Mechanical Control of Polar Patterns in Wrinkled Thin Films via Flexoelectricity.

Intriguing topological polar structures in oxide nanofilms have drawn growing attention owing to their immense potential applications in nanoscale electronic devices. Here, we report a novel route to mechanically manipulate polar structures via flexoelectricity in wrinkled thin films. Our results present a flexoelectric polar transition from a nonpolar state to uniaxial polar stripes, biaxial meronlike or antimeronlike polar structures, and polar labyrinths by varying wrinkle morphologies. The evolution mechanisms and the outstanding mechanical tunability of these flexoelectric polar patterns were investigated theoretically and numerically. This strategy based on flexoelectricity for generating nontrivial polar structures will no longer rely on the superlattice structure and can be widely applicable to all centrosymmetric or noncentrosymmetric materials, providing a broader range of material and structure candidates for polar topologies.

Nuclear isoform of RAPH1 interacts with FOXQ1 to promote aggressiveness and radioresistance in breast cancer.

Radioresistance limits the efficacy of radiotherapy against breast cancer, especially the most lethal subtype of breast cancer, triple-negative breast cancer (TNBC). Epithelial-to-mesenchymal transition (EMT) is closely related to tumor radioresistance. In this work, we attempted to identify the key EMT-related transcription factor(s) that can induce radioresistance in breast cancer cells. A set of 44 EMT transcription factors were analyzed in parental and radioresistant TNBC cell lines. The function of FOXQ1, a differentially expressed transcription factor, was determined in TNBC radioresistance. FOXQ1-interacting proteins were identified by co-immunoprecipitation and mass spectrometry. Compared with parental cells, FOXQ1 was significantly upregulated in radioresistant TNBC cells. Silencing of FOXQ1 increased the radiosensitiviy of radioresistant TNBC cells both in vitro and in vivo. FOXQ1 associated with a nuclear isoform of RAPH1 (named RAPH1-i3) in radioresistant TNBC cells. Overexpression of RAPH1-i3 enhanced TNBC cell proliferation and migration, and most interestingly, induced radioresistance in parental TNBC cells when co-expressed with FOXQ1. Similar findings were observed in estrogen receptor-positive breast cancer cell lines that had co-expression of RAPH1-i3 and FOXQ1. Mechanistically, co-expression of RAPH1-i3 and FOXQ1 activated STAT3 signaling and increased the expression of CCND1, MCL1, Bcl-XL, and MMP2. Depletion of RAPH1-i3 impaired the radioresistance of radioresistant TNBC cells. Additionally, RAPH1-i3 upregulation was associated with advanced tumor stage and reduced disease-free survival in TNBC patients. These results collectively show that RAPH1-i3 interacts with FOXQ1 to promote breast cancer progression and radioresistance. RAPH1-i3 and FOXQ1 represent therapeutic targets for the treatment of breast cancer including TNBC.

Cancer-associated adipocytes release FUCA2 to promote aggressiveness in TNBC.

Cancer-associated adipocytes (CAAs) have been suggested to promote tumor progression. Yet, the role of CAAs in triple-negative breast cancer (TNBC) is poorly investigated. We compared the expression of secretory protein-encoding genes in CAAs and control adipocytes. The effect of key secretory protein(s) on TNBC cell behaviors was explored. CAAs expressed and secreted FUCA2 at greater levels than control adipocytes. When FUCA2 activity was blocked with a neutralizing antibody, TNBC cell proliferation and migration induced by CAA-conditioned medium was impaired. In contrast, supplement of exogenous FUCA2 protein reinforced the proliferation, colony formation, and migration of TNBC cells. In vivo studies confirmed that FUCA2 exposure enhanced tumorigenesis and metastasis of TNBC cells. Mechanistic investigation revealed that FUCA2 induced TNBC aggressiveness through TM9SF3-dependent signaling. Depletion of TM9SF3 blocked CAA- and FUCA2-induced TNBC cell proliferation and migration. Compared to adjacent breast tissues, TNBC tissues had increased expression of TM9SF3. Moreover, high TM9SF3 expression was associated with advanced TNM stage, lymph node metastasis, and shorter overall survival of TNBC patients. Altogether, CAAs secrete FUCA2 to promote TNBC growth and metastasis through interaction with TM9SF3. Inhibition of TM9SF3 may represent a potential therapeutic strategy in the treatment of TNBC.

