Discovery of Natural Ah Receptor Antagonists from Salvia miltiorrhiza Bunge and Synthesis of Analogs for Tumor Immunotherapy.

IDO/TDO/Kyn/AhR signaling plays a crucial role in regulating innate and adaptive immunity, and targeting Ah receptor (AhR) inhibition can potentially redirect immune cells toward an antitumoral phenotype. Therefore, AhR is an attractive drug target for novel small molecule cancer immunotherapies. In this study, natural products tanshinolic A-D (1-4), the first adducts composed of ortho-naphthoquinone-type tanshinone and phenolic acid featuring a unique 1,4-benzodioxan hemiacetal structure, were isolated and characterized from the roots of Salvia miltiorrhiza Bunge. Luciferase reporter gene assay revealed that these adducts exhibited significant AhR inhibitory activity. A linear strategy was developed to construct a cis-3,4-disubstituted 1,4-benzodioxan hemiacetal structure. Encouragingly, in both in vitro and in vivo experiments, (±)-13e demonstrated the ability to inhibit tumor cell proliferation, promote INF-γ secretion in CD8+ T cells, and inhibit PD-1/PD-L1 signal transduction, which could exert tumor inhibition properties by inhibiting AhR activity, positioning it as a promising candidate for tumor immunotherapy.

Construction of a prognostic 6-gene signature for breast cancer based on multi-omics and single-cell data.

Background: Breast cancer (BC) is one of the females' most common malignant tumors there are large individual differences in its prognosis. We intended to uncover novel useful genetic biomarkers and a risk signature for BC to aid determining clinical strategies. Methods: A combined significance (p combined) was calculated for each gene by Fisher's method based on the RNA-seq, CNV, and DNA methylation data from TCGA-BRCA. Genes with a p combined< 0.01 were subjected to univariate cox and Lasso regression, whereby an RS signature was established. The predicted performance of the RS signature would be assessed in GSE7390 and GSE20685, and emphatically analyzed in triple-negative breast cancer (TNBC) patients, while the expression of immune checkpoints and drug sensitivity were also examined. GSE176078, a single-cell dataset, was used to validate the differences in cellular composition in tumors between TNBC patients with different RS. Results: The RS signature consisted of C15orf52, C1orf228, CEL, FUZ, PAK6, and SIRPG showed good performance. It could distinguish the prognosis of patients well, even stratified by disease stages or subtypes and also showed a stronger predictive ability than traditional clinical indicators. The down-regulated expressions of many immune checkpoints, while the decreased sensitivity of many antitumor drugs was observed in TNBC patients with higher RS. The overall cells and lymphocytes composition differed between patients with different RS, which could facilitate a more personalized treatment. Conclusion: The six genes RS signature established based on multi-omics data exhibited well performance in predicting the prognosis of BC patients, regardless of disease stages or subtypes. Contributing to a more personalized treatment, our signature might benefit the outcome of BC patients.

Role of aggressive locoregional surgery in treatment strategies for ipsilateral supraclavicular lymph node metastasis of breast cancer: a real-world cohort study.

