Puerarin suppresses macrophage M1 polarization to alleviate renal inflammatory injury through antagonizing TLR4/MyD88-mediated NF-κB p65 and JNK/FoxO1 activation.

BACKGROUND: Acute kidney injury (AKI) is a clinically common and serious renal dysfunction, characterized by inflammation and damage to tubular epithelial cells. Puerarin, an isoflavone derivative isolated from Pueraria lobata, has been proven to possess exceptional effectiveness in reducing inflammation. However, the effects and underlying mechanisms of puerarin on AKI remain uncertain. PURPOSE: This study investigated the possible therapeutic effects of puerarin on AKI and explored its underlying mechanism. STUDY DESIGN AND METHODS: The effects of puerarin on AKI and macrophage polarization were investigated in lipopolysaccharide (LPS)-induced or unilateral ureteral obstruction (UUO)-induced mouse models in vivo and LPS-treated macrophages (Raw264.7) in vitro. Additionally, the effects of puerarin on inflammation-related signaling pathways were analyzed. RESULTS: Administration of puerarin effectively alleviated kidney dysfunction and reduced inflammatory response in LPS-induced and UUO-induced AKI. In vitro, puerarin treatment inhibited the polarization of M1 macrophages and the release of inflammatory factors in Raw264.7 cells stimulated by LPS. Mechanistically, puerarin downregulated the activities of NF-κB p65 and JNK/FoxO1 signaling pathways. The application of SRT1460 to activate FoxO1 or anisomycin to activate JNK eliminated puerarin-mediated inhibition of JNK/FoxO1 signaling, leading to suppression of macrophage M1 polarization and reduction of inflammatory factors. Further studies showed that puerarin bound to Toll/interleukin-1 receptor (TIR) domain of MyD88 protein, hindering its binding with TLR4, ultimately resulting in downstream NF-κB p65 and JNK/FoxO1 signaling inactivation. CONCLUSIONS: Puerarin antagonizes NF-κB p65 and JNK/FoxO1 activation via TLR4/MyD88 pathway, thereby suppressing macrophage polarization towards M1 phenotype and alleviating renal inflammatory damage.

Characterization of a predictive signature for tumor microenvironment and immunotherapy response in hepatocellular carcinoma involving neutrophil extracellular traps.

Neutrophil extracellular traps (NETs) and other factors play a significant role in impacting the prognosis of patients with Hepatocellular carcinoma (HCC). Nevertheless, further research is warranted to fully elucidate the prognostic implications of NETs in patients with HCC. We employed a hierarchical clustering technique to examine the Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) data and identified subtypes associated with NETs. Subsequently, we utilized LASSO regression analysis to identify a distinct gene expression pattern within these subtypes. The strength of this signature was further validated through analysis of TCGA-LIHC and International Cancer Genome Consortium-Liver Cancer (ICGC-LIRI-JP) data. Our findings resulted in the construction of a six-gene signature related to NETs, which can predict survival outcomes in HCC patients. To enhance the predictive accuracy of our tool, we developed a nomogram that integrates the NETs signature with clinicopathological characteristics. We validated the significance of NETs in HCC patients using qRT-PCR and immunohistochemistry assays, along with in vitro experiments targeting high-risk genes. Furthermore, our exploration of the immune microenvironment uncovered augmented immune-specific metrics within the low-risk cohort, implying potential disparities in immune-related attributes between the high-risk and low-risk contingents. In summary, the NETs signature we discovered serves as a valuable biomarker and provides guidance for personalized therapy in HCC patients.

Fraxetin pretreatment alleviates cisplatin-induced kidney injury by antagonizing autophagy and apoptosis via mTORC1 activation.

