis, which suggest the important role of Nrf2 signaling pathway and cell apoptosis induced by Dex. Taken together, this study provides a novel strategy for molecular intervention against Dex-induced osteoporosis using phytochemicals. Keywords: osteoporosis, glucocorticoid, apoptosis, sulforaphane, Nrf2 pathway

Background: Leucine, a branched-chain amino acid, participates in the regulation of lipid metabolism and the composition of the intestinal microbiota. However, the related mechanism remains unclear., Objectives: Here, we aimed to reveal the potential mechanisms by which hepatic CYP7A1 (a rate-limiting enzyme for bile acid [BA] synthesis) and gut microbiota coregulate BA synthesis under leucine deprivation., Methods: To this end, 8-wk-old C57BL/6J mice were fed with either regular diets or leucine-free diets for 1 wk. Then, we investigated whether secondary BAs were synthesized by Turicibacter sanguinis in 7-wk-old C57BL/6J germ-free mice gavaged with T. sanguinis for 2 wk by determining BA concentrations in the plasma, liver, and cecum contents using liquid chromatography-tandem mass spectrometry., Results: The results showed that leucine deprivation resulted in a significant increase in total BA concentration in the plasma and an increase in the liver, but no difference in total BA was observed in the cecum contents before and after leucine deprivation. Furthermore, leucine deprivation significantly altered BA profiles such as taurocholic acid and ω-muricholic acid in the plasma, liver, and cecum contents. CYP7A1 expression was significantly upregulated in the liver under leucine deprivation. Leucine deprivation also regulated the composition of the gut microbiota; specifically, it significantly upregulated the relative abundance of T. sanguinis, thus enhancing the conversion of primary BAs into secondary BAs by intestinal T. sanguinis in mice., Conclusions: Overall, leucine deprivation regulated BA profiles in enterohepatic circulation by upregulating hepatic CYP7A1 expression and increasing intestinal T. sanguinis abundance. Our findings reveal the contribution of gut microbiota to BA metabolism under dietary leucine deprivation., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Introduction: Fine needle aspiration (FNA) biopsy is a widely accepted method for diagnosing thyroid nodules. However, the influence of maximum diameter (MD) of ACR TIRADS 5 (TR5) thyroid nodules on the FNA outcomes remains debated. This study examined the influence of MD on the FNA outcomes and investigated the optimal MD threshold for FNA in TR5 nodules., Methods: We conducted a retrospective analysis of 280 TR5 thyroid nodules from 226 patients who underwent FNA from January to June 2022 in our department. Probably malignant (PM) group was defined as Bethesda V in cytopathology with confirmed BRAF V600E mutation or Bethesda VI, the other cytopathology outcomes were defined as probably benign (PB) group. We examined factors influencing malignant cytopathology outcomes and determined the optimal MD threshold for FNA in TR5 nodules using logistic regression and restricted cubic spline (RCS) analysis., Results: Among these nodules, 58.2% (163/280) had PM outcomes. The PM group had a significantly larger MD than the PB group [6.5mm (range 5.0-8.4) vs. 5.3mm (range 4.0-7.0), p < 0.001]. In multivariate logistic regression fully adjusted for confounders, MD was significantly associated with PM outcomes [odds ratio 1.16, 95%CI 1.05-1.31; p = 0.042]. The highest quartile of MD had a greater likelihood of PM outcomes compared to the lowest quartile [odds ratio 4.71, 95% CI 1.97-11.69, p = 0.001]. The RCS analysis identified 6.2 mm as the optimal MD threshold for FNA in TR5 nodules., Conclusion: MD significantly affects the probability of malignant outcomes in FNA of TR5 thyroid nodules. A MD threshold of ≥6.2mm is suggested for FNA in these nodules., 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 © 2024 Cao, Shi, Niu, Zhao, Wei, Wu, Peng, Li and Yu.)

