Clinical efficacy and safety analysis of aumolertinib in real-world treatment of EGFR-mutated advanced non-small-cell lung cancer.

Background: This study aims to determine the efficacy and safety profile of aumolertinib in the real-word treatment setting for advanced non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations. Methods: We retrospectively analyzed the clinical data of 173 EGFR-mutated advanced NSCLC patients who received aumolertinib treatment at Henan Cancer Hospital from April 2020 to December 2022. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier survival curves, while a Cox regression model was used for multifactorial analysis and prognostic factor assessment. Results: Among patients administered first-line aumolertinib (n = 77), the objective remission rate (ORR) of 77.92% was observed, along with a disease control rate (DCR) of 100%. The median progression-free survival (mPFS) was 24.97 months, which did not reach the median overall survival (mOS). The patients treated with aumolertinib after progression on prior EGFR-tyrosine kinase inhibitor (TKI) therapy (n = 96) exhibited an ORR of 46.88%, a DCR of 89.58%, an mPFS of 15.17 months, and an mOS of 21.27 months. First-line treatment multivariate Cox regression analysis demonstrated a statistically significant impact of elevated creatine kinase on PFS (p = 0.016) and a similar significant influence of co-mutation on OS (p = 0.034). Furthermore, subsequent-line treatment multivariate Cox regression analysis showed a statistically significant impact of elevated creatine kinase on median PFS (p = 0.026) and a significant effect on the number of metastatic organs (p = 0.017), co-mutation (p = 0.035), and elevated creatine kinase (p = 0.014) on median OS. Conclusion: Aumolertinib has shown clinical significance and can safely be used in the real-world setting for patients with EGFR mutation-positive NSCLC.

Unveiling Synergistic Potency: Exploring Butyrolactone I to Enhance Gentamicin Efficacy against Methicillin-Resistant Staphylococcus aureus (MRSA) Strain USA300.

Staphylococcus aureus, including MRSA strains, poses significant health risks, imposing a significant disease burden and mortality. We investigate butyrolactone I (BL-1), a marine-derived metabolite from Aspergillus terreus, enhancing aminoglycoside efficacy against MRSA. A promising synergy is observed with BL-1 and various aminoglycosides, marked by low fractional inhibitory concentration indexes (FICIs < 0.5). Comprehensive studies utilizing USA300 MRSA and gentamicin reveal a remarkable one-fourth reduction in minimum inhibitory concentration (MIC) with 20 µg/mL BL-1. A relative abundance assay indicates that BL-1 enhances gentamicin uptake while restraining extracellular presence, involving intricate transmembrane signaling and molecular interactions. RNA-Seq analysis yielded an unexpected revelation, unveiling a distinctive gene expression profile and distinguishing it from other treatment approaches. Furthermore, meticulous analyses validated the extensive perturbations induced by BL-1 exposure, affecting diverse biological functions, encompassing glycolysis, amino acid metabolisms, substance transmembrane transport, and virulence generation. These valuable insights inspired further confirmation of bacterial virulence and the modulation of membrane permeability resulting from BL-1 treatment. Phenotypic validations corroborated our observations, revealing reduced membrane permeability and hemolytic toxicity, albeit demanding a deeper comprehension of the intricate interplay underlying these actions. Our study contributes crucial mechanistic insights to the development of therapeutic strategies against this notorious pathogen and the judicious employment of aminoglycosides. Additionally, it elucidates marine-derived metabolites' ecological and functional roles, exemplified by fungal quorum sensing signals. These compounds could give producers a competitive edge, inhibiting microorganism proliferation and suggesting novel approaches for combating resistant pathogens.

Analysis of burnout and its influencing factors among prison police.

Background: Burnout among prison police is an occupational health issue in the field of public health. Although burnout has been a hot issue for decades, there has not been a focus on the specific group of prison police. This study explores the burnout status and its influencing factors among prison police. Methods: The Maslach Burnout Questionnaire-General Survey (MBI-GS) was used to conduct a questionnaire survey among 1,024 prison police. Results: It indicates that emotional exhaustion, negative detachment, and self-efficacy were the most significant dimensions of the burnout among prison police officers. The results of multiple linear regression analysis showed that gender (-0.201, P = 8.8958E-11 <0.05), workload (-0.441, P = 1.6287E-9 <0.05), whether they have direct contact with supervisory subjects (-0.394, P = 2.1449E-39 <0.05), and a sense of organizational support (-0.298, P = 3.7182E-7 <0.05) were risk factors for burnout in prison police. Conclusions: Burnout among prison officers can be reduced through preferential treatment of prison police, sound organizational mechanisms, and self-improvement of prison police.