Background: Breast cancer patients with synchronous ipsilateral supraclavicular lymph node metastases (ISLNM) have unfavorable prognoses. The role of supraclavicular lymph node dissection (SLND) as a surgical intervention in the treatment of this condition remains controversial. In this study, we aimed to evaluate the prognostic factors associated with breast cancer with ISLNM and to assess the potential impact of aggressive locoregional surgical management on patient outcomes. Methods: We conducted a retrospective analysis of 250 breast cancer patients with ISLNM who were treated with curative intent at our institution between 2000 and 2020. The cohort was stratified into groups based on the extent of axillary surgery. The first group, comprising 185 patients, underwent level I/II axillary dissection. The second group, consisting of 65 patients, underwent aggressive locoregional surgery, including levels I/II/III (infraclavicular) dissection in 37 patients and levels I/II/III + SLND in 28 patients. Our study evaluated overall survival (OS) and disease-free survival (DFS) as primary endpoints, and locoregional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS) as secondary endpoints. Results: The median follow-up time among all patients was 5.92 years (1.05-15.36 years). The 5-year OS rate was 71.89%, while the DFS rate, LRRFS rate, and DMFS rates were 59.25%, 66.38%, and 64.98%, respectively. A significant difference in OS, DFS, LRRFS, and DMFS was observed between the second group and the first group (p < 0.01). No beneficial impact on recurrence, metastasis, or survival outcomes was observed in the levels I/II/III + SLND group compared to the levels I/II/III dissection group. Multivariate logistic regression analysis revealed that levels I/II/III ± SLND surgery and T stage were associated with OS (p = 0.006 and p = 0.026), while levels I/II/III ± SLND surgery, ER+/HER2-, and histologic grade were associated with DFS (p = 0.032, p = 0.001, p = 0.032). Conclusion: Breast cancer with ISLNM may be considered a locoregional disease, requiring a combination of systemic and local therapies. Aggressive locoregional surgery has been shown to positively impact recurrence, metastasis, and survival outcomes. This approach may provide improved management of the ISLNM for breast cancer patients.

LETMD1, a target of KLF4, hinders endothelial inflammation and pyroptosis: A protective mechanism in the pathogenesis of atherosclerosis.

Atherosclerosis (AS), a metabolic disorder, is usually caused by chronic inflammation. LETM1 Domain-Containing Protein 1 (LETMD1) is a mitochondrial outer membrane protein required for mitochondrial structure. This study aims to evaluate the functional role of LETMD1 in endothelial pathogenesis of AS. Oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cells (HUVECs) and high-fat diet apolipoprotein E-deficient (ApoE-/-) mice were used to establish in vitro and in vivo models, respectively. Recombinant adenovirus vectors were constructed to investigate the role of LETMD1 in AS. mRNA sequencing was used to explore the effect of LETMD1 overexpression on gene expression in ox-LDL-induced HUVECs. A dual-luciferase reporting assay and chromatin immunoprecipitation (ChIP)-PCR were further conducted to verify the relationship between KLF4 and LETMD1. Results showed that LETMD1 was highly expressed in the aortas of atherosclerotic animals. LETMD1 overexpression reduced the expression of inflammatory factors, pyroptosis, ROS production, and NF-κB activation in ox-LDL-induced HUVECs, whereas LETMD1 knockdown had the opposite impact. LETMD1 overexpression was involved in regulating gene expression in ox-LDL-induced HUVECs. Overexpression of LETMD1 in mice reduced serum lipid levels as well as atherosclerotic lesions in the aortic roots. Furthermore, LETMD1 overexpression suppressed inflammatory reactions, cell pyroptosis, nuclear p65 protein level, cell apoptosis, and ROS generation in the aortas of AS mice. KLF4 (Krüppel-like factor 4) was found to be the transcriptional regulator of LETMD1. In conclusion, LETMD1, a target of KLF4, hinders endothelial inflammation and pyroptosis, which is a mechanism inhibiting the development of atherosclerosis.

Identifying clinicopathological risk factors for regional lymph node metastasis in Chinese patients with T1 breast cancer: a population-based study.

Objectives: To analyze clinicopathological risk factors and regular pattern of regional lymph node metastasis (LNM) in Chinese patients with T1 breast cancer and the effect on overall survival (OS) and disease-free survival (DFS). Materials and methods: Between 1999 and 2020, breast cancer patients meeting inclusion criteria of unilateral, no distant metastatic site, and T1 invasive ductal carcinoma were reviewed. Clinical pathology characteristics were retrieved from medical records. Survival analysis was performed using Kaplan-Meier methods and an adjusted Cox proportional hazards model. Results: We enrolled 11,407 eligible patients as a discovery cohort to explore risk factors for LNM and 3484 patients with stage T1N0 as a survival analysis cohort to identify the effect of those risk factors on OS and DFS. Compared with patients with N- status, patients with N+ status had a younger age, larger tumor size, higher Ki67 level, higher grade, higher HR+ and HER2+ percentages, and higher luminal B and HER2-positive subtype percentages. Logistic regression indicated that age was a protective factor and tumor size/higher grade/HR+ and HER2+ risk factors for LNM. Compared with limited LNM (N1) patients, extensive LNM (N2/3) patients had larger tumor sizes, higher Ki67 levels, higher grades, higher HR- and HER2+ percentages, and lower luminal A subtype percentages. Logistic regression indicated that HR+ was a protective factor and tumor size/higher grade/HER2+ risk factors for extensive LNM. Kaplan-Meier analysis indicated that grade was a predictor of both OS and DFS; HR was a predictor of OS but not DFS. Multivariate survival analysis using the Cox regression model demonstrated age and Ki67 level to be predictors of OS and grade and HER2 status of DFS in stage T1N0 patients. Conclusion: In T1 breast cancer patients, there were several differences between N- and N+ patients, limited LNM and extensive LNM patients. Besides, HR+ plays a dual role in regional LNM. In patients without LNM, age and Ki67 level are predictors of OS, and grade and HER2 are predictors of DFS.

