Hypermethylation of the Gene Body in SRCIN1 Is Involved in Breast Cancer Cell Proliferation and Is a Potential Blood-Based Biomarker for Early Detection and a Poor Prognosis.

Breast cancer is a leading cause of cancer mortality in women worldwide. Using the Infinium MethylationEPIC BeadChip, we analyzed plasma sample methylation to identify the SRCIN1 gene in breast cancer patients. We assessed SRCIN1-related roles and pathways for their biomarker potential. To verify the methylation status, quantitative methylation-specific PCR (qMSP) was performed on genomic DNA and circulating cell-free DNA samples, and mRNA expression analysis was performed using RT‒qPCR. The results were validated in a Western population; for this analysis, the samples included plasma samples from breast cancer patients from the USA and from The Cancer Genome Atlas (TCGA) cohort. To study the SRCIN1 pathway, we conducted cell viability assays, gene manipulation and RNA sequencing. SRCIN1 hypermethylation was identified in 61.8% of breast cancer tissues from Taiwanese patients, exhibiting specificity to this malignancy. Furthermore, its presence correlated significantly with unfavorable 5-year overall survival outcomes. The levels of methylated SRCIN1 in the blood of patients from Taiwan and the USA correlated with the stage of breast cancer. The proportion of patients with high methylation levels increased from 0% in healthy individuals to 63.6% in Stage 0, 80% in Stage I and 82.6% in Stage II, with a sensitivity of 78.5%, an accuracy of 90.3% and a specificity of 100%. SRCIN1 hypermethylation was significantly correlated with increased SRCIN1 mRNA expression (p < 0.001). Knockdown of SRCIN1 decreased the viability of breast cancer cells. SRCIN1 silencing resulted in the downregulation of ESR1, BCL2 and various cyclin protein expressions. SRCIN1 hypermethylation in the blood may serve as a noninvasive biomarker, facilitating early detection and prognosis evaluation, and SRCIN1-targeted therapies could be used in combination regimens for breast cancer patients.

Robotic Versus Conventional or Endoscopic-assisted Nipple-sparing Mastectomy and Immediate Prosthesis Breast Reconstruction in the Management of Breast Cancer: A Prospectively Designed Multicenter Trial Comparing Clinical Outcomes, Medical Cost, and Patient-reported Outcomes (RCENSM-P).

OBJECTIVE: To compare the clinical and patient-reported outcomes of minimal access and conventional nipple-sparing mastectomy (C-NSM). The secondary outcomes investigated included medical costs and oncological safety. BACKGROUND: Minimal-access NSM has been increasingly applied in the treatment of patients with breast cancer. However, prospective multicenter trials comparing robotic-assisted NSM (R-NSM) versus C-NSM or endoscopic-assisted NSM (E-NSM) are lacking. METHODS: A prospectively designed 3-arm multicenter, nonrandomized trial (NCT04037852) was conducted from October 1, 2019 to December 31, 2021, to compare R-NSM with C-NSM or E-NSM. RESULTS: A total of 73 R-NSM, 74 C-NSM, and 84 E-NSM procedures were enrolled. The median wound length and operation time of C-NSM was (9 cm, 175 minutes), (4 cm, and 195 minutes) in R-NSM, and (4 cm and 222 minutes) in E-NSM. Complications were comparable among the groups. Better wound healing was observed in the minimal-access NSM group. The R-NSM procedure was 4000 and 2600 United States Dollars more expensive than C-NSM and E-NSM, respectively. Wound/scar and postoperative acute pain evaluation favored the use of minimal access NSM over C-NSM. Quality of life in terms of chronic breast/chest pain, mobility, and range of motion of the upper extremity showed no significant differences. The preliminary oncologic results showed no differences among the 3 groups. CONCLUSIONS: R-NSM or E-NSM is a safe alternative if compared with C-NSM in terms of perioperative morbidities, especially with better wound healing. The advantage of minimal access groups was higher wound-related satisfaction. Higher costs remain one of the major limiting factors in the widespread adoption of R-NSM.