Correlations of switch/sucrose nonfermentable complex mutations with clinical outcomes in advanced non-small cell lung cancer.

BACKGROUND: The switch/sucrose nonfermentable complex mutations (SWI/SNF-mut) are common in non-small cell lung cancer (NSCLC). However, the association of SWI/SNF-mut with the clinical outcomes of immune checkpoint inhibitors (ICIs), particularly of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), has not been established. METHODS: We retrospectively collected data of patients at Cancer Hospital Chinese Academy of Medical Sciences. Patients with advanced NSCLC who received programmed cell death protein-1 or programmed cell death ligand 1 (PD-[L]1) inhibitors were included in cohort 1 and those with EGFR mutations (EGFR-mutant) received EGFR-TKIs monotherapy were included in cohort 2. Two reported Memorial Sloan-Kettering Cancer Center (MSKCC) cohorts received immunotherapy alone used as the validation for cohort 1. We analyzed the relationship between SWI/SNF alterations and clinical outcomes in each cohort. RESULTS: In total, 1162 patients were included, of which 230 patients (19.8%) were identified as SWI/SNF-mut with the most common genetic alterations being ARID1A (33.4%) and SMARCA4 (28.3%). In cohort 1 (n = 146), patients with co-mutations of SWI/SNF and Kirsten rat sarcoma oncogene (KRAS) (SWI/SNFmutKRASmut, n = 18) had significantly prolonged progression-free survival (PFS) (8.6 m vs. 1.9 m; hazard ratio [HR],  0.31; 95% confidence intervals [CI], 0.11-0.83; p = 0.032) to PD-(L)1 inhibitors monotherapy, which was consistent with the MSKCC cohorts (not reach [NR] vs. 6.3 m; HR, 0.36, 95% CI, 0.15-0.82; p = 0.016). In cohort 2 (n = 205), ARID1A-mut (n = 16) was associated with improved PFS after EGFR-TKIs (20.6 m vs. 11.2 m; HR, 0.47, 95% CI, 0.27-0.94; p = 0.023). CONCLUSIONS: In advanced NSCLC, patients with SWI/SNFmutKRASmut seem to benefit more from ICIs. Furthermore, ARID1A-mut may provide a protective effect to EGFR-TKIs in EGFR-mutant patients. However, this is a retrospective single-institution analysis that requires further validation by large prospective studies.

Establishment of prognostic nomograms for predicting the progression free survival of EGFR-sensitizing mutation, advanced lung cancer patients treated with EGFR-TKIs.

BACKGROUND: There is a lack of clinically available predictive models for patients with epidermal growth factor receptor (EGFR) mutation positive, advanced non-small cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors (TKIs). METHODS: The clinical data of patients at the Cancer Hospital, Chinese Academy of Medical Sciences between from January 2016 to January 2021 were retrospectively retrieved as training set. The patients from BENEFIT trial were for the validation cohort. The nomogram was built based on independent predictors identified by univariate and multivariate Cox regression analyses. The discrimination and calibration of the nomogram were evaluated by C-index and calibration plots. RESULTS: A total of 502 patients with complete clinical data and follow-up information were enrolled in this study. Five independent prognostic factors, including The Eastern Cooperative Oncology Group Performance Status scale (ECOG PS), EGFR mutation subtype, EGFR co-mutation, liver metastasis and malignant pleural effusion (p < 0.05). The C-indexes of the nomogram were 0.694 (95% confidence interval [CI], 0.663-0.725) for the training set and 0.653 (95% CI, 0.610-0.696) for the validation set. The calibration curves for the probabilities of 9-, 12- and 18-month progression-free survival (PFS) revealed satisfactory consistency in both the internal and external validations. Additionally, the patients were divided into two groups according to risk (high-risk, low-risk), and significant differences in PFS were observed between the groups in the training and external validation cohorts (p < 0.001). CONCLUSIONS: We constructed and validated a convenient nomogram that have the potential to become an accurate and reliable tool for patients with EGFR mutation positive, advanced NSCLC to individually predict their potential benefits from EGFR-TKIs, and facilitate clinical decision-making.

Integrating transcriptomics and metabolomics analysis on kojic acid combating Acinetobacter baumannii biofilm and its potential roles.