Background: Gallbladder mucinous adenocarcinoma (GBMAC) is a rare subtype of gallbladder adenocarcinoma (GBAC), with limited knowledge of its survival outcomes from small case series and single-center retrospective analysis., Aim: To compare the clinicopathological characteristics of GBMAC with typical GBAC and its prognostic factors to gain insights into this field., Methods: This study was conducted using data from the Surveillance, Epidemiology, and End Results database, including cases of GBMAC and typical GBAC diagnosed from 2010 to 2017. The Pearson chi-square test or Fisher exact test was used to examine the differences in clinicopathological features between these two cohorts. In addition, propensity score matching (PSM) analysis was performed to balance the selection biases. Univariate and multivariate Cox hazards regression analyses were performed to determine independent prognostic factors for cancer-specific survival (CSS) and overall survival (OS). The Kaplan-Meier curves and log-rank tests were used to assess the OS and CSS of GBMAC and typical GBAC patients., Results: The clinicopathological and demographic characteristics of GBMAC were different from typical GBAC. They included a larger proportion of patients with unmarried status, advanced American Joint Committee on Cancer (AJCC) stage, higher T stage, higher N1 stage rate and lower N0 and N2 stage rates ( P < 0.05). Multivariate analyses demonstrated that surgery [OS: Hazard ratio (HR) = 2.27, P = 0.0037; CSS: HR = 2.05, P = 0.0151], chemotherapy (OS: HR = 6.41, P < 0.001; CSS: HR = 5.24, P < 0.001) and advanced AJCC stage (OS: Stage IV: HR = 28.99, P = 0.0046; CSS: Stage III: HR = 12.31, P = 0.015; stage IV: HR = 32.69, P = 0.0015) were independent prognostic indicators for OS and CSS of GBMAC patients. Furthermore, after PSM analysis, there was no significant difference between GBMAC and matched typical GBAC patients regarding OS ( P = 0.82) and CSS ( P = 0.69)., Conclusion: The biological behaviors of GBMAC are aggressive and significantly different from that of typical GBAC. However, they show similar survival prognoses. Surgery, chemotherapy, and lower AJCC stage were associated with better survival outcomes. Further research is needed in the future to verify these results., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Pancreatic adenocarcinoma (PDAC) is a fatal disease with a 5-year survival rate of 8% and a median survival of 6 mo. In PDAC, several mutations in the genes are involved, with Kirsten rat sarcoma oncogene (90%), cyclin-dependent kinase inhibitor 2A (90%), and tumor suppressor 53 (75%-90%) being the most common. Mothers against decapentaplegic homolog 4 represents 50%. In addition, the self-preserving cancer stem cells, dense tumor microenvironment (fibrous accounting for 90% of the tumor volume), and suppressive and relatively depleted immune niche of PDAC are also constitutive and relevant elements of PDAC. Molecular targeted therapy is widely utilized and effective in several solid tumors. In PDAC, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. There is currently only one United States Food and Drug Administration-approved targeted therapy for PDAC - erlotinib, but the absolute benefit of erlotinib in combination with gemcitabine is also minimal (2 wk). In this review, we summarize current targeted therapies and clinical trials targeting dysregulated signaling pathways and components of the PDAC oncogenic process, analyze possible reasons for the lack of positive results in clinical trials, and suggest ways to improve them. We also discuss emerging trends in targeted therapies for PDAC: combining targeted inhibitors of multiple pathways. The PubMed database and National Center for Biotechnology Information clinical trial website (www.clinicaltrials.gov) were queried to identify completed and published (PubMed) and ongoing (clinicaltrials.gov) clinical trials (from 2003-2022) using the keywords pancreatic cancer and targeted therapy. The PubMed database was also queried to search for information about the pathogenesis and molecular pathways of pancreatic cancer using the keywords pancreatic cancer and molecular pathways., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interests to declare., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Current pulse driven Néel vector rotation in metallic antiferromagnets is one of the most promising concepts in antiferromagnetic spintronics. We show microscopically that the Néel vector of epitaxial thin films of the prototypical compound Mn 2 Au can be reoriented reversibly in the complete area of cross shaped device structures using single current pulses. The resulting domain pattern with aligned staggered magnetization is long term stable enabling memory applications. We achieve this switching with low heating of ≈20 K, which is promising regarding fast and efficient devices without the need for thermal activation. Current polarity dependent reversible domain wall motion demonstrates a Néel spin-orbit torque acting on the domain walls., (© 2023. The Author(s).)