The role of thrombomodulin in modulating ITGB3 expression and its implications for triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) compared to other BC subtypes in clinical settings. Currently, there are no effective therapeutic strategies for TNBC treatment. Therefore, there is an urgent need to identify suitable biomarkers or therapeutic targets for TNBC patients. Thrombomodulin (TM) plays a role in cancer progression and metastasis in many different cancers. However, the role of TM in TNBC is not yet fully understood. First, silenced-TM in MDA-MB-231 cells caused an increase in proliferative and metastatic activity. In contrast, overexpression of TM in Hs578T cells caused a reduction in proliferation, invasion, and migration rate. Using RNA-seq analysis, we found that Integrin beta 3 (ITGB3) expression may be a downstream target of TM. Furthermore, we found an increase in ITGB3 levels in TM-KD cells by QPCR and western blot analysis but a decrease in ITGB3 levels in TM-overexpressing cells. We found phospho-smad2/3 levels were increased in TM-KD cells but decreased in TM-overexpressing cells. This implies that TM negatively regulates ITGB3 levels through the activation of the smad2/3 pathway. Silencing ITGB3 in TM-KD cells caused a decrease in proliferation and migration. Finally, we found that higher ITGB3 levels were correlated with poor overall survival and relapse-free survival in patients with TNBC. Our results indicated a novel regulatory relationship between TM and ITGB3 in TNBC.

Machine learning approaches for predicting 5-year breast cancer survival: A multicenter study.

The study used clinical data to develop a prediction model for breast cancer survival. Breast cancer prognostic factors were explored using machine learning techniques. We conducted a retrospective study using data from the Taipei Medical University Clinical Research Database, which contains electronic medical records from three affiliated hospitals in Taiwan. The study included female patients aged over 20 years who were diagnosed with primary breast cancer and had medical records in hospitals between January 1, 2009 and December 31, 2020. The data were divided into training and external testing datasets. Nine different machine learning algorithms were applied to develop the models. The performances of the algorithms were measured using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and F1-score. A total of 3914 patients were included in the study. The highest AUC of 0.95 was observed with the artificial neural network model (accuracy, 0.90; sensitivity, 0.71; specificity, 0.73; PPV, 0.28; NPV, 0.94; and F1-score, 0.37). Other models showed relatively high AUC, ranging from 0.75 to 0.83. According to the optimal model results, cancer stage, tumor size, diagnosis age, surgery, and body mass index were the most critical factors for predicting breast cancer survival. The study successfully established accurate 5-year survival predictive models for breast cancer. Furthermore, the study found key factors that could affect breast cancer survival in Taiwanese women. Its results might be used as a reference for the clinical practice of breast cancer treatment.

The Role of Thrombomodulin in Estrogen-Receptor-Positive Breast Cancer Progression, Metastasis, and Curcumin Sensitivity.

Estrogen and estrogen receptors (ER) play a key role in breast cancer progression, which can be treated with endocrine therapy. Nevertheless, resistance to endocrine therapies is developed over time. The tumor expression of thrombomodulin (TM) is correlated with favorable prognosis in several types of cancer. However, this correlation has not yet been confirmed in ER-positive (ER+) breast cancer. This study aims to evaluate the role of TM in ER+ breast cancer. Firstly, we found that lower TM expression correlates to poor overall survival (OS) and relapse-free survival (RFS) rates in ER+ breast cancer patients through Kaplan-Meier survival analysis (p < 0.05). Silencing TM in MCF7 cells (TM-KD) increased cell proliferation, migration, and invasion ability. Additionally, TM-KD MCF7 cells showed higher sensitivity (IC50 15 µM) to the anti-cancer agent curcumin than the scrambled control cells. Conversely, overexpression of TM (TM-over) in T47D cells leads to decreased cell proliferation, migration, and invasion ability. Furthermore, TM-over T47D cells showed more resistance (IC50 > 40 µM) to the curcumin treatment. The PI staining, DAPI, and tunnel assay also confirmed that the curcumin-induced apoptosis in TM-KD MCF7 cells was higher (90.34%) than in the scrambled control cells (48.54%). Finally, the expressions of drug-resistant genes (ABCC1, LRP1, MRP5, and MDR1) were determined by qPCR. We found that the relative mRNA expression levels of ABCC1, LRP1, and MDR1 genes after curcumin treatment were higher in scrambled control cells than in TM-KD cells. In conclusion, our results demonstrated that TM plays a suppressive role in the progression and metastasis of ER+ breast cancer, and it regulates curcumin sensitivity by interfering with ABCC1, LRP1, and MDR1 gene expression.