As a major secondary metabolite derived from a dominant marine filamentous fungus A7, kojic acid might confer the strain a competitive advantage in natural colonization. The bioactivities of kojic acid against bacterial growth and biofilm formation were investigated against Acinetobacter baumannii (A. baumannii) ATCC 19606. Then, transcriptomics and metabolomics were integrated to characterize the underlying mechanisms. It turned out that kojic acid exhibited a significantly suppressive impact against biofilm but a weak bacteriostatic activity. Meanwhile, a variety of transcriptional and metabolomic profiles were altered within biofilm formation as a result of kojic acid exposure. The alterations highlighted the mechanisms underlying biofilm formation, comprising of quorum sensing, fimbria assembly, bacterial virulence and metabolic plasticity, which could somewhat be hampered by kojic acid. The present study comprehensively elucidated multifactorial schemes for kojic acid combating biofilm formation of A. baumannii, which might provide mechanistic insights into the development of therapeutic strategies against this notorious pathogen. Meanwhile, our observations might shed new light on the ecological roles of kojic acid, e.g., serving as chemical deterrents for host adaptation to marine niches, which, however, awaits further validation.

Identification and validation of tissue or ctDNA PTPRD phosphatase domain deleterious mutations as prognostic and predictive biomarkers for immune checkpoint inhibitors in non-squamous NSCLC.

BACKGROUND: With the revolutionary progress of immune checkpoint inhibitors (ICIs) achieved in non-small cell lung cancers (NSCLC), identifying patients benefiting from ICIs becomes critical and urgent. The associations of genomic alterations in protein tyrosine phosphatase receptor-type (PTPRs) and ICIs responses are unknown. METHODS: Whole-exome sequencing (WES) of 73 advanced NSCLC tumors sampled before anti-PD-(L)1 therapy was carried out with corresponding clinical data collected as a discovery cohort to find the associations of PTPR mutations and ICI responses. Three validation cohorts consolidated by 7 public cohorts of 1920 NSCLC patients with WES or target sequencing data of tumor tissue-derived DNA or circulating tumor DNA (ctDNA) and relevant clinical data were applied as validation cohorts. The lung adenocarcinoma (LUAD) cohort (n=586) in The Cancer Genome Atlas (TCGA) database was used for analyzing the potential anti-tumor immunologic mechanisms. RESULTS: With the highest mutation frequency among all PTPRs, PTPRD mutations in non-squamous NSCLC (ns-NSCLC) were linked to longer progression-free survivals (PFS, 324 vs 63 days, hazard ratio (HR)=0.36, p= 0.0152) and higher objective response rate (ORR, p=0.0099). In validation cohort 1 (n=377), ns-NSCLC patients with tissue PTPRD mutations had favorable PFS (9.10 vs 4.33 months, HR=0.62, p=0.0184) and ORR (p=0.013). In validation cohort 2 (n=406), ns-NSCLC patients with tissue PTPRD mutations had favorable overall survivals (OS, over 40 vs 11.94 months, HR=0.57, p=0.011). In validation cohort 3 (n=1137), ns-NSCLC patients with ctDNA PTPRD mutations had longer PFS (6.97 vs 2.73 months, HR=0.63, p=0.028) and higher ORR (p=0.047). Moreover, it was deleterious mutations in phosphatase domains (phosphatase-mut), rather than other mutations (other-mut), that were responsible of PTPRD's prediction efficiency. In addition, in validation cohort 3, ctDNA phosphatase-mut also functioned as a predictive biomarker helping identify patients benefiting more from ICIs than chemotherapy (interaction P for PFS=0.0506, for OS=0.04). Univariate and multivariate regression analysis revealed that phosphatase-mut was independent on PD-L1 expression and tumor mutation burden (TMB) to predict. In silico analysis based on TCGA LUAD cohort discovered enhanced anti-tumor immunity in phosphatase-mut patients. CONCLUSIONS: Tissue or ctDNA PTPRD phosphatase domain deleterious mutations might function as a both prognostic and predictive biomarker predicting clinical outcomes of ICIs in ns-NSCLC patients, independent on TMB or PD-L1 expression.

Genome mining of secondary metabolites from a marine-derived Aspergillus terreus B12.