Background: Accumulating evidence indicates that circular RNAs (circRNAs) play important roles in various cancers. Hsa&#95;circ&#95;0008832 (circFBXO7) is a circRNA generated from the second exon of the human F-box only protein 7 (FBXO7). Mouse circFbxo7 is a circRNA generated from the second exon of mouse F-box only protein 7 (Fbxo7). The role of human circFBXO7 and mouse circFbxo7 in non-small cell lung cancer (NSCLC) has not been reported., Methods: The expression of circFBXO7 was measured by quantitative real-time PCR. Survival analysis was performed to explore the association between the expression of circFBXO7 and the prognosis of patients with NSCLC. Lung cancer cell lines were transfected with plasmids. Cell proliferation, cell cycle, and tumorigenesis were evaluated to assess the effects of circFBXO7. Fluorescence in situ hybridization assay was used to identify the location of circFBXO7 and circFbxo7 in human and mouse lung cancer cells. Luciferase reporter assay was conducted to confirm the relationship between circFBXO7 and microRNA., Results: In this study, we found that circFBXO7 was downregulated in NSCLC tissues and cell lines. NSCLC patients with high circFBXO7 expression had prolonged overall survival. Overexpression of circFBXO7 inhibited cell proliferation both in vitro and in vivo. Mechanistically, we demonstrated that circFBXO7 upregulated the expression of miR-296-3p target gene Krüppel-like factor 15 (KLF15) and KLF15 transactivated the expression of CDKN1A., Conclusions: CircFBXO7 acts as a tumor suppressor by a novel circFBXO7/miR-296-3p/KLF15/CDKN1A axis, which may serve as a potential biomarker and therapeutic target for NSCLC., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Malignant pleural effusion (MPE) is a functional 'cold' tumor microenvironment in which the antitumor activity of CD8 + T cells and natural killer T (NKT)-like cells is suppressed and the function of regulatory T (T reg ) cells is enhanced. Using flow cytometry and immunofluorescence staining, we detected a distinct subset of NKT-like cells expressing FOXP3 in MPE. Through single-cell RNA sequencing (scRNA-seq) analysis, we found that the glycolysis pathway and pyruvate metabolism were highly activated in FOXP3 + NKT-like cells. Similar to T reg cells, FOXP3 + NKT-like cells highly expressed monocarboxylate transporter 1 (MCT1) and lactate dehydrogenase B to uptake and utilize lactate, thereby maintaining their immunosuppressive function and hyperlactylation in MPE. Furthermore, we found that MCT1 small molecule inhibitor 7ACC2 significantly reduced FOXP3 expression and histone lactylation levels in NKT-like cells in vitro. In conclusion, we reveal for the first time the altered phenotypic and metabolic features of FOXP3 + NKT-like cells in human MPE., Competing Interests: We declare no competing interests., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Since the "seed and soil" hypothesis was proposed, the biological functions of the tumor microenvironment (TME), especially its stromal components, have received increasing attention. Cancer-associated fibroblasts (CAFs) are the major components of the stromal region, providing material support for tumor cell proliferation, migration, and invasion. Furthermore, CAFs are important mediators of suppressing immune responses by attracting the accumulation of immunosuppressive cells through cytokine/chemokine secretion. In this review, we summarized the major cytokines, chemokines and metabolites, including transforming growth factor-β (TGF-β), interleukin-6 (IL-6), C-X-C chemokine ligand (CXCL)12, C-C chemokine ligand (CCL) 2, prostaglandin E2 (PGE2), and other factors, by which CAFs suppress the immune systems in a variety of cancers. More importantly, we highlight potential therapeutic strategies to alleviate the immunosuppression produced by CAFs, thereby inhibiting tumor progression., Competing Interests: Declaration of Competing Interest All authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Twenty-four-hour oscillations of circadian rhythms control comprehensive biological processes in the human body. In lung adenocarcinoma (LUAD), chronic circadian rhythm disruption is positively associated with tumorigenesis. However, few studies focus on circadian clock gene signatures (CGSs) for prognosis evaluation of patients with early-stage LUAD., Methods: In this study, we aimed to construct a robust prognostic circadian rhythm-related biomarker from multiple public databases, including the Gene Expression Omnibus database and The Cancer Genome Atlas database. The least absolute shrinkage and selection operator (LASSO)-penalized Cox regression model was performed to select optimal circadian clock gene pairs. Bioinformatic analyses were performed to estimate the abundance of different immune cells and immunohistochemical analyses were conducted to validate the differential proportion of tumor-infiltrating lymphocytes in different groups., Results: Results demonstrated that the CGS could accurately identify patients with early-stage LUAD at a high risk in the training dataset [hazard ratio (HR) =3.06; 95% confidence interval (CI): 2.47-3.78; P<0.001], testing dataset (HR =2.44; 95% CI: 1.74-3.43; P<0.001), and validation dataset (HR =2.09, 95% CI: 1.09-4.00; P=0.023). Bioinformatic and immunohistochemical analyses demonstrated that the abundance of tumor-infiltrating CD4 + T cells was higher in the low-CGS groups. Integration of the CGS and clinical characteristics improved the accuracy of the CGS in predicting overall survival (OS) of patients with early-stage LUAD., Conclusions: In conclusion, the CGS was an independent immune-related circadian biomarker that could identify early-stage LUAD patients with different OS., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-570/coif). The authors have no conflicts of interest to declare., (2022 Journal of Thoracic Disease. All rights reserved.)

In antiferromagnetic spintronics, the read-out of the staggered magnetization or Néel vector is the key obstacle to harnessing the ultra-fast dynamics and stability of antiferromagnets for novel devices. Here, we demonstrate strong exchange coupling of Mn 2 Au, a unique metallic antiferromagnet that exhibits Néel spin-orbit torques, with thin ferromagnetic Permalloy layers. This allows us to benefit from the well-established read-out methods of ferromagnets, while the essential advantages of antiferromagnetic spintronics are only slightly diminished. We show one-to-one imprinting of the antiferromagnetic on the ferromagnetic domain pattern. Conversely, alignment of the Permalloy magnetization reorients the Mn 2 Au Néel vector, an effect, which can be restricted to large magnetic fields by tuning the ferromagnetic layer thickness. To understand the origin of the strong coupling, we carry out high resolution electron microscopy imaging and we find that our growth yields an interface with a well-defined morphology that leads to the strong exchange coupling., (© 2021. The Author(s).)