Neoadjuvant pegylated liposomal doxorubicin- and epirubicin-based combination therapy regimens for early breast cancer: a multicenter retrospective case-control study.

PURPOSE: This study aimed to compare the effectiveness and safety of pegylated liposomal doxorubicin (PLD)-based and epirubicin-based combination therapy regimen as neoadjuvant therapy for early breast cancer. METHODS: Patients with stage I-III breast cancer who underwent neoadjuvant therapy followed by surgery between January 2018 and December 2019 were retrospectively reviewed. The primary outcome was pathological complete response (pCR) rate. The secondary outcome was radiologic complete response (rCR) rate. Outcomes were compared between treatment groups PLD-cyclophosphamide followed by docetaxel (LC-T group) or epirubicin-cyclophosphamide followed by docetaxel (EC-T group), using both propensity-score matched (matched) and unmatched data. RESULTS: Data were analyzed from patients who received neoadjuvant LC-T (n = 178) or EC-T (n = 181) treatment. The overall pCR rate and rCR rate were higher in the LC-T group compared with the EC-T group (unmatched pCR: 25.3% vs. 15.5%, p = 0.026; rCR: 14.7% vs. 6.7%, p = 0.016; matched pCR: 26.9% vs. 16.1%, p = 0.034; rCR: 15.5% vs. 7.4%, p = 0.044). Analysis by molecular subtype showed that compared with EC-T treatment, LC-T treatment achieved significantly greater pCR rate in triple-negative subtype and greater rCR rate in Her2 (+) subtype. CONCLUSIONS: Neoadjuvant PLD-based therapy may be a potential option for patients with early-stage breast cancer. The current results warrant further investigation.

Promoter hypomethylation and overexpression of TSTD1 mediate poor treatment response in breast cancer.

Epigenetic alterations play a pivotal role in cancer treatment outcomes. Using the methylation array data and The Cancer Genome Atlas (TCGA) dataset, we observed the hypomethylation and upregulation of thiosulfate sulfurtransferase-like domain containing 1 (TSTD1) in patients with breast cancer. We examined paired tissues from Taiwanese patients and observed that 65.09% and 68.25% of patients exhibited TSTD1 hypomethylation and overexpression, respectively. A significant correlation was found between TSTD1 hypomethylation and overexpression in Taiwanese (74.2%, p = 0.040) and Western (88.0%, p < 0.001) cohorts. High expression of TSTD1 protein was observed in 68.8% of Taiwanese and Korean breast cancer patients. Overexpression of TSTD1 in tumors of breast cancer patients was significantly associated with poor 5-year overall survival (p = 0.021) and poor chemotherapy response (p = 0.008). T47D cells treated with TSTD1 siRNA exhibited lower proliferation than the control group, and transfection of TSTD1 in MDA-MB-231 induced the growth of MDA-MB-231 cells compared to the vector control. Additionally, overexpression of TSTD1 in MCF7 cells mediated a poor response to chemotherapy by epirubicin (p < 0.001) and docetaxel (p < 0.001) and hormone therapy by tamoxifen (p =0.025). Circulating cell-free hypomethylated TSTD1 was detected in plasma of Taiwanese breast cancer patients with disease progression and poor chemotherapy efficacy. Our results indicate that promoter hypomethylation and overexpression of TSTD1 in patients with breast cancer are potential biomarkers for poor 5-year overall survival and poor treatment response.