Cisplatin-induced kidney injury (CKI) is a common complication of chemotherapy. Fraxetin, derived from Fraxinus bungeana A. DC. bark, has antioxidant, anti-inflammatory, and anti-fibrotic effects. This study aims to investigate fraxetin's effects on CKI and its underlying mechanism in vivo and in vitro. Tubular epithelial cells (TECs) and mice were exposed to cisplatin with and without fraxetin preconditioning assess fraxetin's role in CKI. TECs autophagy was observed using transmission electron microscopy. Apoptosis levels in animal tissues were measured using TUNEL staining. The protective mechanism of fraxetin was explored through pharmacological and genetic regulation of mTORC1. Molecular docking was used to identify potential binding sites between fraxetin and mTORC1. The results indicated that fraxetin pretreatment reduced cisplatin-induced kidney injury in a time- and concentration-dependent way. Fraxetin also decreased autophagy in TECs, as observed through electron microscopy. Tissue staining confirmed that fraxetin pretreatment significantly reduced cisplatin-induced apoptosis. Inhibition of mTORC1 using rapamycin or siRNA reversed the protective effects of fraxetin on apoptosis and autophagy in cisplatin-treated TECs, while activation of mTORC1 enhanced fraxetin's protective effect. Molecular docking analysis revealed that fraxetin can bind to HEAT-repeats binding site on mTORC1 protein. In  summary, fraxetin pretreatment alleviates CKI by antagonizing autophagy and apoptosis via mTORC1 activation. This provides evidence for the potential therapeutic application of fraxetin in CKI.

Smad4 regulates TGF-ß1-mediated hedgehog activation to promote epithelial-to-mesenchymal transition in pancreatic cancer cells by suppressing Gli1 activity.

Pancreatic cancer (PC) is an aggressive and metastatic gastrointestinal tumor with a poor prognosis. Persistent activation of the TGF-ß/Smad signaling induces PC cell (PCC) invasion and infiltration via epithelial-to-mesenchymal transition (EMT). Hedgehog signaling is a crucial pathway for the development of PC via the transcription factors Gli1/2/3. This study aimed to investigate the underlying molecular mechanisms of action of hedgehog activation in TGF-ß1-triggered EMT in PCCs (PANC-1 and BxPc-3). In addition, overexpression and shRNA techniques were used to evaluate the role of Smad4 in TGF-ß1-treated PCCs. Our data showed that TGF-ß1 promoted PCC invasion and infiltration via Smad2/3-dependent EMT. Hedgehog-Gli signaling axis in PCCs was activated upon TGF-ß1 stimulation. Inhibition of hedgehog with cyclopamine effectively antagonized TGF-ß1-induced EMT, thereby suggesting that the hedgehog signaling may act as a downstream cascade signaling of TGF-ß1. As a key protein that assists the nuclear translocation of Smad2/3, Smad4 was highly expressed in PANC-1 cells, but not in BxPc-3 cells. Conversely, Gli1 expression was low in PANC-1 cells, but high in BxPc-3 cells. Furthermore, knockdown of Smad4 in PANC-1 cells by shRNA inhibited TGF-ß1-mediated EMT and collagen deposition. Overexpression of Smad4 did not affect TGF-ß1-mediated EMT due to the lack of significant increase in nuclear expression of Smad4. Importantly, Gli1 activity was upregulated by Smad4 knockdown in PANC-1 cells and downregulated by Smad4 overexpression in BxPc-3 cells, indicating that Gli1 may be a negative target protein downstream of Smad4. Thus, Smad4 regulates TGF-ß1-mediated hedgehog activation to promote EMT in PCCs by suppressing Gli1 activity.

Investigating the impact of inflammatory response-related genes on renal fibrosis diagnosis: a machine learning-based study with experimental validation.

Renal fibrosis plays a crucial role in the progression of renal diseases, yet the lack of effective diagnostic markers poses challenges in scientific and clinical practices. In this study, we employed machine learning techniques to identify potential biomarkers for renal fibrosis. Utilizing two datasets from the GEO database, we applied LASSO, SVM-RFE and RF algorithms to screen for differentially expressed genes related to inflammatory responses between the renal fibrosis group and the control group. As a result, we identified four genes (CCL5, IFITM1, RIPK2, and TNFAIP6) as promising diagnostic indicators for renal fibrosis. These genes were further validated through in vivo experiments and immunohistochemistry, demonstrating their utility as reliable markers for assessing renal fibrosis. Additionally, we conducted a comprehensive analysis to explore the relationship between these candidate biomarkers, immunity, and drug sensitivity. Integrating these findings, we developed a nomogram with a high discriminative ability, achieving a concordance index of 0.933, enabling the prediction of disease risk in patients with renal fibrosis. Overall, our study presents a predictive model for renal fibrosis and highlights the significance of four potential biomarkers, facilitating clinical diagnosis and personalized treatment. This finding presents valuable insights for advancing precision medicine approaches in the management of renal fibrosis.Communicated by Ramaswamy H. Sarma.