The role of autophagy in lung cancer is context-dependent and complex. Recent studies have reported the important role of autophagy in tumor immune escape. However, the association between autophagy and tumor-infiltrating lymphocytes (TILs) in early-stage lung adenocarcinoma (LUAD) remains unclear. In this study, we aimed to develop and validate the autophagy-related gene pair index (ATGPI) and autophagy clinical prognostic index (ACPI) in multiple LUAD cohorts, including The Cancer Genome Atlas (TCGA) cohort, Gene Expression Omnibus cohorts, and one cohort from Union Hospital, Wuhan (UH cohort), using a Cox proportional hazards regression model with the least absolute shrinkage and selection operator. Multivariate Cox regression analysis demonstrated that there was a significant difference in overall survival (OS) between patients with high and low ATGPI in the testing [hazard ratio (HR) = 1.97; P < 0.001] and TCGA validation (HR = 2.25; P < 0.001) cohorts. Time-dependent receiver operating characteristic curve analysis was also performed. We found that high ATGPI could accurately identify patients with early-stage LUAD with shorter OS, with the areas under the curve of 0.703 and 0.676 in the testing and TCGA validation cohorts, respectively. Concordance index (C-index) was used to evaluate the efficiency of ATGPI and ACPI. The C-index of ACPI was higher than that of ATGPI in the testing (0.71 vs. 0.66; P < 0.001), TCGA validation (0.69 vs. 0.65; P = 0.028), and UH (0.80 vs. 0.70; P = 0.015) cohorts. TIL analysis demonstrated that the proportions of tumor-infiltrating CD4 + T cells were lower in the high-ATGPI group than in the low-ATGPI group in both the TCGA validation and UH cohorts. These results indicate the potential clinical use of ATG signatures which are associated with TILs, in identifying patients with early-stage LUAD with different OS., 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 © 2021 Wang, Li, Zhang, Xiang, Wei, Niu, Ye, Peng, Zhang, Xue and Zhou.)

Objective: To investigate the clinicopathological features and differential diagnosis of metastatic tumors in the lung. Methods: The clinicopathological data of 226 metastatic tumors in the lung were collected at Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, from January 2014 to December 2018, and the pathomorphological characteristics were analyzed. Results: There were 84 males and 142 females, with an age range from 13 to 77 years. There were 122 patients with multiple pulmonary nodules and 104 patients with solitary pulmonary nodule. The tumors of the highest frequencies were colorectal cancer ( n =59), followed by trophoblast tumor ( n =44), kidney cancer ( n =31), breast cancer ( n =20), cervix cancer ( n =14), and urinary urothelium cancer ( n =8). The time from the diagnosis of primary tumors to metastasis and the status of surgical treatment varied by tumor origin. The morphology of metastatic lung tumors overlapped with that of the primary tumors to some extent. The relative specific morphological characteristics and the presence of carcinoma in situ surrounding the tumors should be carefully searched for to confirm the tumor origin. The metastatic tumors of the lung had morphological characteristics, immunohistochemical TTF1 (-) and tumor of various sources, while the primary tumor differentiation had relatively specific antibodies: colorectal cancer CK20 (+), CDX2 (+), CK7 (-); malignant trophoblastic tumor, HCG (+); renal clear cell carcinoma CD10 (+), vimentin (+), CK7 (-); breast cancer, GATA3 and ER (+); cervical cancer, p16 (+); urothelial carcinoma, CK20, p63 and GATA3 (+). Conclusions: There is overlap between pulmonary metastatic tumor and primary tumor in morphology. Therefore, the diagnosis should be made by combining clinical history, pathological morphology and immunophenotypic characteristics.

Background: Coronavirus Disease 19 (COVID-19) is a global health concern that has become a pandemic over the past few months. This study aims at understanding the clinical manifestations of COVID-19 patients with pleural effusion., Methods: COVID-19 patients were retrospectively enrolled from the Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. Pharyngeal swabs from patients were tested using real-time polymerase chain reaction. Patients with COVID-19 were divided into two groups based on their computed tomography (CT) scans for the presence of pleural effusion at admission. We compared the clinical features, laboratory findings, scans and clinical outcomes between the two groups., Results: Pleural effusion was observed in 9.19% of the patients. Patients with pleural effusion were more likely to be severe or critical cases. Moreover, patients with pleural effusion were associated with increased mortality. Of the 799 discharged patients, patients with pleural effusion had longer hospital stays and duration of viral shedding since the onset of symptoms as compared with that for patients without pleural effusion. After discharge, 217 patients visited for a follow-up CT re-examination at the Union Hospital. The CT scans showed that patients with pleural effusion required a longer time to resolve the lung inflammation after the onset of COVID-19 as compared with the time required by patients without pleural effusion., Conclusion: This population of patients requires special attention and pleural effusion may be an indicator of poor prognosis in COVID-19 patients., (© 2021 John Wiley & Sons Ltd.)