Hypermethylation of TMEM240 predicts poor hormone therapy response and disease progression in breast cancer.

BACKGROUND: Approximately 25% of patients with early-stage breast cancer experience cancer progression throughout the disease course. Alterations in TMEM240 in breast cancer were identified and investigated to monitor treatment response and disease progression. METHODS: Circulating methylated TMEM240 in the plasma of breast cancer patients was used to monitor treatment response and disease progression. The Cancer Genome Atlas (TCGA) data in Western countries and Illumina methylation arrays in Taiwanese breast cancer patients were used to identify novel hypermethylated CpG sites and genes related to poor hormone therapy response. Quantitative methylation-specific PCR (QMSP), real-time reverse transcription PCR, and immunohistochemical analyses were performed to measure DNA methylation and mRNA and protein expression levels in 394 samples from Taiwanese and Korean breast cancer patients. TMEM240 gene manipulation, viability, migration assays, RNA-seq, and MetaCore were performed to determine its biological functions and relationship to hormone drug treatment response in breast cancer cells. RESULTS: Aberrant methylated TMEM240 was identified in breast cancer patients with poor hormone therapy response using genome-wide methylation analysis in the Taiwan and TCGA breast cancer cohorts. A cell model showed that TMEM240, which is localized to the cell membrane and cytoplasm, represses breast cancer cell proliferation and migration and regulates the expression levels of enzymes involved in estrone and estradiol metabolism. TMEM240 protein expression was observed in normal breast tissues but was not detected in 88.2% (67/76) of breast tumors and in 90.0% (9/10) of metastatic tumors from breast cancer patients. QMSP revealed that in 54.5% (55/101) of Taiwanese breast cancer patients, the methylation level of TMEM240 was at least twofold higher in tumor tissues than in matched normal breast tissues. Patients with hypermethylation of TMEM240 had poor 10-year overall survival (p = 0.003) and poor treatment response, especially hormone therapy response (p < 0.001). Circulating methylated TMEM240 dramatically and gradually decreased and then diminished in patients without disease progression, whereas it returned and its levels in plasma rose again in patients with disease progression. Prediction of disease progression based on circulating methylated TMEM240 was found to have 87.5% sensitivity, 93.1% specificity, and 90.2% accuracy. CONCLUSIONS: Hypermethylation of TMEM240 is a potential biomarker for treatment response and disease progression monitoring in breast cancer.

Aldehyde Dehydrogenase 2 Family Member (ALDH2) Is a Therapeutic Index for Oxaliplatin Response on Colorectal Cancer Therapy with Dysfunction p53.

Oxaliplatin resistance is a major issue in the treatment of p53 mutant colorectal cancer (CRC). Finding the specific biomarkers would improve therapeutic efficacy of patients with CRC. In order to figure out the biomarker for CRC patients with mutant p53 access oxaliplatin, a Gene Expression Omnibus dataset (GSE42387) was used to determine differentially expressed genes (DEGs). The Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software were used to predict protein-protein interactions. The Database for Annotation, Visualization, and Integrated Discovery online tool was used to group the DEGs into their common pathways. 138 DEGs were identified with 46 upregulated and 92 downregulated. In the PPI networks, 7 of the upregulated genes and 13 of the downregulated genes were identified as hub genes (high degrees). Four hub genes, aldehyde dehydrogenase 2 family member (ALDH2), aldo-keto reductase family 1 member B1 (AKR1B1), aldo-keto reductase family 1 member B10 (AKR1B10), and monoglyceride lipase (MGLL) were enriched in the most significant pathway, glycerolipid metabolism. Further, we found that low expression of ALDH2 is correlated with poor overall survival and oxaliplatin resistance. Finally, we found that combined treatment with ALDH2 inhibitor and oxaliplatin will reduce the sensitivity to oxaliplatin in p53 mutant HT29 cells. In conclusion, we demonstrate that ALDH2 may be a biomarker for oxaliplatin resistance status in CRC patients and bring new insight into treatment strategy for p53 mutant CRC patients.