EIF4A3-mediated hsa_circ_0088088 promotes the carcinogenesis of breast cancer by sponging miR-135-5p.

Circular RNAs have participated in oncology progress. Nevertheless, the potential mechanisms are not completely understood. We intended to inspect the functions of hsa_circ_0088088 on breast malignancy, together with the possible mechanism(s). hsa_circ_0088088 expression in breast malignancy was studied using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). The overall survival was studied by the Kaplan-Meier curve. The biological functions of hsa_circ_0088088 aberrant expression on cell growth and metastasis were evaluated in MDA-MB-231 cells. Bioinformatics analysis, RNA immunoprecipitation (RIP), and qRT-PCR were accomplished to confirm the possible regulatory effects of eukaryotic initiation factor 4A3 (EIF4A3) on the biogenesis of hsa_circ_0088088. Furthermore, a dual-luciferase reporter assay, qRT-PCR, and RNA pull-down assay were used to confirm the association between the hsa_circ_0088088 and miR-135-5p in MDA-MB-231 cells. hsa_circ_0088088 was upregulated in the tumor tissues and cells, and higher expression presented an unfavorable prognosis. hsa_circ_0088088 overexpression promoted cell growth and metastasis in MDA-MB-231 cells. EIF4A3 was found to positively regulate hsa_circ_0088088. Furthermore, we confirmed that hsa_circ_0088088 sponges miR-135-5p and directly targets miR-135-5p with respect to the cell growth and metastasis in MDA-MB-231 cells. Our data suggest that EIF4A3-induced hsa_circ_0088088 stimulates the carcinogenic effects of breast tumors by sponging miR-135-5p.

Telemedicine and Community Health Projects in Asia.

Telemedicine has the potential to deliver high-quality, affordable health care to underserved populations that otherwise would not have adequate access to care. The authors provide a snapshot of several telemedicine initiatives that have used information and communication technologies to connect patients with health care providers across various Asian countries with differing socioeconomic statuses. They highlight several factors thought to contribute to the success of telemedicine programs, such as financial sustainability, ease of use, and utilization of existing resources. Challenges these programs have faced include lack of technological infrastructure, limitations in funding, and conflicting health system priorities.

Long Non-coding RNA LOXL1-AS1 Drives Breast Cancer Invasion and Metastasis by Antagonizing miR-708-5p Expression and Activity.

LOXL1-AS1, a recently characterized long non-coding RNA (lncRNA), has been reported to modulate tumor progression in several types of cancer. However, the expression and role of LOXL1-AS1 in breast cancer remain unclear. In this study, we sought to identify novel lncRNA regulators engaged in breast cancer metastasis. To this end, we examined 42 cancer-related lncRNAs between MCF7 (with low metastatic potential) and MDA-MB-231 (with high metastatic potential) cells. These lncRNAs have been found to affect the invasiveness of several cancer types, but they are still undefined in breast cancer. Among the 42 candidates, LOXL1-AS1 is significantly increased in MDA-MB-231 cells relative to MCF7 cells. We also show that LOXL1-AS1 is upregulated in breast cancer tissues and cells compared to noncancerous counterparts. Increased LOXL1-AS1 expression is correlated with tumor stage and lymph node metastasis in breast cancer patients. Biologically, overexpression of LOXL1-AS1 enhances and knockdown of LOXL1-AS1 suppresses breast cancer cell migration and invasion. In vivo studies demonstrate that depletion of LOXL1-AS1 inhibits breast cancer metastasis. Mechanistically, LOXL1-AS1 sponges miR-708-5p to increase nuclear factor κB (NF-κB) activity. LOXL1-AS1 can also interact with EZH2 protein to enhance EZH2-mediated transcriptional repression of miR-708-5p. Rescue experiments indicate that co-expression of miR-708-5p attenuates LOXL1-AS1-induced invasiveness in breast cancer. In addition, there is a negative correlation between LOXL1-AS1 and miR-708-5p expression in breast cancer specimens. Overall, LOXL1-AS1 upregulation facilitates breast cancer invasion and metastasis by blocking miR-708-5p expression and activity. LOXL1-AS1 serves as a potential therapeutic target for breast cancer treatment.

Dietary isoflavones or isoflavone-rich food intake and breast cancer risk: A meta-analysis of prospective cohort studies.