Owing to the prominent capabilities of bioconversion and biosynthesis, A. terreus has become attractive in biotechnical and pharmaceutical industry. In this work, an Aspergillus strain with potential antibacterial activities, was isolated from sponge in South China Sea. Based on the morphological and phylogenetic analysis, the strain was identified as A. terreus B12. Via the Illumina MiSeq sequencing platform, the complete genome was obtained, showing a genetic richness of biosynthetic gene clusters (BGCs), which might underpin the metabolic plasticity and adaptive resilience for the strain. Genome mining identified 67 BGCs, among which, 6 gene clusters could allocate to known BGCs (100% identity), corresponding to diverse metabolites like clavaric acid, dihydroisoflavipucine/isoflavipucine, dimethylcoprogen, alternariol, aspterric acid, and pyranonigrin E. Moreover, a range of compounds was isolated from B12 fermentation, e.g., terrein, butyrolactone I, terretonin A&E, acoapetaline B, and epi-aszonalenins A. Of note, acoapetaline B and epi-aszonalenins A, which had been respectively reported in plants and A. novofumigatus but with scarce information, was unexpectedly obtained from this species for the first time. The genomic and metabolic heterogeneity observed in strain B12, should be at least partially attributed to the genetic variability and biochemical diversity of A. terreus, which could be an interesting issue open to future efforts.

Efficacy and Safety of First-Line Immunotherapy Combinations for Advanced NSCLC: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: A series of randomized controlled trials have investigated different first-line immunotherapy combinations, but the optimal combination strategy is yet to be established. METHODS: We performed a systematic review and Bayesian network meta-analysis by retrieving relevant literature from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences. We included published and gray sources of randomized clinical trials comparing immunotherapy combinations with other treatments as first-line treatments for patients with advanced NSCLC. This study was registered in the Prospective Register of Systematic Reviews (CRD42020210501) to ensure transparency. RESULTS: We analyzed a total of 16 studies involving 8278 patients and including 10 immunotherapy combinations. For patients without programmed death-ligand 1 (PD-L1) selection, pembrolizumab plus chemotherapy was found to be comparable with sintilimab plus chemotherapy in providing the best overall survival (OS) benefit (hazard ratio = 0.96, 95% confidence interval [CI]: 0.72-1.29). Furthermore, atezolizumab plus bevacizumab plus chemotherapy seemed to provide the best progression-free survival (hazard ratio = 0.45, 95% CI: 0.36-0.55) and the best objective response rate (OR = 0.23, 95% CI: 0.12-0.42). Subgroup analysis by PD-L1 suggested that nivolumab plus ipilimumab plus chemotherapy was associated with the best OS in patients with PD-L1 less than 1% and that pembrolizumab plus chemotherapy was associated with the best OS in patients with PD-L1 greater than or equal to 1%. Pembrolizumab and sintilimab were associated with relatively fewer grade greater than or equal to 3 adverse events when compared with other immunotherapies combined with chemotherapy. CONCLUSIONS: Our results suggest that antiprogrammed death-1 combinations are associated with potentially higher survival outcomes than anti-PD-L1 combinations with comparable safety profiles. Moreover, pem-chemo and nivo-ipi-chemo seem to be superior first-line immunotherapy combinations for patients with advanced NSCLC with positive and negative PD-L1 expression, respectively. Although atezo-beva-chemo treatment provided the best progression-free survival and objective response rate, the addition of chemotherapy to immunotherapy would increase the toxicity, especially when antiangiogenesis drugs are simultaneously added.

Genome sequence of Aspergillus flavus A7, a marine-derived fungus with antibacterial activity.

Due to the specific properties of the marine environment, marine microorganisms have exclusive physicochemical characteristics that are different from those of terrestrial microorganisms, which can produce various secondary metabolites (SMs) with considerable structural diversity and biological activity. In this study, three strains of coepiphytic Aspergillus with potential antibacterial activities, A7 (Aspergillus flavus), B27 (Aspergillus flavipes), and R12 (Aspergillus sydowii), were isolated from the South China Sea. Via the Illumina MiSeq sequencing platform, the genomes of the three strains were sequenced, and genome comparison showed the highest diversity of the biosynthetic gene clusters (BGCs) in A7. In addition, a comparison of physiological and genomic characteristics between A7 and other A. flavus strains demonstrated the superior environmental adaptability of A7, which is apparently consistent with the genetic richness of BGCs. By assigning reads to known BGCs, putative BGCs were allocated in A7 that corresponded to various SMs, including naphthopyrone, pyranonigrin E, and cyclopiazonic acids. Based on gene homology analysis, we surmise that a region is involved in the biosynthesis of ustiloxin-like RiPPs, a less thoroughly studied SM in fungi. Our results provide genetic information for the investigation of marine Aspergillus spp., which may help to elucidate their chemical diversity and adaptive strategies.

Safety, Antitumor Activity, and Pharmacokinetics of Toripalimab, a Programmed Cell Death 1 Inhibitor, in Patients With Advanced Non-Small Cell Lung Cancer: A Phase 1 Trial.