KPNA2 Silencing, Regulated by E3 Ubiquitin Ligase FBXW7, Alleviates Endothelial Dysfunction and Inflammation Through Inhibiting the Nuclear Translocation of p65 and IRF3: A Possible Therapeutic Approach for Atherosclerosis.

Atherosclerosis (AS), characterized by a maladaptive inflammatory response, is one of the most common causes of death among the elderly. Karyopherin subunit alpha 2 (KPNA2), a member of the nuclear transport protein family, has been reported to play a pro-inflammatory role in various pathological processes by regulating the nuclear translocation of pro-inflammatory transcription factors. However, the function of KPNA2 in AS remains unknown. ApoE-/- mice were fed high-fat diets for 12 weeks to establish an AS mice model. Human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS) to establish an AS cell model. We found that KPNA2 was upregulated in the aortic roots of atherosclerotic mice and LPS-stimulated cells. KPNA2 knockdown inhibited LPS-induced secretion of pro-inflammatory factors and monocyte-endothelial adhesion in HUVECs, whereas KPNA2 overexpression exerted the opposite effects. p65 and interferon regulatory factor 3 (IRF3), the transcription factors known to regulate the transcription of pro-inflammatory genes, interacted with KPNA2, and their nuclear translocations were blocked following KPNA2 silencing. Furthermore, we found that KPNA2 protein level was decreased by E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBXW7), which was downregulated in the atherosclerotic mice. FBXW7 overexpression induced ubiquitination with subsequent proteasomal degradation of KPNA2. Meanwhile, the effects of KPNA2 deficiency on atherosclerotic lesions were further confirmed by in vivo experiments. Taken together, our study indicates that KPNA2 downregulation, regulated by FBXW7, may alleviate endothelial dysfunction and related inflammation in the progression of AS by suppressing the nuclear translocation of p65 and IRF3.

Working from anywhere: yin-yang cognition paradoxes of knowledge sharing and hiding for developing careers in China.

Digital technology coupled with the quarantines caused by the COVID-19 pandemic has made working from anywhere (WFA)-a modern form of remote working-a widespread phenomenon. Given that WFA brings new career challenges to and engenders paradoxes of knowledge exchange among employees, this research aims to examine how the interactions of remote work time (RWT), knowledge sharing (KS), and knowledge hiding (KH) affect career development (CD) from a culturally grounded paradoxical framing of yin-yang harmonizing. The data were collected from Chinese manufacturing employees, and a moderated hierarchical regression analysis was used to examine the hypotheses. The results show an inverted U-shaped relationship between RWT and CD. The interaction of KS and KH is significantly related to CD, and the inverted U-shaped RWT-CD relationship is moderated by the interaction term, in which RWT exerts the most substantial positive impact on CD when KS is high and KH is low. This study offers valuable implications for coping with perplexing employment relationships and increasing career challenges in volatile work environments. The primary originality is to adopt a novel cognitive frame of yin-yang harmonizing to examine the nonlinear effect of remote working and the symbiotic impact of KS and KH on CD, which not only enriches the understanding of flexible work arrangements in the digital economy but also provides novel insights into the interconnectedness of KS and KH and their interacting effects on HRM-related outcomes.