Targeted inhibition of mTOR by BML-275 induces mitochondrial-mediated apoptosis and autophagy in prostate cancer.

Prostate cancer (PCa) is the most frequently diagnosed cancer among men and the second leading cause of death in Western countries. Clinically, screening drugs and develop developing new therapeutics to treat PCa is of great significance. In this study, BML-275 was demonstrated to exert potent antitumor effects in PCa by antagonizing mTOR activity. In cultured PCa cells, BML-275 treatment reduced the expression levels of c-Myc and survivin, promoted the activation of p53, and thereby induced p21/cyclin D1/CDK4/6-dependent cell cycle G1/S arrest. As a result, BML-275 inhibited cellular proliferation and induced mitochondrial-mediated apoptosis. In addition, BML-275 treatment triggered autophagy. Interestingly, EACC-mediated suppression of autophagy did not affect BML-275-induced proliferation and apoptosis. Nude mouse tumorigenic experiments also confirmed that BML-275 inhibited PCa growth, induced PCa cell apoptosis and autophagy. Mechanistically, the activities of PI3K/AKT and AMPK pathways were downregulated by BML-275 treatment in vitro and in vivo. Importantly, mTOR, a common downstream negative protein of PI3K/AKT and AMPK signaling, was induced to inactivate, which may be associated with the induction of apoptosis and autophagy. The pharmacological activation of mTOR by MHY1485 abolished the induction of apoptosis and autophagy of BML-275. Molecular docking results showed that BML-275 can bind to the FKRP12-rapamycin binding site on mTOR protein, and thereby may have the same inhibitory activity on mTOR as rapamycin. Thus, these findings indicated that BML-275 induces mitochondrial-mediated apoptosis and autophagy in PCa by targeting mTOR inhibition. BML-275 may be a potential candidate for the treatment of PCa.

S100A2 induces epithelial-mesenchymal transition and metastasis in pancreatic cancer by coordinating transforming growth factor ß signaling in SMAD4-dependent manner.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor and is associated with a poor prognosis. Treatment strategies for PDAC are largely ineffective primarily because of delay in its diagnosis and limited efficacy of systematic treatment. S100A2 is associated with the proliferation, migration, and differentiation of several tumors; however, its effects on PDAC and the associated molecular mechanisms remain to be explored. We studied the mechanisms underlying the effect of S100A2 on epithelial-mesenchymal transition (EMT) and metastasis in PDAC cells. We found that the level of S100A2 remarkably increased and was associated with poor PDAC prognosis. The overexpression of S100A2 in PANC-1 cells also induced EMT, in addition to increasing the invasion and migration of PDAC cells, whereas the knockdown of S100A2 markedly inhibited cell metastasis. Furthermore, S100A2 was found to enhance metastatic abilities in vivo. The overexpression of S100A2 increased SMAD4 expression, whereas the knockdown of S100A2 reduced SMAD4 expression. SMAD4 overexpression could effectively rescue the effects of S100A2 knockdown on EMT. S100A2 mechanistically activated the transforming growth factor (TGF)-ß/Smad2/3 signaling pathway, upregulated SMAD4 expression, induced EMT, and increased PANC-1 cell metastasis. In conclusion, the S100A2/SMAD4 axis modulates EMT to accelerate PDAC development. Our results supplement and enrich the understanding of the pathogenesis underlying PDAC and provide a new theoretical basis and strategy targeting S100A2 for the diagnosis and treatment of PDAC.

STAT3 inhibition enhances gemcitabine sensitivity in pancreatic cancer by suppressing EMT, immune escape and inducing oxidative stress damage.