Human α-defensin 6 (HD6) suppresses CRC proliferation and metastasis through abolished EGF/EGFR signaling pathway.

The incidence of colorectal cancer (CRC) has increased significantly in the past decade. Early diagnosis and new therapeutics are still urgently needed for CRC in clinical practice. Human α-defensin 6 (HD6) plays a defense role against microbes in the gastrointestinal tract. However, the role and mechanism of HD6 in CRC is still unresolved. Specimens from CRC patients with higher HD6 showed better outcomes. Overexpressed HD6 in CRC cells caused a reduction of cell proliferative, migratory, and invasive ability in vitro and in vivo. HD6-overexpressed caused S phase arrest through changes in cyclin-A and B and CDK2 levels. In addition, serpine-1 may be negatively regulated by HD6 altering the translocation of c-Jun N-terminal kinases (JNK), extracellular regulated protein kinases (ERK), and p38. Higher HD6 and lower serpine-1 levels in CRC patients reflected better outcomes. Finally, we found that HD6 interacts directly with epidermal growth factor receptor (EGFR) by co-immunoprecipitated assay. EGF treatment caused an increase of the level of serpine-1 and pEGFR levels and then increased growth activity in HD6 overexpressing cells. Together, our study shows that HD6 may compete with EGF to bind to EGFR and interrupt cancer progression in CRC. We believe these findings may give new insights for HD6 in CRC therapy.

Areca nut extract (ANE) inhibits the progression of hepatocellular carcinoma cells via activation of ROS production and activation of autophagy.

Hepatocellular carcinoma (HCC) is a worldwide health problem. Currently, there is no effective therapeutic strategy for HCC patients. Chewing areca nut is closely associated with oral cancer and liver cirrhosis. The therapeutic effect of areca nut extract (ANE) on HCC is unknown. Our results revealed that ANE treatment caused a reduction in cell viability and an increase in cell apoptosis and suppressed tumor progression in xenograft models. ANE-treated didn't induce liver tumor in nude mice. For mechanism dissection, ANE treatment caused ROS-mediated autophagy and lysosome formation. Pretreatment with an ROS inhibitor, aminoguanidine hemisulfate (AGH), abolished ANE-induced ROS production. ANE treated cells caused an increase in light chain 3 (LC3)-I to -II conversion, anti-thymocyte globulin 5+12 (ATG5+12), and beclin levels, and apoptosis related-protein changes (an increases in BAX, cleaved poly(ADP-ribose) polymerase (c-PARP), and a decrease in the Bcl-2 level). In conclusion, our study demonstrated that the ANE may be a new potential compound for HCC therapy.

A Novel Signature of CCNF-Associated E3 Ligases Collaborate and Counter Each Other in Breast Cancer.

Breast cancer (BRCA) malignancy causes major fatalities amongst women worldwide. SCF (Skp1-cullin-F-box proteins) E3 ubiquitin ligases are the most well-known members of the ubiquitination-proteasome system (UPS), which promotes cancer initiation and progression. Recently, we demonstrated that FBXL8, a novel F-box protein (SCFF-boxes) of SCF E3 ligase, accelerates BRCA advancement and metastasis. Since SCFF-boxes is a key component of E3 ligases, we hypothesized that other SCFF-boxes besides FBXL8 probably collaborate in regulating breast carcinogenesis. In this study, we retrospectively profiled the transcriptome of BRCA tissues and found a notable upregulation of four SCFF-box E3 ligases (FBXL8, FBXO43, FBXO15, and CCNF) in the carcinoma tissues. Similar to FBXL8, the knockdown of FBXO43 reduced cancer cell viability and proliferation, suggesting its pro-tumorigenic role. The overexpression of CCNF inhibited cancer cell progression, indicating its anti-tumorigenic role. Unexpectedly, CCNF protein was markedly downregulated in BRCA tissues, although its mRNA level was high. We showed that both E3 ligases, FBXL8 and FZR1, pulled down CCNF. Double knockdown of FBXL8 and FZR1 caused CCNF accumulation. On the other hand, CCNF itself pulled down a tumorigenic factor, RRM2, and CCNF overexpression reduced RRM2. Altogether, we propose a signature network of E3 ligases that collaboratively modulates CCNF anti-cancer activity. There is potential to target BRCA through modulation of the partnership axes of (i) CCNF-FBXL8, (ii) CCNF-FZR1, and (iii) CCNF-RRM2, particularly, via CCNF overexpression and activation and FBXL8/FZR1 suppression.