Microbiome and its implications in oncogenesis: a Mendelian randomization perspective.

The human microbiome, an intricate ecological network, has garnered significant attention due to its potential implications in oncogenesis. This paper delves into the multifaceted relationships between the microbiome, its metabolites, and cancer development, emphasizing the human intestinal tract as the primary microbial habitat. Highlighting the potential causative associations between microbial disturbances and cancer progression, we underscore the role of specific bacterial strains in various cancers, such as stomach and colorectal cancer. Traditional causality assessment methods, like randomized controlled trials (RCTs), have limitations. Therefore, we advocate using Mendelian Randomization (MR) as a powerful alternative to study causal relationships, leveraging genetic variants as instrumental variables. With the proliferation of genome-wide association studies, MR harnesses genetic variations to infer causality, which is especially beneficial when addressing confounders like diet and lifestyle that can skew microbial research. We systematically review MR's application in understanding the microbiome-cancer nexus, emphasizing its strengths and challenges. While MR offers a unique perspective on causality, it faces hurdles like horizontal pleiotropy and weak instrumental variable bias. Integrating MR with multi-omics data, encompassing genomics, transcriptomics, proteomics, and metabolomics, holds promise for future research, potentially heralding groundbreaking discoveries in microbiology and genetics. This comprehensive review underscores the critical role of the human microbiome in oncogenesis and champions MR as an indispensable tool for advancing our understanding in this domain.

Promotion strategy for online healthcare platform during the COVID-19 pandemic: Evidence from Spring Rain Doctor in China.

Introduction: Online healthcare platform (OHP) is a new form of medical treatment that solves the problems of an unbalanced distribution of medical resources in China. Especially during the COVID-19 pandemic, OHP has greatly reduced the medical pressure of the hospital and the risk of cross-infection. Methods: Based on self-determination theory (SDT) (Ryan and Deci, 2000), privacy calculus theory (PCT) (Culnan, 1999) and perceived value theory (PVT) (Choi, 2004), this study uses evolutionary game theory to analyze behavioral strategies and their dynamic evolution in the promotion of OHP. Moreover, we conduct numerical simulations with the help of program compilation. Results: The results demonstrate that (1) both the qualification inspection of doctors and the investment in information protection influence doctors' participation in and patients' usage of OHP; (2) both the initial probabilities of doctor participation and patient usage influence the multi-game results; (3) the trend of doctors joining OHP is affected by registration cost, time cost, and reputation loss; and (4) the trend of patients using online healthcare is mainly decided by the cost. Conclusion: This study takes the Spring Rain Doctor as an example to verify the game results. To further popularize online medical treatment among patients, the platform should attach importance to the inspection of doctors and the protection of privacy information and strengthen its publicity in remote places.

Antibacterial Effect of Eugenol on Shigella flexneri and Its Mechanism.

Shigella flexneri (Sh. flexneri), which can be found in food and the environment, is a widespread food-borne pathogen that causes human diarrhea termed "shigellosis". In this study, eugenol, a natural active substance, was investigated for its antibacterial activity against Sh. flexneri. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of eugenol against Sh. flexneri ATCC 12022 was 0.5 and 0.8 mg/mL. The growth curves and inhibitory effect in LB broth, PBS, vegetable juice, and minced pork showed that eugenol had a good activity against Sh. flexneri. Research findings indicated the superoxide dismutase activity of Sh. flexneri was inhibited after eugenol treatment, resulting in concentrations of intracellular reactive oxygen species and an increase in malondialdehyde. The flow cytometry analysis and field emission scanning electron microscopy results revealed obvious damage to cell membrane integrity and changes in the morphology of Sh. flexneri. In addition, the intracellular ATP concentration leaked from 0.5 µM to below 0.05 µM and the membrane potential showed a concentration-dependent depolarization after eugenol treatment. In summary, eugenol exerted strong antibacterial activity and has the potential to control Sh. flexneri in the food industry.

A review of studies on omitting surgery after neoadjuvant chemotherapy in breast cancer.