Pancreatic cancer (PC) is a highly-malignant tumor of the digestive system with a very poor prognosis and high mortality. Chemotherapy and PD-1/PD-L1 immune checkpoint blockade are important treatment strategies for advanced PC. However, chemotherapy resistance and poor therapeutic effect of immune checkpoint inhibitors is are the main clinical problems to be solved urgently at present. The effects of combined application of gemcitabine and STAT3 inhibition on the proliferation, apoptosis, migration, and invasion of PC cells (PCCs) were investigated. In addition, oxidative stress (OS), ferroptosis, immune escape, and the epithelial-mesenchymal transition (EMT) were evaluated. STAT3 inhibition with Stattic enhanced the inhibitory activity of gemcitabine on PCC proliferation by regulating the cell cycle. STAT3 inhibition enhanced mitochondrial-dependent apoptosis in gemcitabine-treated PCCs, but did not induce autophagy and ferroptosis. Further study showed that the anti-proliferative and pro-apoptotic effects may be associated with increased OS damage by inactivating Nrf2-HO-1 signaling, as well as DNA damage by inducing the imbalance between ATM andATR-Chk1 pathway. In addition, STAT3 inhibition strengthened gemcitabine-mediated suppression in PCC invasion and migration by antagonizing Smad2/3-dependent EMT. Moreover, the anti-tumorimmuneresponse of gemcitabine was upregulated by Stattic through reducing the expression of PD-L1 and CD47. Mechanistically, combined application of gemcitabine and Stattic suppressed the phosphorylation and nuclear expression of STAT3. Interestingly, the activities of AKT and ß-catenin signaling were also regulated, suggesting that drug combination has a broad-spectrum signal regulation effect. STAT3 inhibition enhanced the sensitivity of PCCs to the chemotherapy drug gemcitabine by suppressing EMT and immune escape and inducing OS damage.

Diagnostic model constructed by five EMT-related genes for renal fibrosis and reflecting the condition of immune-related cells.

Background: Renal fibrosis is a physiological and pathological characteristic of chronic kidney disease (CKD) to end-stage renal disease. Since renal biopsy is the gold standard for evaluating renal fibrosis, there is an urgent need for additional non-invasive diagnostic biomarkers. Methods: We used R package "limma" to screen out differently expressed genes (DEGs) based on Epithelial-mesenchymal transformation (EMT), and carried out the protein interaction network and GO, KEGG enrichment analysis of DEGs. Secondly, the least absolute shrinkage and selection operator (LASSO), random forest tree (RF), and support vector machine-recursive feature elimination (SVM-RFE) algorithms were used to identify candidate diagnostic genes. ROC curves were plotted to evaluate the clinical diagnostic value of these genes. In addition, mRNA expression levels of candidate diagnostic genes were analyzed in control samples and renal fibrosis samples. CIBERSORT algorithm was used to evaluate immune cells level. Additionally, gene set enrichment analysis (GSEA) and drug sensitivity were conducted. Results: After obtaining a total of 24 DEGs, we discovered that they were mostly involved in several immunological and inflammatory pathways, including NF-KappaB signaling, AGE-RAGE signaling, and TNF signaling. Five genes (COL4A2, CXCL1, TIMP1, VCAM1, and VEGFA) were subsequently identified as biomarkers for renal fibrosis through machine learning, and their expression levels were confirmed by validation cohort data sets and in vitro RT-qPCR experiment. The AUC values of these five genes demonstrated significant clinical diagnostic value in both the training and validation sets. After that, CIBERSORT analysis showed that these biomarkers were strongly associated with immune cell content in renal fibrosis patients. GSEA also identifies the potential roles of these diagnostic genes. Additionally, diagnostic candidate genes were found to be closely related to drug sensitivity. Finally, a nomogram for diagnosing renal fibrosis was developed. Conclusion: COL4A2, CXCL1, TIMP1, VCAM1, and VEGFA are promising diagnostic biomarkers of tissue and serum for renal fibrosis.

Trans-cinnamaldehyde attenuates renal ischemia/reperfusion injury through suppressing inflammation via JNK/p38 MAPK signaling pathway.