Importance: Programmed cell death 1 (PD-1) antibodies have shown substantial survival benefit in patients with advanced non-small cell lung cancer (NSCLC). Toripalimab is a promising and practicable PD-1 antibody; however, its performance in NSCLC has not been established. Objectives: To assess the safety, antitumor activity, and pharmacokinetics of toripalimab in patients with advanced NSCLC and to evaluate the utility of JS311, a novel PD ligand 1 (PD-L1) immunohistochemistry (IHC) assay. Design, Setting, and Participants: This single-arm open-label phase 1 trial enrolled 41 patients with advanced NSCLC that had progressed after at least 3 lines of therapy between September 21, 2017, and June 5, 2018, with a median (interquartile range) follow-up of 14.9 (3.2-22.5) months and included a cohort study comparing JS311 with other PD-L1 IHC assays that included 280 NSCLC specimens collected from January 1, 2016, to May 21, 2018. Data collection was conducted from September 21, 2017, to September 27, 2019, and analysis was conducted from September 27, 2019, to December 30, 2019. Exposure: Enrolled patients were administered a single dose of toripalimab, under 2 manufacturing processes and scales (200 L and 500 L), for safety and pharmacokinetic analysis within 28 days, followed by subsequent multidose infusions every 2 weeks. PD-L1 expression was determined by IHC with JS311, comparing its results with results from 22C3, 28-8, and SP263 simultaneously. Main Outcomes and Measures: Progression-free survival (PFS) and overall survival (OS), estimated by Kaplan-Meier curves, and continuous variables compared by t test or Mann-Whitney test. Correlations between PD-L1 IHC antibodies were evaluated by Spearman correlation test. Results: A total of 41 patients (29 [70.7%] men) with a median (interquartile range) age of 59 (53 to 63) years who experienced disease progression following chemotherapy were included. The most common treatment-related adverse events were rash (6 [14.6%]), increased amylase level (5 [12.2%]), and increased aspartate aminotransferase level (5 [12.2%]). In 35 patients included in the pharmacokinetic analysis, drug exposure and area under curve after 1 dose was similar under both manufacturing processes and scales (mean [SD] for 200-L group: 12 465.28 [4128.17] hour × µg/mL; for 500-L group: 12 331.42 [2472.58] hour × µg/ml). In 28 patients included in the response and survival analysis, the median PFS and OS were 2.8 (95% CI, 2.7 to 4.6) months and 13.8 months (95% CI, 10.0 months to not reached), respectively. Stratified by PD-L1 tumor proportion score of at least 50%, 1% to 49%, and less 1%, median PFS rates were 11.2 months (95% CI, 2.3 months to not evaluable), 2.3 (95% CI, 1.7 to 2.7) months, and 2.8 (95% CI, 2.7 to 4.6) months, respectively. A total of 4 anti-PD-L1 IHC antibodies were compared during PD-L1 staining, using 280 NSCLC specimens. The consistency rates between the 4 antibodies were 80.8% to 89.5% (ρ, 0.619 to 0.790) and 93.3% to 95.5% (ρ, 0.691 to 0.773), with PD-L1 tumor proportion scores of 1% and 50% as cut points, respectively. Conclusions and Relevance: In this study, toripalimab exhibited encouraging antitumor activity and manageable safety profiles among patients with heavily treated NSCLC. The novel PD-L1 IHC antibody JS311 was highly consistent with previously verified PD-L1 IHC assays.

Clinical course and characteristics of patients with coronavirus disease 2019 in Wuhan, China: a single-centered, retrospective, observational study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) is the virus responsible for the coronavirus disease 2019(COVID-19) pandemic. Despite the extensive studies aiming to understand the pathology of COVID-19, the clinicopathological characteristics and risk factors associated with COVID-19 remain mostly unclear. In this study, we assessed the clinical course and features of COVID-19 patients. FINDINGS: There were 59 patients (54.1%) that had no fever. One-hundred(91.7%) patients required oxygen therapy, which improved percutaneous oxygen saturation (SpO2). Seventy-two (66.1%) patients aged over 60; these patients were more likely to develop respiratory symptoms. Only 13(11.9%) patients were positive for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleic acid, and computed tomography (CT) findings. We found significant differences in age, respiratory symptoms, and heart rates between patients with and without underlying conditions. CONCLUSIONS: Our findings suggest that oxygen plays an important role in the treatment of COVID-19 patients and that age and underlying diseases are significant risk factors for COVID-19. Most COVID-19 patients have no fever, and CT provides higher detection rates than antibody- and nucleic acid-based detection methods. METHODS: We analyzed data from 109 confirmed COVID-19 cases. We compared the clinicopathological characteristic of patients stratified according to age and underlying diseases, as well as assessed the detection rates of different diagnostic methods.