The advancement in systemic neoadjuvant therapy has significantly increased the pathological complete response (pCR) rate in breast cancer. As surgeries inevitably affect patients physically and psychologically and the accuracy of pCR prediction and diagnosis by minimal invasive biopsy is improving, the necessity of surgery in neoadjuvant chemotherapy (NAC) patients who achieve pCR is under debate. Thus, we conducted a literature review of studies on the selective omission of breast surgery after NAC for breast cancer patients. We summarized the existing predictive models and technologies to predict and diagnose pCR after NAC. Our research indicates that, for nearly half a century, the extent of surgery on both breast and axillary lymph nodes is decreasing, while more precise systematic treatments are increasing. NAC has advanced significantly and its pCR rates have improved, so surgery may be omitted in certain patients. However, accurately predicting pCR after NAC is still a challenge. We also described the design for a randomized clinical trial and the potential problems of omitting surgical treatment after NAC. In summary, the decrease in breast cancer surgery is an unavoidable trend, and more high-quality clinical trials need to be conducted.

How Do Government Policies Promote Green Housing Diffusion in China? A Complex Network Game Context.

To reduce energy consumption and environmental pollution in the construction industry, many countries have focused on the development of green housing (GH), which is a type of green building for residential use. In China, the local governments have introduced various incentive policies to encourage the development of GH; however, its scale is still small and unevenly distributed. This implies a necessity to optimize the policies that apply to the GH incentive. To promote GH diffusion, we built an evolutionary game model on a complex network to analyze the impacts of government policies on GH pricing and demand and the profits of real estate enterprises developing GH. By implementing simulations, we further explored the incentive effect and operational mechanism of the government policies. The results show that the subsidy policy, the preferential policy for GH, and the restriction policy for ordinary housing can effectively promote the diffusion of GH to 0.6752, 0.506, and 0.5137 respectively. Meanwhile, the incentive effect of the enterprise subsidy policy and GH preferential policy gradually decreases with the increase in policy strength. In terms of the demand side, the consumer subsidy policy could promote GH diffusion to 0.7097. If the subsidy is below 120 CNY/m2, the effect of the consumer subsidy policy is less powerful than that of the enterprises subsidy policy; conversely, the former is slightly more effective than the latter. The outcome of the study has managerial implications on governmental decision-making, especially on the strategy design of incentive policies for GH.

DrABC: deep learning accurately predicts germline pathogenic mutation status in breast cancer patients based on phenotype data.

BACKGROUND: Identifying breast cancer patients with DNA repair pathway-related germline pathogenic variants (GPVs) is important for effectively employing systemic treatment strategies and risk-reducing interventions. However, current criteria and risk prediction models for prioritizing genetic testing among breast cancer patients do not meet the demands of clinical practice due to insufficient accuracy. METHODS: The study population comprised 3041 breast cancer patients enrolled from seven hospitals between October 2017 and 11 August 2019, who underwent germline genetic testing of 50 cancer predisposition genes (CPGs). Associations among GPVs in different CPGs and endophenotypes were evaluated using a case-control analysis. A phenotype-based GPV risk prediction model named DNA-repair Associated Breast Cancer (DrABC) was developed based on hierarchical neural network architecture and validated in an independent multicenter cohort. The predictive performance of DrABC was compared with currently used models including BRCAPRO, BOADICEA, Myriad, PENN II, and the NCCN criteria. RESULTS: In total, 332 (11.3%) patients harbored GPVs in CPGs, including 134 (4.6%) in BRCA2, 131 (4.5%) in BRCA1, 33 (1.1%) in PALB2, and 37 (1.3%) in other CPGs. GPVs in CPGs were associated with distinct endophenotypes including the age at diagnosis, cancer history, family cancer history, and pathological characteristics. We developed a DrABC model to predict the risk of GPV carrier status in BRCA1/2 and other important CPGs. In predicting GPVs in BRCA1/2, the performance of DrABC (AUC = 0.79 [95% CI, 0.74-0.85], sensitivity = 82.1%, specificity = 63.1% in the independent validation cohort) was better than that of previous models (AUC range = 0.57-0.70). In predicting GPVs in any CPG, DrABC (AUC = 0.74 [95% CI, 0.69-0.79], sensitivity = 83.8%, specificity = 51.3% in the independent validation cohort) was also superior to previous models in their current versions (AUC range = 0.55-0.65). After training these previous models with the Chinese-specific dataset, DrABC still outperformed all other methods except for BOADICEA, which was the only previous model with the inclusion of pathological features. The DrABC model also showed higher sensitivity and specificity than the NCCN criteria in the multi-center validation cohort (83.8% and 51.3% vs. 78.8% and 31.2%, respectively, in predicting GPVs in any CPG). The DrABC model implementation is available online at http://gifts.bio-data.cn/ . CONCLUSIONS: By considering the distinct endophenotypes associated with different CPGs in breast cancer patients, a phenotype-driven prediction model based on hierarchical neural network architecture was created for identification of hereditary breast cancer. The model achieved superior performance in identifying GPV carriers among Chinese breast cancer patients.