Background: Regulatory T cells (Tregs) may represent a major cellular mechanism in immune suppression by dampening the anti-tumor response in malignant pleural effusion (MPE). Tumor necrosis factor receptor type II (TNFR2) has emerged as a novel identification for the maximally suppressive subset of Tregs in the tumor environment. At present, the significance of TNFR2 expression on Tregs in MPE remains unclear., Methods: The distribution of TNFR2 + cells in Tregs and effector T cells (Teffs) in MPE, peripheral blood (PB), and tuberculosis pleural effusion (TPE) were determined. The associations between TNFR2 + Tregs frequencies present in MPE and the clinical and laboratorial characteristics of patients with lung cancer were investigated. The immunosuppressive phenotype of TNFR2 + Tregs in MPE was analyzed. The effects of the TNF-TNFR2 interaction on the immunosuppressive function of Tregs was explored. The efficacy of targeting TNFR2 for MPE therapy was examined. The source of TNF in MPE was identified., Results: We observed that markedly higher levels of TNFR2 were expressed in MPE Tregs compared with the levels expressed in MPE Teffs, PB Tregs, or in TPE Tregs. The frequencies of TNFR2 + Tregs were positively correlated with the number of tumor cells in MPE, as well as the volume of MPE. High frequencies of TNFR2 + Tregs in MPE indicated short survival time and poor performance status for MPE patients. Compared to TNFR2 - Tregs, TNFR2 + Tregs expressed higher levels of immunosuppressive molecules cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death-ligand 1 (PD-L1), and replicating marker Ki-67. Consequently, the proportions of interferon gamma (IFN-γ)-producing cytotoxic T lymphocytes (CTLs) were significantly increased after TNFR2 blockade. Furthermore, tumor necrosis factor (TNF), through interaction with TNFR2, enhanced the suppressive capacity of Tregs by up-regulating CTLA-4 and PD-L1 expression. Interestingly, T helper 1 (Th1) and T helper 17 (Th17) cells are the major source of TNF in MPE, suggesting that MPE Teffs may paradoxically promote tumor growth by boosting MPE Treg activity via the TNF-TNFR2 pathway., Conclusions: Our data expanded the immunosuppressive mechanism present in MPE induced by Tregs, and provides novel insight for the diagnosis, disease evaluation, and treatment of MPE patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-7181). The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Background: Long noncoding RNAs (lncRNAs) and mRNAs are widely involved in various physiological and pathological processes. The use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) is a novel therapeutic strategy that could promote insulin secretion and decrease the rate of β-cell apoptosis in type 2 diabetes mellitus (T2DM) patients. However, the specific lncRNAs and mRNAs and their functions in these processes have not been fully identified and elucidated., Aim: To identify the lncRNAs and mRNAs that are involved in the protective effect of GLP-1RA in β cells, and their roles., Methods: Rat gene microarray was used to screen differentially expressed (DE) lncRNAs and mRNAs in β cells treated with geniposide, a GLP-1RA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to assess the underlying functions of DE mRNAs. Hub mRNAs were filtered using the STRING database and the Cytoscape plugin, CytoHubba. In order to reveal the regulatory relationship between lncRNAs and hub mRNAs, their co-expression network was constructed based on the Pearson coefficient of DE lncRNAs and mRNAs, and competing endogenous RNA (ceRNA) mechanism was explored through miRanda and TargetScan databases., Results: We identified 308 DE lncRNAs and 128 DE mRNAs with a fold change filter of ≥ 1.5 and P value < 0.05. GO and KEGG pathway enrichment analyses indicated that the most enriched terms were G-protein coupled receptor signaling pathway, inflammatory response, calcium signaling pathway, positive regulation of cell proliferation, and ERK1 and ERK2 cascade. Pomc , Htr2a , and Agtr1a were screened as hub mRNAs using the STRING database and the Cytoscape plugin, CytoHubba. This result was further verified using SwissTargetPrediction tool. Through the co-expression network and competing endogenous (ceRNA) mechanism, we identified seven lncRNAs (NONRATT027738, NONRATT027888, NONRATT030038, etc .) co-expressed with the three hub mRNAs ( Pomc, Htr2a, and Agtr1a ) based on the Pearson coefficient of the expression levels. These lncRNAs regulated hub mRNA functions by competing with six miRNAs ( r no-miR-5132-3p, rno-miR-344g, rno-miR-3075, etc .) via the ceRNA mechanism. Further analysis indicated that lncRNA NONRATT027738 interacts with all the three hub mRNAs, suggesting that it is at a core position within the ceRNA network., Conclusion: We have identified key lncRNAs and mRNAs, and highlighted here how they interact through the ceRNA mechanism to mediate the protective