Identified the novel resistant biomarkers for taxane-based therapy for triple-negative breast cancer.

Developing treatment strategies for triple-negative breast cancer (TNBC) has become an important clinical challenge. Currently, taxane-based chemotherapy is one of the standard treatments for TNBC. However, determining the key factor of taxane-resistance is urgently in need for clinical treatment for breast cancer. We used GEO data to generate paclitaxel resistance in two basal-like TNBC cell lines (SUM149 and MDA-MB-468). Seventy-one common upregulated differentially expressed genes (DEGs) and 11 downregulated DEGs were found to be related to paclitaxel resistance. By constructing protein-protein interactions, 28 hub proteins with a degree cutoff criterion of ≥1 were found. Nine hub genes (COL4A6, COL4A5, IL6, PDGFA, LPAR1, FYB, IL20, IL18R1 and INHBA) are involved in important signaling pathways. We found that upregulated PDGFA and downregulated COL4A6 were significantly associated with an insensitive response to neoadjuvant paclitaxel-based therapy. A Kaplan-Meier plot was created to check the prognostic values of 11 hub DEGs in terms of recurrence-free survival. High expressions of PDGFA and LAMB3 were correlated with poor recurrence-free survival, while low levels of FYB, IL18R1, and RASGRP1 indicated poorer relapse-free survival. Our results suggest that PDGFA, COL4A6, LPAR1, FYB, COL4A5, and RASGRP1 might be candidate target genes for taxane-based therapy in basal-like TNBC.

Automatic Detection of the Circulating Cell-Free Methylated DNA Pattern of GCM2, ITPRIPL1 and CCDC181 for Detection of Early Breast Cancer and Surgical Treatment Response.

The early detection of cancer can reduce cancer-related mortality. There is no clinically useful noninvasive biomarker for early detection of breast cancer. The aim of this study was to develop accurate and precise early detection biomarkers and a dynamic monitoring system following treatment. We analyzed a genome-wide methylation array in Taiwanese and The Cancer Genome Atlas (TCGA) breast cancer (BC) patients. Most breast cancer-specific circulating methylated CCDC181, GCM2 and ITPRIPL1 biomarkers were found in the plasma. An automatic analysis process of methylated ccfDNA was established. A combined analysis of CCDC181, GCM2 and ITPRIPL1 (CGIm) was performed in R using Recursive Partitioning and Regression Trees to establish a new prediction model. Combined analysis of CCDC181, GCM2 and ITPRIPL1 (CGIm) was found to have a sensitivity level of 97% and an area under the curve (AUC) of 0.955 in the training set, and a sensitivity level of 100% and an AUC of 0.961 in the test set. The circulating methylated CCDC181, GCM2 and ITPRIPL1 was also significantly decreased after surgery (all p < 0.001). The aberrant methylation patterns of the CCDC181, GCM2 and ITPRIPL1 genes means that they are potential biomarkers for the detection of early BC and can be combined with breast imaging data to achieve higher accuracy, sensitivity and specificity, facilitating breast cancer detection. They may also be applied to monitor the surgical treatment response.

Eps15 Homology Domain-Containing Protein 3 Hypermethylation as a Prognostic and Predictive Marker for Colorectal Cancer.