Overexpression of IncRNA SAMMSON Promotes Triple-Negative Breast Cancer Cell Proliferation by Interacting with p53.

This study was carried out to explore the role of the long noncoding RNA (lncRNA) SAMMSON in triple-negative breast cancer (TNBC). The research patients in this study included 68 TNBC patients. Cell Counting Kitcck-8 were utilized to determine cell proliferation abilities, respectively. Proteins and mRNAs were estimated by western blot and Methylation-specific polymerase chain reaction, respectively. We found that SAMMSON was upregulated, while p53 was downregulated in cancer (TNBC) tissues than in non-cancer tissues of TNBC patients. SAMMSON expression levels in TNBC tissues increased with the increase of clinical stages of TNBC patients. SAMMSON and p53 were inversely correlated in TNBC tissues. In TNBC cells, SAMMSON overexpression decreased p53 expression, while p53 overexpression failed to affect SAMMSON expression. In addition, SAMMSON overexpression increased TNBC cell proliferation, while p53 overexpression decreased the proliferation rates of TNBC cells. In addition, p53 overexpression attenuated the effects of SAMMSON overexpression. Therefore, overexpression of SAMMSON could promote TNBC cell proliferation by interacting with p53.

The Regime of Rural Ecotourism Stakeholders in Poverty-Stricken Areas of China: Implications for Rural Revitalization.

The rural ecotourism system can be defined as a complex association of stakeholders. This system of rural ecotourism in relatively poor areas of China can influence rural revitalization strategies. The purpose of this study is to plan a rural ecotourism system among the tourism enterprises, local residents and government by using an evolutionary game theory. Based on the theoretical analysis, an evolution game model for the three stakeholders is developed and the evolution process of strategies is described by replicator dynamic equations. Then, a simulation method and case was used to analyze the stability of interactions among the stakeholders and determine an equilibrium solution in the finite rationality case. Finally, specific control strategies were proposed to suppress instability and an ideal evolutionarily stable strategy was obtained. This provides a theoretical basis for achieving a win-win situation among the three parties. The results of this study suggest appropriate roles for stakeholders in the rural ecotourism project that provide management implications for rural tourism activities, local economy and rural revitalization.

Contralateral risk-reducing local therapy in breast cancer patients with BRCA1/2 mutations: systemic review and meta-analysis.