Inflammation is the major contributor to the mechanisms of acute kidney injury due to renal ischemia-reperfusion injury (IRI). Trans-cinnamaldehyde (TCA) is a main bioactive component extracted from the bark of cinnamon and has been proved to have good anti-inflammatory properties. The current study was to demonstrate the effect of TCA on renal IRI and explore its specific mechanism. C57BL/6J mice were injected prophylactically intraperitoneally for TCA 3 days, and IRI for 24 h. In parallel, Human Kidney-2 (HK-2) cells were prophylactically treated with TCA, and then exposed to oxygen glucose deprivation/reperfusion (OGD/R) and cobalt chloride (CoCl2). TCA was found to significantly attenuate renal pathological changes and renal dysfunction, and inhibit gene and protein expression of kidney injury molecule-1 (Kim-1) and neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, TCA significantly suppressed the expression of TNF-α, IL-6, IL-1ß, COX-2, iNOS, and MCP-1. Mechanistically, the activation of the JNK/p38 MAPK signaling pathway was inhibited by TCA in renal IRI as well as in OGD/R and CoCl2-stimulated cells. However, following pretreatment with anisomycin before OGD/R treatment, we found that the activation of the JNK/p38 MAPK signaling pathway was significantly enhanced, and concomitant abrogation of the TCA inhibitory effect on the JNK/p38 MAPK signaling pathway, which was followed by a worsening of cell injury that was characterized by an increased number of cell necrosis and an increase in the expression of Kim-1, NGAL as well as proinflammatory factors (IL-6, IL-1ß, iNOS). In summary, TCA inhibited renal inflammation via the JNK/p38 MAPK signaling pathway and attenuated renal IRI.

Effectiveness of adjuvant chemotherapy for elderly patients with triple-negative breast cancer.

There is little evidence determining whether elderly patients (from 70 to 90 years old) with triple-negative breast cancer could benefit from adjuvant chemotherapy (AC).  This study explores the effect of AC in these population following surgery. A total of 4610 patients were identified in the Surveillance, Epidemiology, and End Results database (2010-2018). Multiple imputation by chained equations was performed to impute missing data. Inverse probability of treatment weighting (IPTW) was applied to reduce the selection bias. IPTW-adjusted Kaplan-Meiers survival analysis and Cox proportional hazards models were performed to compare breast cancer specific survival (BCSS) and overall survival (OS) in the two treatment groups. The patients were classified into the chemotherapy (n=1989) and the observation (n=2621) groups. The percentage of patients receiving AC versus observation increased significantly from 2010 to 2018 (estimated annual percentage change, 1.49%; 95%CI, 0.75-2.16%, p=0.002). The 5-year IPTW-adjusted rates of BCSS and OS in AC group were better than that in observation group (BCSS: 82.32% vs. 78.42%, p=0.010; OS: 75.54% vs. 64.65%, p<0.001). The patients could benefit from AC based on the results of IPTW-adjusted Cox proportional hazards regression analysis (BCSS: HR, 0.77, 95%CI, 0.62-0.94, p=0.012; OS: HR, 0.66, 95%CI, 0.57-0.78, p<0.001). AC was associated with a significant outcome benefit across the year at diagnosis, marital status, stage, lymph node, surgery, and radiation subgroups (all p<0.050). Patients with T1ab could not benefit from AC (p>0.050). In conclusion, we presented a BCSS and OS benefit from AC in elderly patients with triple-negative breast cancer (TNBC). AC remained a reasonable treatment approach in these specific patients. For the patients with T1ab, de-escalated treatment would be administrated with caution.

The Role of Adjuvant Chemotherapy in Metaplastic Breast Carcinoma: A Competing Risk Analysis of the SEER Database.

Purpose: Chemotherapy is the clinically recommended treatment for patients with operable metaplastic breast carcinoma (MBC); however, its impact remains controversial. This study investigated the possible role of chemotherapy in the treatment of MBC. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify the operable MBC patients. The competing risk analysis along with the propensity score matching (PSM) method was performed to evaluate the effect of chemotherapy. Moreover, a competing risk nomogram was built to identify prognosis in patients with MBC. Results: Of the 1137 patients with MBC, 775 received chemotherapy and 362 did not receive chemotherapy. The 5-year cumulative incidence of breast cancer-specific death (BCSD) showed similar outcomes in both the Chemo and No-Chemo groups (21.1 vs. 24.3%, p = 0.57). Chemotherapy showed no apparent association with BCSD (HR, 1.07; 95% CI, 0.72-1.60; p = 0.72), even after subgroup analysis or PSM. Race, tumor size, lymph node status, and radiation were identified as the significant factors for MBC after a penalized variable selection process. In addition, a competing risk nomogram showed relatively good accuracy of prediction with a C-index of 0.766 (95% CI, 0.700-0.824). Conclusion: Our findings demonstrated that chemotherapy did not improve BCSD for operable MBC patients. Thus, it may indicate the need to reduce exposure to the current chemotherapy strategies for patients with resectable MBC. Additionally, some novel treatment strategies are required urgently to identify and target the potential biomarkers.