effect of GLP-1RA in β cells., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests and have nothing to disclose., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background & Aims: We compared clinical, laboratory, radiological, and outcome features of patients with SARS-CoV-2 infection (COVID-19) with pneumonia, with vs without diarrhea., Methods: We performed a retrospective, single-center analysis of 84 patients with SARS-CoV-2 pneumonia in Wuhan Union Hospital, China, from January 19 through February 7, 2020. Cases were confirmed by real-time reverse-transcriptase PCR of nasal and pharyngeal swab specimens for SARS-CoV-2 RNA. Blood samples were analyzed for white blood cell count, lymphocyte count, alanine aminotransferase, creatine kinase, lactate dehydrogenase, D-dimer, C-reactive protein, and in some cases, immunoglobulins, complement, lymphocyte subsets, and cytokines. Virus RNA was detected in stool samples by real-time PCR., Results: Of the 84 patients with SARS-CoV-2 pneumonia, 26 (31%) had diarrhea. The duration of fever and dyspnea in patients with diarrhea was significantly longer than those without diarrhea (all P < .05). Stool samples from a higher proportion of patients with diarrhea tested positive for virus RNA (69%) than from patients without diarrhea (17%) (P < .001). As of February 19, a lower proportion of patients with diarrhea had a negative result from the latest throat swab for SARS-CoV-2 (77%) than patients without diarrhea (97%) (P = .010), during these patients' hospitalization. Of 76 patients with a negative result from their latest throat swab test during hospitalization, a significantly higher proportion of patients with diarrhea had a positive result from the retest for SARS-CoV-2 in stool (45%) than patients without diarrhea (20%) (P = .039)., Conclusions: At a single center in Wuhan, China, 31% of patients with SARS-CoV-2 pneumonia had diarrhea. A significantly higher proportion of patients with diarrhea have virus RNA in stool than patients without diarrhea. Elimination of SARS-CoV-2 from stool takes longer than elimination from the nose and throat., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: To study the clinicopathologic characteristics and relevant factors affecting prognosis of patients with synchronous bilateral breast cancer. Methods: The clinical data, pathologic characteristics and immunohistochemical expression characteristics of 151 patients with synchronous bilateral breast cancers diagnosed in Peking Union Medical College Hospital from 2008 to 2018 were collected and analyzed. The factors affecting the prognosis were analyzed by Log rank test, Kaplan-Meier survival analysis, Cox regression and other methods. Results: Synchronous bilateral breast cancer cases accounted for 1.2% (151/12 239) of all breast cancer patients in the same period, and 14.6% (22/151) had a family history. The patients' age range was 22-88 years, mainly female, with a mean survival of 42.5 months. There were 106 patients with synchronous bilateral invasive breast cancers, 6 patients with synchronous bilateral breast cancer in situ, and 39 patients with unilateral invasive breast cancer and unilateral breast cancer in situ. In synchronous bilateral invasive breast cancers, the histological type was mainly non-specific type (84.9%, 180/212), the histological grade was mainly Grade 2 (60.8%,129/212), the TNM stage was mainly stage Ⅰ (50.5%, 107/212), the tumor size was mainly T1 (68.9%, 146/212), and the regional lymph node was mainly N0 (61.8%, 131/212). The molecular subtypes were mainly Luminal A-like (38.1%, 75/197) and Luminal B-like (43.7%, 86/197); ER (78.2%, 154/197) and PR (72.1%,142/197)were mainly positive, and HER2 was mainly negative (91.9%, 181/197). There were 85 (80.2%) patients and 75 (70.8%) patients with the same histological type and histological grade on both sides, respectively. The concordance of tumor size T stage and the regional lymph nodes N stage were 58.5% (62/106) and 55.7% (59/106), respectively. The concordance of molecular subtype was 54.9% (50/91), and the concordance of ER, PR, HER2 and Ki-67 were 83.5% (76/91), 76.9% (70/91), 89.0% (81/91) and 59.3% (54/91), respectively. The expression of ER and PR in synchronous bilateral invasive breast cancer was significantly correlated with prognosis ( P< 0.05). Conclusions: Among patients with synchronous bilateral breast cancers, bilateral invasive breast cancer is the most common, the prognosis is the worst, and the pathologic characteristics of bilateral breast cancer tend to be consistent. The expression of ER and PR in synchronous bilateral invasive breast cancer is significantly correlated with prognosis, that is, best for bilateral ER-positive patients, worst for bilateral ER-negative patients, and intermediate for unilateral ER-positive patients, thus suggesting the importance of ER and PR detection in synchronous bilateral invasive breast cancers.