BACKGROUND: Unilateral breast cancer (UBC) patients with germline pathogenic BRCA1/2 variants have a higher risk of developing contralateral breast cancer (CBC) and need contralateral risk-reducing local treatments, including contralateral risk-reducing mastectomy (CRRM) and prophylactic irradiation (CPI). The aim of our study was to systematically explore the efficacy of CRRM and CPI in reducing CBC risk and increasing survival. METHODS: A search was done, and eligible randomized trials and cohort studies should include and compare UBC patients with germline pathogenic BRCA1/2 variants who have and have not received contralateral risk-reducing local treatment. Random-effects meta-analysis was used in this study. Primary outcomes of the studies included overall survival (OS) and the incidence of contralateral breast cancer (CBC), and secondary outcomes included breast cancer-specific survival (BCSS). RESULTS: A total of five studies with 1769 UBC patients with germline pathogenic BRCA1/2 variants were enrolled in our meta-analysis. CRRM was correlated with a lower risk of CBC in UBC patients with germline pathogenic BRCA1/2 variants (summary RR = 0.07; 95%CI 0.03-0.13, I2 = 3%), a significantly increased OS (summary RR, 1.15; 95%CI 1.04-1.26, I2 = 26%) and a significantly increased BCSS (summary RR, 1.18; 95%CI 1.07-1.31, I2 = 64%) compared with surveillance. CPI also decreased the risk of CBC (RR 0.02; 95%CI 0.05-0.88) but did not significantly improve OS (RR 0.97; 95%CI 0.90-1.05) and BCSS (RR 0.97; 95%CI 0.90-1.05) compared with surveillance. CONCLUSIONS: CRRM reduces CBC risk and increases OS and BCSS in UBC patients with germline pathogenic BRCA1/2 variants, and could be offered as a risk-reducing local treatment. For those who oppose CRRM, CPI could be offered for CBC-risk reduction, while its survival benefit is still uncertain.

Effect of MiR-210 on the Chemosensitivity of Breast Cancer by Regulating JAK-STAT Signaling Pathway.

The study is aimed at exploring the effect of microribonucleic acid- (miR-) 210 on the chemosensitivity of breast cancer and its potential molecular mechanism. Cell Counting Kit-8 (CCK-8) was applied to detect the half maximal inhibitory concentration (IC50) of cisplatin (DDP) on cell, and quantitative polymerase chain reaction (qPCR) was carried out to measure the relative expression level of miR-210. The IC50 value of DDP on cells was detected via CCK-8 after downregulating the expression of miR-210 in MCF-7/DDP cells. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) confirmed the effect of themiR-210 downregulation on the apoptosis of drug-resistant MCF-7/DDP cells. Besides, the impacts of the miR-210 downregulation on apoptosis-related proteins and Janus-activated kinase- (JAK-) signal transducer and activator of transcription (STAT) signaling pathway-related proteins were examined by Western blotting. The interaction between miR-210 and the target protein was detected through luciferase activity assay, qPCR, and Western blotting. Drug-resistant MCF-7/DDP cells had significantly stronger resistance to DDP and a remarkably higher expression level of miR-210 than control parental MCF-7 cells (p < 0.05). After the downregulation of the miR-210 expression, MCF-7/DDP cells had markedly reduced resistance but obviously increased sensitivity to DDP (p < 0.05). MiR-210 downregulation increased the apoptosis of MCF-7/DDP cells (p < 0.05). In addition, after miR-210 was knocked down, the expression level of b-cell lymphoma 2 (Bcl-2) was decreased, while the expression levels of Bcl-2-associated X protein (Bax) and cysteinyl aspartate-specific proteinase-3 (caspase-3) were increased. Besides, miR-210 was able to suppress the expression of protein inhibitor of the activated STAT 4 (PIAS4) gene by directly targeting its 3' untranslated region (3'UTR). The expression of miR-210 has a correlation with chemoresistance of breast cancer MCF-7 cells. MiR-210 regulates the JAK-STAT signal transduction pathway by targeting PIAS4, thus exerting an effect on breast cancer chemosensitivity.

The Distinct Performances of Ultrasound, Mammograms, and MRI in Detecting Breast Cancer in Patients With Germline Pathogenic Variants in Cancer Predisposition Genes.