The role of chemotherapy in patients with T1bN0M0 triple-negative breast cancer: a real-world competing risk analysis.

The objective of the present study was to implement Kaplan-Meier analysis, competing risk analysis, and propensity score matching to evaluate whether the patients with T1bN0M0 triple-negative breast (TNBC) could benefit from adjuvant chemotherapy. A total of 1849 patients were identified in the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015. All eligible patients were divided into two cohorts, the chemotherapy (1155 patients) and the no-chemotherapy (694 patients) cohorts. Similar 5-year breast cancer-specific survival (BCSS) was observed in the chemotherapy and no-chemotherapy cohorts (96.1% vs. 96.0%, p=0.820). The results of the competing risk analysis showed a comparable 5-year breast cancer-specific death (BCSD) in both groups (chemotherapy 3.6% vs. no-chemotherapy 3.4%, p=0.778). Also, a higher 5-year other causes death (OCD) was observed in the no-chemotherapy cohort (0.7% vs. 5.4%, p<0.001). Multivariable competing risks regression models showed no association between chemotherapy and BCSS (HR, 1.21; 95%CI, 0.64-2.31; p=0.560). After 1:1 PSM, no significant difference was also observed for BCSD and OCD between two cohorts. The value of adjuvant chemotherapy in patients with T1bN0M0 TNBC is less than the present guidelines recommend, suggesting that de-escalated treatment could be a potentially beneficial strategy in appropriately selected patients.

Effects of Marital Status on Prognosis in Women with Infiltrating Ductal Carcinoma of the Breast: A Real-World 1: 1 Propensity-Matched Study.

BACKGROUND The effects of marital status on infiltrating ductal carcinoma of breast cancer (IDC) have not been studied in detail. This study investigated the impact of marital status on IDC patients. MATERIAL AND METHODS SEER databases were searched from 2010 to 2015 for subjects who were married, divorced, single, and widowed. The influence of marital status on breast cancer-specific survival (BCSS) and overall survival (OS) of IDC patients was investigated through multivariate Cox regression analysis and Kaplan-Meier analysis. To prevent bias, propensity score matching (PSM) analysis was performed. RESULTS The 5-year OS was 89.6%in married patients, 84.9% in divorced patients, 83.5% in single patients, and 71.3% in widowed patients (p<0.001). The 5-year BCSS were 92.9%, 90.2%, 87.6%, and 86.4%, respectively (p<0.001). Multivariate Cox regression analysis revealed that marriage was a protective factor for patients with IDC in terms of OS (divorced: HR, 1.27; 95% CI, 1.21-1.32; p<0.001; single: HR, 1.36; 95% CI, 1.31-1.42; p<0.001; widowed: HR, 1.42; 95% CI, 1.36-1.48; p<0.001) and BCSS (divorced: HR, 1.15; 95% CI, 1.09-1.21; p<0.001; single: HR, 1.27; 95% CI, 1.21-1.33; p<0.001; widowed: HR, 1.32; 95% CI, 1.25-1.40; p<0.001). Following subgroup and PSM analysis, married patients were shown to have better OS and BCSS as opposed to divorced, single, or widowed patients. CONCLUSIONS We identify marital status as a predictor of survival in those with IDC. Widowed patients showed the highest mortality risk.

Intracystic papillary carcinoma of the breast in males: Three case reports.