Colorectal cancer (CRC) arises from chromosomal instability, resulting from aberrant hypermethylation in tumor suppressor genes. This study identified hypermethylated genes in CRC and investigated how they affect clinical outcomes. Methylation levels of specific genes were analyzed from The Cancer Genome Atlas dataset and 20 breast cancer, 16 esophageal cancer, 33 lung cancer, 15 uterine cancer, 504 CRC, and 9 colon polyp tissues and 102 CRC plasma samples from a Taiwanese cohort. In the Asian cohort, Eps15 homology domain-containing protein 3 (EHD3) had twofold higher methylation in 44.4% of patients with colonic polyps, 37.3% of plasma from CRC patients, and 72.6% of CRC tissues, which was connected to vascular invasion and high microsatellite instability. Furthermore, EHD3 hypermethylation was detected in other gastrointestinal cancers. In the Asian CRC cohort, low EHD3 mRNA expression was found in 45.1% of patients and was connected to lymph node metastasis. Multivariate Cox proportional-hazards survival analysis revealed that hypermethylation in women and low mRNA expression were associated with overall survival. In the Western CRC cohort, EHD3 hypermethylation was also connected to overall survival and lower chemotherapy and antimetabolite response rates. In conclusion, EHD3 hypermethylation contributes to the development of CRC in both Asian and Western populations.

Exposure to radiofrequency radiation increases the risk of breast cancer: A systematic review and meta-analysis.

[This retracts the article DOI: 10.3892/etm.2020.9455.].

Methyl gallate, gallic acid-derived compound, inhibit cell proliferation through increasing ROS production and apoptosis in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is a global health problem. Currently, there is no effective therapeutic strategy for HCC. Methyl gallate (MG), from plant-derived phenolic gallic acid, has exhibited antitumor efficacy. However, the effect of MG on HCC is unclear. In vitro growth activity was detected by a sulforhodamine assay. A zebrafish xenotransplantation was applied to evaluate the inhibitory effect of MG. Reactive oxygen species (ROS) production, autophagy, and lysosome formation were detected by specific dyes. Finally, apoptosis was examined using annexin V-FITC/PI staining and western blot was performed to determine the molecular mechanism. It was demonstrated that MG treatment inhibited the proliferation of Hep3B, Mahlavu, and HepJ5 cells. Xenotransplantation also showed that MG inhibited the growth of Hep3B and HepJ5 cells. MG treatment increased cellular levels of superoxide and oxidative stress. Increases in autophagy and lysosome formation were found after MG treatment. The western blot analysis showed that MG activated cleavage of caspase-3 and poly (SDP ribose) polymerase (PARP), modulated levels of the Bcl2, Bax, and Bad ligands, and induced apoptosis. MG induced autophagy with notable activation of beclin-1, autophagy related 5+12 (ATG5+12), and conversion of light chain 3-I (LC3-I) to II. Our study showed that MG exposure inhibited HCC proliferation both in vitro and in vivo. And blocking autophagy enhanced MG-induced cytotoxicity in HCC cells. These findings suggested MG might serve as a powerful therapeutic supplement for human HCC patients.

Exposure to radiofrequency radiation increases the risk of breast cancer: A systematic review and meta-analysis.

The present systematic review and meta-analysis investigated the association between exposure to radiofrequency radiation and the risk of breast cancer. The published studies that were available in PubMed, Embase, Cochrane Library, Ovid MEDLINE, CINAHL Plus, Web of Science, Airiti Library, Networked Digital Library of Theses and Dissertations and ProQuest until May 2020 were investigated. A total of eight studies (four case-control and four cohort studies) were eligible for quantitative analysis. A significant association between radiofrequency radiation exposure and breast cancer risk was detected [pooled relative risk (RR)=1.189; 95% confidence interval (CI), 1.056-1.339]. Subgroup analyses indicated that radiofrequency radiation exposure significantly increased the risk of breast cancer susceptibility among subjects aged ≥50 years (RR=2.179; 95% CI, 1.260-3.770). Pooled estimates revealed that the use of electrical appliances, which emit radiofrequency radiation, such as mobile phones and computers, significantly increased breast cancer development (RR=2.057; 95% CI, 1.272-3.327), while occupational radiofrequency exposure and transmitters did not increase breast cancer development (RR=1.274; 95% CI, 0.956-1.697; RR=1.133; 95% CI, 0.987-1.300, respectively). It was concluded that radiofrequency radiation exposure significantly increased the risk of breast cancer, especially in women aged ≥50 years and in individuals who used electric appliances, such as mobile phones and computers. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-analysis, an evaluation protocol was prepared and registered with the PROSPERO database (registration no. CRD42018087283).