A proportion of up to 10% of breast cancer resulted from hereditary germline pathogenic variants (GPVs) in cancer predisposition genes (CPGs), which been demonstrated distinct clinical features and imaging manifestations. However, the performance of imaging modalities for breast cancer surveillance in CPG mutation-carriers is still unclear, especially in Asian women. A population of 3002 breast cancer patients who received germline genetic testing of CPGs was enrolled from three hospitals in China. In total, 343 (11.6%) patients were found to harbor GPVs in CPGs, including 137 (4.6%) in BRCA1 and 135 (4.6%) in BRCA2. We compared the performances of ultrasound, mammograms, MRI, and the combining strategies in CPG mutation carriers and non-carriers. As a result, the ultrasound showed a higher detection rate compared with mammograms regardless of the mutation status. However, its detection rate was lower in CPG mutation carriers than in non-carriers (93.2% vs 98.0%, P=2.1×10-4), especially in the BRCA1 mutation carriers (90.9% vs 98.0%, P=2.0×10-4). MRI presented the highest sensitivity (98.5%) and the lowest underestimation rate (14.5%) in CPG mutation carriers among ultrasound, mammograms, and their combination. Supplemental ultrasound or mammograms would add no significant value to MRI for detecting breast cancer (P>0.05). In multivariate logistic regression analysis, the family or personal cancer history could not replace the mutation status as the impact factor for the false-negative result and underestimation. In summary, clinicians and radiologists should be aware of the atypical imaging presentation of breast cancer in patients with GPVs in CPGs.

Effects of Ulinastatin on Proliferation and Apoptosis of Breast Cancer Cells by Inhibiting the ERK Signaling Pathway.

PURPOSE: To explore the effects of ulinastatin on the proliferation and apoptosis of breast cancer cells and the relevant mechanism of action. METHODS: Breast cancer cells (MCF-7) were cultured and randomly divided into three groups, namely, control group, ulinastatin group, and ulinastatin+extracellular-regulated protein kinase (ERK) inhibitor group. Then, the Cell Counting Kit-8 (CCK-8) assay was carried out to detect the effect of ulinastatin on the viability of breast cancer cells. The effects of ulinastatin on the proliferation and apoptosis of breast cancer cells were determined via EdU staining and Hoechst 33258 staining assays, respectively. The messenger ribonucleic acid (mRNA) and protein expression levels of ERK and forkhead box O3 (FOXO3) in breast cancer cells were measured through reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. RESULTS: In comparison with the control group, the ulinastatin group displayed decreased viability of breast cancer cells, a decreased positive rate of 5-ethynyl-2'-deoxyuridine (EdU) staining, an increased positive rate of Hoechst 33258 staining, and reduced mRNA and protein levels of ERK and FOXO3 in breast cancer cells. Compared with those in the ulinastatin group, the viability of breast cancer cells was lowered, the positive rate of EdU staining was reduced, the positive rate of Hoechst 33258 staining was raised, and the mRNA and protein levels of ERK and FOXO3 in breast cancer cells clearly declined in the ulinastatin+ERK inhibitor group. CONCLUSION: Ulinastatin inhibits the proliferation and promotes the apoptosis of breast cancer cells. The possible mechanism of action is associated with the suppression of the ERK signaling pathway.

CircRNA circ-PDCD11 promotes triple-negative breast cancer progression via enhancing aerobic glycolysis.

Well-described evidence has demonstrated the critical roles of aerobic glycolysis in triple-negative breast cancer (TNBC) oncotherapy. Moreover, next-generation high-throughput sequencing indicates the potential regulation of energy metabolism by circular RNAs (circRNAs) in TNBC. However, circRNA modulation of TNBC aerobic glycolysis is still unclear. Here, the present research aimed to investigate the function and underlying mechanisms of novel circPDCD11 (hsa_circ_0019853) in TNBC aerobic glycolysis. The results revealed that circPDCD11 expression was significantly upregulated in TNBC tissues and cells. Clinical data demonstrated that the high expression of circPDCD11 was closely correlated with a poor prognosis and acted as an independent risk factor for TNBC prognosis. Functionally, in vitro gain- and loss-of-function experiments revealed that circPDCD11 accelerated glucose uptake, lactate production, ATP generation, and the extracellular acidification rate in TNBC cells. In vivo, circPDCD11 silencing repressed tumor growth. Mechanistically, circPDCD11 acted as a miRNA sponge to enhance LDHA expression by sponging miR-432-5p. In conclusion, these combined results demonstrated that circPDCD11 acts as an oncogene for TNBC, providing a promising prognostic biomarker for TNBC.