RATIONALE: Intracystic papillary breast carcinoma is extremely rare in males with a favorable prognosis. Clinical and mammographic manifestations of IPC are not specific, and no consensus has been reached on its management. PATIENT CONCERNS: Three cases of IPC of the breast in male patients who underwent surgery are presented. In each patient, clinical manifestations, radiological appearance, surgical procedures, pathological diagnosis, and prognosis were investigated. DIAGNOSIS: Ultrasonography showed a complex mass with cystic and nodular solid components in 2 patients and a solid hypoechoic mass in the other 1. Contrast-enhanced ultrasonography(CEUS) was performed for 1 patient demonstrated a solid component of the characteristic enhancement patterns. The final diagnosis of IPC was made after an excisional biopsy. INTERVENTIONS: A mastectomy with sentinel lymph node mapping was carried out in 2 patients, and it was negative for metastatic disease. The third patient received a mastectomy without an investigation of the axillary lymph node status. OUTCOMES: All the patients are disease-free during a median follow-up of 67 months (range, 13-120) months. LESSONS: It is difficult to diagnose IPC of the male breast before surgery, excisional biopsy is necessary. CEUS can be useful to diagnose IPC in male patients in the preoperative evaluation. Sentinel node biopsy may be considered in patients with IPC associated with DCIS or invasive carcinoma.

A six-microRNA signature can better predict overall survival of patients with esophagus adenocarcinoma.

BACKGROUND: The microRNAs (miRNAs) have been validated as prognostic markers in many cancers. Here, we aimed at developing a miRNA-based signature for predicting the prognosis of esophagus adenocarcinoma (EAC). METHODS: The RNA-sequencing data set of EAC was downloaded from The Cancer Genome Atlas (TCGA). Eighty-four patients with EAC were classified into a training set and a test set randomly. Using univariate Cox regression analysis and the least absolute shrinkage and selection operator (LASSO), we identified prognostic factors and constructed a prognostic miRNA signature. The accuracy of the signature was evaluated by the receiver operating characteristic (ROC) curve. RESULT: In general, in the training set, six miRNAs (hsa-mir-425, hsa-let-7b, hsa-mir-23a, hsa-mir-3074, hsa-mir-424 and hsa-mir-505) displayed good prognostic power as markers of overall survival for EAC patients. Relative to patients in the low-risk group, those assigned to the high-risk group according to their risk scores of the designed miRNA model displayed reduced overall survival. This 6-miRNA model was validated in test and entire set. The area under curve (AUC) for ROC at 3 years was 0.959, 0.840, and 0.868 in training, test, and entire set, respectively. Molecular functional analysis and pathway enrichment analysis indicated that the target messenger RNAs associated with 6-miRNA signature were closely related to several pathways involved in carcinogenesis, especially cell cycle. CONCLUSION: In summary, a novel 6-miRNA expression-based prognostic signature derived from the EAC data of TCGA was constructed and validated for predicting the prognosis of EAC.

Role of high mobility group A1 and body mass index in the prognosis of patients with breast cancer.

The high mobility group A1 (HMGA1) protein is associated with poor prognosis in patients with a wide range of cancers. However, the affect of HMGA1 on the risk of mortality from breast cancer (BC) has not been fully characterized. In the present retrospective multiple center study, the HMGA1 expression level was determined by performing immunohistochemistry on surgical tissue samples of 273 BC specimens from the Second Affiliated Hospital of Zhejiang University (Zhejiang, China) and 310 BCs from the National Engineering Center for Biochip (Shanghai, China). Kaplan-Meier analysis and Cox proportional hazard model were employed to analyze the survivability. HMGA1 expression was significantly associated with tumor histological degree and body mass index (BMI). However, HMGA1 expression showed no prognostic value in patients with BC. Combined evaluation of HMGA1 expression and high BMI (≥24 kg/m2) predicted worse overall survival of BC. Therefore, HMGA1 and BMI were considered to serve synergistic roles in the development and progression of BC, and combined evaluation of HMGA1 expression and high BMI may be an effective marker in predicting poor prognosis of BC patients.

Elevated HMGA2 expression is associated with cancer aggressiveness and predicts poor outcome in breast cancer.