Berberine Reverses Doxorubicin Resistance by Inhibiting Autophagy Through the PTEN/Akt/mTOR Signaling Pathway in Breast Cancer.

PURPOSE: Berberine (BBR), a traditional Chinese medicine, has been shown effects on inhibiting cancer development. Autophagy-mediated resistance plays an important role in cancer progression; therefore, regulation of autophagy is a novel therapeutic strategy for cancer treatment. However, effects of BBR on autophagy-mediated resistance have not been reported. METHODS: MCF-7 breast cancer cells and the doxorubicin (ADR)-resistant MCF-7 cells (MCF-7/ADR) were used for analyses. Western blotting was conducted to evaluate protein expression; MTT, colony formation, and EdU assays were conducted to assess cell proliferation; transmission electron microscopy was used to monitor autophagy levels; and a xenograft tumor model was established to assess the effects of BBR on reversing doxorubicin resistance. RESULTS: We confirmed that BBR, recently identified as a suppressor of autophagy, inhibits autophagosome formation in MCF-7/ADR cells. Treatment with BBR blocked the accumulation of the autophagy-associated protein LC3II, resulting in cellular accumulation of p62, reduced cell proliferation, and reversal of doxorubicin resistance. Mechanistically, we found that BBR inhibited autophagy by modulating the PTEN/Akt/mTOR signaling pathway. In vivo, our study showed that BBR exerts clear anti-tumor effects. CONCLUSION: The results of this study suggest that BBR reverses doxorubicin resistance in breast cancer cells by inhibiting autophagy. This finding highlights the potential clinical application of BBR in the treatment of breast cancer.

The Anti-Cancer Mechanisms of Berberine: A Review.

Berberine (BBR) has been extensively studied in vivo and vitro experiments. BBR inhibits cell proliferation by regulating cell cycle and cell autophagy, and promoting cell apoptosis. BBR also inhibits cell invasion and metastasis by suppressing EMT and down-regulating the expression of metastasis-related proteins and signaling pathways. In addition, BBR inhibits cell proliferation by interacting with microRNAs and suppressing telomerase activity. BBR exerts its anti-inflammation and antioxidant properties, and also regulates tumor microenvironment. This review emphasized that BBR as a potential anti-inflammation and antioxidant agent, also as an effective immunomodulator, is expected to be widely used in clinic for cancer therapy.

Cystatin SN Affects Cell Proliferation by Regulating the ERα/PI3K/AKT/ERα Loopback Pathway in Breast Cancer.

BACKGROUND: Cystatin SN (CST1) has been reported to act as an oncogene in cancers, but its underlying mechanism remains unclear. METHODS: We performed Western blotting analyses to observe protein expression and conducted transwell invasion, wound healing, and colony formation assays to assess cell invasion, migration, and proliferation, respectively. We also performed cell cycle analyses by flow cytometry to determine the role of CST1 in the cell cycle. In vivo experiments used subcutaneous tumor models in BALB/c-nu athymic female mice to evaluate the effect of CST1 on tumor growth. RESULTS: Western blotting analyses showed that CST1 was upregulated in ER+ breast cancer cells such as MCF7, T47D, and BT474. CST1 knockdown led to slower cell growth and inhibited the G1 to S phase transition in ER+ breast cancer cells. In vivo experiments showed that CST1 deletion inhibited tumor growth, and led to decreased expression of estrogen receptor α (ERα) and p-AKT. In vitro experiments showed that the over-expression of CST1 led to the upregulation of ERα, and inhibition of CST1 inhibited the expression of ERα. Western blotting analyses showed that CST1 regulated the activity of the PI3K/AKT signaling pathway in breast cancer cells. We confirmed that CST1 acted as an oncogene in ER+ breast cancer by regulating the ERα/PI3K/AKT/ERα loopback pathway. CONCLUSION: CST1 acts as an oncogene in ER+ breast cancer, and CST1 contributes to cancer development by regulating the ERα/PI3K/AKT/ERα loopback pathway in ER+ breast cancer. Our findings indicate that CST1 could be a significant therapeutic target for ER+ breast cancer patients. Our discovery should inspire further studies on the role of CST1 in cancers.