We have directly imaged the spontaneous formation of metastable surface phase domains on GaAs(001) during Langmuir evaporation. Eventually, these metastable phases transform to the thermodynamically stable parent phase, producing a dynamic phase coexistence with a temperature dependent, time-averaged coverage. Monte Carlo simulations are used to identify the key kinetic processes and investigate the interplay between phase metastability and evolving surface morphology. This is used to explain the measured temperature dependence of the time-averaged coverage.

We propose a general strategy for surface phase discrimination by dark-field imaging using low energy electrons, which maximizes contrast using diffraction spots, at selected optimal energies. The method can be automated to produce composite phase maps in real space and study the dynamics of complex phase transformations in real-time. To illustrate the capabilities of the technique, surface phases are mapped in the vicinity of liquid Ga droplets on the technologically important GaAs (001) surface., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

IL-26 is a potentially important player in host defense and may be a pathogenic factor in the chronic inflammatory disorders of humans. However, the involvement of IL-26 in tuberculous pleural effusion (TPE) has not been investigated. The concentration of IL-26 was determined in pleural fluids and sera from patients with pleural effusions. Flow cytometry was performed to identify the cell origin of IL-26. The effects of tuberculosis-specific antigen (ESAT-6/CFP-10) on IL-26 expression of CD4 + T cell were explored. The impacts of IL-26 on modulating CD4 + T cell polarization were also investigated. The concentrations of IL-26 were much higher in tuberculous, malignant, and infectious PE than those in the corresponding serum. The expression of IL-26 on CD4 + T cells was much higher in tuberculous PE than those in the corresponding serum, and pleural Th1 and Th17 cells might be the major cell sources of IL-26. The addition of ESAT-6/CFP-10 to CD4 + T cells led to increasing the number of IL-26-producing CD4 + T cells and IL-26 expression on Th1 and Th17 cells. IL-26 could induce the differentiation and generation of IL-22 by memory and naive CD4 + T cells. IL-26 also upregulated the mRNA encoding CC-chemokine ligand 20 (CCL20) and CCL22 by mononuclear cells isolated from TPE. This study implies that pleural Th1 and Th17 cells are the major cell sources of IL-26, which could induce the differentiation and generation of Th22 cells by CD4 + T cells, suggesting the involvement of IL-26 in the pathogenesis of human TPE. KEY MESSAGES: IL-26 is overexpressed in TPE patients and presents a higher concentration in pleural effusion than the corresponding peripheral blood. Pleural Th1 and Th17 cells might be the major cell sources of IL-26 in TPE patients. IL-26 promotes IL-22 secretion and Th22 generation by CD4 + T cells isolated from TPE patients. IL-26 may play an active role in the pathogenesis of tuberculous pleurisy.

Emergent order at mesoscopic length scales in condensed matter can provide fundamental insight into the underlying competing interactions and their relationship with the order parameter. Using spectromicroscopy, we show that mesoscopic stripe order near the metal-insulator transition (MIT) of strained VO&#95;{2} represents periodic modulations in both crystal symmetry and V-V dimerization. Above the MIT, we unexpectedly find the long-range order of V-V dimer strength and crystal symmetry become dissociated beyond ≈200  nm, whereas the conductivity transition proceeds homogeneously in a narrow temperature range.

Tumor necrosis factor (TNF) is a pleiotropic cytokine that has both pro-inflammatory and anti-inflammatory functions. The biological functions of TNF are mediated by two receptors, TNF receptor type I (TNFR1) and TNF receptor type II (TNFR2). TNFR1 is expressed universally on almost all cell types and has been extensively studied, whereas TNFR2 is mainly restricted to immune cells and some tumor cells and its role is far from clarified. Studies have shown that TNFR2 mediates the stimulatory activity of TNF on CD4 + Foxp3 + regulatory T cells (Tregs) and CD8 + Foxp3 + Tregs, and is involved in the phenotypic stability, proliferation, activation, and suppressive activity of Tregs. TNFR2 can also be expressed on CD8 + effector T cells (Teffs), which delivers an activation signal and cytotoxic ability to CD8 + Teffs during the early immune response, as well as an apoptosis signal to terminate the immune response. TNFR2-induced abolition of TNF receptor-associated factor 2 (TRAF2) degradation may play an important role in these processes. Consequently, due to the distribution of TNFR2 and its pleiotropic effects, TNFR2 appears to be critical to keeping the balance between Tregs and Teffs, and may be an efficient therapeutic target for tumor and autoimmune diseases. In this review, we summarize the biological functions of TNFR2 expressed on CD8 + Foxp3 + Tregs and CD8 + Teffs, and highlight how TNF uses TNFR2 to coordinate the complex events that ultimately lead to efficient CD8 + T cell-mediated immune responses.