High mobility group AT-hook 2 (HMGA2) is involved in a wide spectrum of biological processes and is upregulated in several tumors. Here, we collected 273 breast cancer (BC) specimens as a training set and 310 specimens as a validation set to examine the expression of HMGA2 by immunohistochemical staining. It was found that HMGA2 expression was significantly positively correlated with advanced tumor grade and poor survival. Subgroup analysis indicated that high level of HMGA2 was significantly correlated with poor prognosis, especially in the subgroups of stage II-III, low pathological grade and non-triple negative breast cancer cases. Gene set enrichment analysis (GSEA) demonstrated a significant positive correlation between HMGA2 level and the gene expression signature of metaplastic and mesenchymal phenotype. Importantly, we also observed that ectopic expression of HMGA2 promoted the migration and invasion of breast cancer cells, and protected cancer cells against genotoxic stress from agents stimulating P53 (Ser15) phosphorylation. As a conclusion, expression of HMGA2 might indicate more advanced malignancy of breast cancer. Thus we believe HMGA2 could serve as a biomarker of poor prognosis and a novel target in treating BC tumors.

[Diagnostic value of automated breast volume scanner in high-risk and small breast lesions].

OBJECTIVE: To assess the accuracy of detection by automated breast volume scanner (ABVS) in diagnosis of high-risk and small breast lesions. METHODS: One hundred and twelve patients with solid high-risk and small breast lesions were identified by ABVS. The patients were divided into benign lesion group and cancer group after pathological examination. The clinicopathological findings and ultrasonographic features of the lesions were compared. RESULTS: Among the 112 lesions there were 49 benign and 63 malignant lesions. The mean size on ABVS and pathology were (1.59 ± 0.52) cm and (1.52 ± 0.58) cm. There was no significant difference in tumor sizes determined by ABVS and pathology (P = 0.194). The mean age of patients with benign lesions was (38.5 ± 7.4) years and that of malignant lesions was (52.4 ± 13.6) years, showing a significant difference between the two groups (P < 0.001) . The mass shape, orientation, margin, lesion boundary, echo pattern, calcification, BI-RADS category and retraction phenomenon were significantly different of the malignant and benign masses (P < 0.05). But there was no significant difference in the location of lesions and posterior acoustic features (P > 0.05) . Retraction phenomenon was significantly associated with pathological type and histologic grade of the breast cancer (P < 0.01). The specificity, sensitivity and accuracy of retraction phenomenon were 100% (46/46), 73.0% (46/63), and 84.8% (95/112), respectively. CONCLUSIONS: ABVS provides advantages of better size prediction of high-risk and small breast lesions. Furthermore, the retraction phenomenon in coronal plane shows high specificity and sensitivity in detecting breast cancer.

[Vacuum-assisted biopsy and wire localization for the diagnosis of non-palpable breast lesions].

OBJECTIVE: To compare the effectiveness and accuracy of the use of vacuum-assisted biopsy (VAB) versus wire localization (WL) in the diagnosis of non-palpable breast lesions (NPBL). METHODS: Ninety-seven consecutive women with NPBL were randomized into VAB group and WL group. All specimens were identified by mammography. The patients were requested to score the cosmetic appearance of their breast after operation, and a numerical rating scale was used to measure pain on the first postoperative day. Underestimation rates for atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) were recorded if open surgical biopsy revealed DCIS and invasive cancer, respectively. Clear margins were also recorded in the two groups. RESULTS: VAB and WL located all the NPBL successfully. In the VAB group, the specimen volume was smaller than that of the WL group (2.3 cm(3) vs. 18.4 cm(3), P = 0.03). Underestimation rates of ADH and DCIS in the VAB group were 16.7% and 11.1%, respectively. The diagnostic accordance rate of VAB was 97.9%, the false negative rate was 2.1%, and there was no false positive case. The means of the numerical rating pain scale were different in both groups (1.7 for VAB vs. 2.5 for WL, P = 0.02). When cosmetic results were taken into account, 40 VAB patients had excellent outcomes and 8 good outcomes, compared with 25 excellent and 24 good for the WL group. There were better cosmetic outcomes with the VAB procedure (P < 0.05). CONCLUSION: VAB is highly reliable and may avoid diagnostic open surgery in the majority of patients with benign lesions. However, because of the underestimation of histologic diagnosis and tumor margin involvement, VAB can not be used to completely substitute wire localization.