Endoscopy-Assisted Total Mastectomy with and without Immediate Reconstruction: An Extended Follow-Up, Multicenter Study.

BACKGROUND: Endoscopy-assisted total mastectomy has been used for surgical intervention of breast cancer patients; however, large cohort studies with long-term follow-up data are lacking. METHODS: Breast cancer patients who underwent endoscopy-assisted total mastectomy from May of 2009 to March of 2018 were collected prospectively from multiple centers. Clinical outcome, impact of different phases, oncologic results, and patient-reported aesthetic outcomes of endoscopy-assisted total mastectomy were reported. RESULTS: A total of 436 endoscopy-assisted total mastectomy procedures were performed; 355 (81.4 percent) were nipple-sparing mastectomy, and 81 (18.6 percent) were skin-sparing mastectomy. Three hundred fourteen (75.4 percent) of the procedures were associated with immediate breast reconstruction; 255 were prosthesis based and 59 were associated with autologous flaps. The positive surgical margin rate for endoscopy-assisted total mastectomy was 2.1 percent. In morbidity evaluation, there were 19 cases (5.4 percent) with partial nipple necrosis, two cases (0.6 percent) with total nipple necrosis, and three cases (0.7 percent) with implant loss. Compared with the early phase, surgeons operating on patients in the middle or late phase had significantly decreased operation time and blood loss. With regard to patient-reported cosmetic outcomes, approximately 94.4 percent were satisfied with the aesthetic results. Patients who underwent breast reconstruction with preservation of the nipple had higher satisfaction rates. Over a median follow-up of 54.1 ± 22.4 months, there were 14 cases of locoregional recurrence (3.2 percent), three distant metastases (0.7 percent), and one mortality (0.2 percent). CONCLUSION: This multicenter study showed that endoscopy-assisted total mastectomy is a reliable surgical intervention for early breast cancer, with high patient satisfaction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The Association Between Smartphone Use and Breast Cancer Risk Among Taiwanese Women: A Case-Control Study.

INTRODUCTION: Breast cancer is a common malignancy worldwide. Smartphones have gradually become indispensable to our modern lives and have already changed lifestyles of human beings. To our best knowledge, no study has investigated the relationship between smartphone use and breast cancer. This case-control study purposely investigated the relationship between smartphone use and breast cancer risk. MATERIALS AND METHODS: This was a case-control study comprising 894 healthy controls and 211 patients with breast cancer. All participants were asked to respond to standard questionnaires to collect information on sleep quality, smartphone addiction, and smartphone use. RESULTS: Participants with smartphone addiction had a significantly higher 1.43-fold risk of breast cancer. Individuals with the habitual behavior of smartphone use >4.5 minutes before bedtime had a significantly increased 5.27-fold risk of breast cancer compared to those who used a smartphone for ≤4.5 minutes before bedtime. Additionally, a closer distance between the smartphone and the breasts when using the smartphone exhibited a significantly increased 1.59-fold risk. Participants who carried their smartphone near their chest or waist-abdomen area had significantly increased 5.03-fold and 4.06-fold risks of breast cancer, respectively, compared to those who carried the smartphone below the waist. Moreover, there was a synergistic effect of smartphone addiction and smartphone use of >4.5 minutes before bedtime which increased the breast cancer risk. CONCLUSION: Excessive smartphone use significantly increased the risk of breast cancer, particularly for participants with smartphone addiction, a close distance between the breasts and smartphone, and the habit of smartphone use before bedtime.