The Sn intercalation into a buffer layer graphene grown on 4H-SiC(0001) substrate has been studied with spectroscopic photoemission and low energy electron microscope. Both SnSi x and SnO x interfacial layers are found to form below the buffer layer, converting it into a quasi-free-standing monolayer graphene. Combining the various operation modes of the microscope allows a detailed insight into the formation processes of the interlayers and their thermal stability. In particular, at the interface we observed a reversible transition from silicide to oxide after exposure to ambient pressure and subsequent annealing. This metal-dielectric transition might be useful for interface engineering in graphene-based devices., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Autophagy and apoptosis are critical for controlling Toxoplasma gondii (T. gondii) infection. T. gondii infection during pregnancy can damage the fetus and cause birth defects; however, the molecular mechanisms of this process are poorly understood. This study aims to determine the activities of autophagy and apoptosis as well as their regulatory mechanisms during T. gondii infection by using human umbilical cord mesenchymal stem cells (hUC-MSCs) as a model of congenital diseases. LC3B, a hallmark protein of autophagy was incrementally upregulated with the infection duration, whereas p62 was downregulated in T. gondii-infected hUC-MSCs. Concurrent to this result, the invasion of T. gondii into hUC-MSCs increased in a time-dependent manner. The expression levels of Bcl-2 family proteins including Bcl-2, Bcl-xL, Bim, Bax, Bid and Bak were not altered; however, Mcl-1 levels in hUC-MSCs were dramatically decreased upon T. gondii infection. In addition, at 24 h post-infection, cleaved PARP and cleaved caspase-3 protein levels were elevated in hUC-MSCs. Importantly, Mcl-1 overexpression reduced the levels of autophagy- and apoptosis-related proteins in T. gondii-infected hUC-MSCs. Mcl-1 proteins were primarily expressed in the fraction containing mitochondria and strongly interacted with Beclin-1 under normal conditions; however, these interactions were remarkably attenuated by T. gondii infection. These results suggest that mitochondrial Mcl-1 is an essential signaling mediator regulating the activation of autophagy and apoptosis during T. gondii infection.

We develop a method for patterning a buried two-dimensional electron gas (2DEG) in silicon using low kinetic energy electron stimulated desorption (LEESD) of a monohydride resist mask. A buried 2DEG forms as a result of placing a dense and narrow profile of phosphorus dopants beneath the silicon surface; a so-called δ-layer. Such 2D dopant profiles have previously been studied theoretically, and by angle-resolved photoemission spectroscopy, and have been shown to host a 2DEG with properties desirable for atomic-scale devices and quantum computation applications. Here we outline a patterning method based on low kinetic energy electron beam lithography, combined with in situ characterization, and demonstrate the formation of patterned features with dopant concentrations sufficient to create localized 2DEG states.

Zearalenone (ZEA) is a nonsteroidal estrogenic mycotoxin produced mainly by Fusarium. ZEA causes reproductive disorders and is both cytotoxic and genotoxic in animals; however, little is known regarding the molecular mechanism(s) leading to ZEA toxicity. Sertoli cells are somatic cells that support the development of spermatogenic cells. The objective of this study was to explore the effects of ZEA on the proliferation, apoptosis, and necrosis of rat Sertoli cells to uncover signaling pathways underlying ZEA cytotoxicity. ZEA reduced the proliferation of rat Sertoli cells in a dose-dependent manner, as indicated by a CCK8 assay, while flow cytometry revealed that ZEA caused both apoptosis and necrosis. Immunoblotting revealed that ZEA treatment increased the ratio of Bax/Bcl-2, as well as the expression of FasL and caspases-3, -8, and -9, in a dose-dependent manner. Collectively, these data suggest that ZEA induced apoptosis and necrosis in rat Sertoli cells via extrinsic and intrinsic apoptotic pathways. This study provides new insights into the molecular mechanisms by which ZEA exhibits cytotoxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1731-1739, 2016., (© 2015 Wiley Periodicals, Inc.)

Amodiaquine (AQ) is routinely prescribed as an anti-malarial drug. Here, we evaluated AQ-induced toxicity in the male reproductive system. Eighty adult male Sprague-Dawley rats were randomly divided into four groups that received distilled water (control) or daily doses of 5 mg/kg body weight, 10 mg/kg, or 15 mg/kg AQ for 2 weeks. Testes morphology was analyzed using hematoxylin-and-eosin staining, terminal dUTP nicked-end labeling (TUNEL), and immunostaining whereas protein expression was determined by Western blotting. AQ dose-dependently led to abnormal spermatogenesis. Disruption of the blood-testis barrier and increased germ cell apoptosis were observed in all three AQ-treated groups. Interestingly, AQ-induced damage of spermatogenesis recovered over time, based on the survival of promyelocytic leukemia zinc-finger (PLZF)-positive, undifferentiated spermatogonia. Serum levels of luteinizing hormone and testosterone, as well as testicular testosterone levels, were not significantly altered in AQ-treated groups compared with controls. Collectively, our study suggests that AQ exerts substantial acute side effects on the reproductive systems of adult male rats by inducing the apoptosis of differentiating spermatogenic cells and disruption of blood-testis barrier function., (© 2015 Wiley Periodicals, Inc.)

We report the simultaneous measurement of the structural and electronic components of the metal-insulator transition (MIT) of VO2 using electron and photoelectron spectroscopies and microscopies. We show that these evolve over different temperature scales, and are separated by an unusual monocliniclike metallic phase. Our results provide conclusive evidence that the new monocliniclike metallic phase, recently identified in high-pressure and nonequilibrium measurements, is accessible in the thermodynamic transition at ambient pressure, and we discuss the implications of these observations on the nature of the MIT in VO2.