BACKGROUND & AIMS: Previous studies implied that dietary isoflavone intake may reduce the risk of developing breast cancer, but some have shown ambiguous results. This study aimed to systematically evaluate and summarize available evidence on the effect dietary isoflavone intake has on the risk of developing breast cancer. METHODS: PubMed, Embase, and the Cochrane Library were searched for prospective cohort studies published through April 2017 that evaluated the effect of dietary isoflavone intake on the development of breast cancer. RESULTS: Sixteen prospective cohort studies, involving 11,169 breast cancer cases and 648,913 participants, were identified and included in our data analysis. The pooled relative risk (RR) of breast cancer was 0.99 for high versus low intake of isoflavones (95% confidence interval [CI], 0.91-1.09; P = 0.876) and 0.99 for moderate versus low intake of isoflavones (95%CI, 0.92-1.05; P = 0.653), with insignificant heterogeneity (P = 0.187 for high versus low, and P = 0.192 for moderate versus low). While a moderate consumption of soy-based foods did not significantly affect breast cancer risk, a high intake of soy-based foods associated with a lower risk of developing breast cancer. Considering specific foods, an increased the risk of developing breast cancer was seen with a moderate intake of formononetin, but no significant associations were found between breast cancer risk and other isoflavone-rich diets. CONCLUSIONS: The present meta-analysis indicates that women with a high dietary intake of soy foods may experience a statistically significant reduction in breast cancer risk. However, moderate formononetin consumption may increase the risk of developing breast cancer.

ALDH1 Expression and Vasculogenic Mimicry Are Positively Associated with Poor Prognosis in Patients with Breast Cancer.

BACKGROUND/AIMS: This study aimed to explore the prognostic value of aldehyde dehydrogenase 1 (ALDH1) expression and vasculogenic mimicry (VM) in patients with breast cancer. METHODS: ALDH1 expression and the presence of VM were examined by immunohistochemistry and CD31/PAS double staining, respectively, using formalin-fixed paraffin-embedded tissues from 202 breast cancer patients. The mean follow-up period ranged from 15 to 115 months. The Kaplan-Meier method was used to plot survival curves. Prognostic values were assessed by multivariate analysis using the Cox regression model. RESULTS: ALDH1 expression was strongly associated with VM (P = 0.005). ALDH1 expression was positively correlated with histological grade (P = 0.011). Both ALDH1 expression and VM were negatively related to the status of the estrogen receptor and progesterone receptor and were statistically increased in triple-negative breast cancer. Patients with ALDH1 expression or VM displayed poorer disease-free survival (DFS) and overall survival (OS) than ALDH1-negative or VM-negative patients, with the worst OS and DFS observed in ALDH1/VM-double-positive patients. ALDH1-positive and VM-positive were independent survival risk factors for DFS and OS. CONCLUSION: ALDH1 expression and VM are correlated with the survival rate of patients with breast cancer. ALDH1 and VM, either alone or together, are prognostic factors in patients with breast cancer.

Preoperative assessment of axillary lymph node status in breast cancer patients by ultrasonography combined with mammography: A STROBE compliant article.

Preoperative assessment of nodal stage is of importance in breast cancer treatment decision-making. This study was done to determine the power of combined mammography and ultrasonography in differentiating N0-N1 from N2-N3 breast cancer.We retrospectively reviewed clinical data of 3944 female patients with invasive breast cancer by preoperative mammography and ultrasonography between January 2006 and December 2013 at our hospital. Pathological diagnosis was available for each patient. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of mammography alone, ultrasonography alone, and combination of them for assessment of axillary lymph node (ALN) status were calculated, using definitive histological results as the baseline.The sensitivity, specificity, PPV, NPV, and accuracy was 90.4%, 68.2%, 36.5%, 97.2%, and 71.9% for ultrasonography; was 66.9%, 80.8%, 41.3%, 92.3%, and 78.4% for mammography; and was 94.9%, 62.4%, 33.8%, and 98.4% for combined mammography and ultrasonography. For combination, accuracy and the area under the receiver operating characteristic curve was 67.9% and 0.85, respectively.In conclusion, combining ultrasonography and mammography improves the sensitivity in differentiating N0-N1 breast cancer from N2-N3 breast cancer, but leading to a reduced specificity. Addition of mammography to ultrasonography seems not to provide significant benefits in predicting ALN status in breast cancer patients.

Downregulation of RASSF6 promotes breast cancer growth and chemoresistance through regulation of Hippo signaling.

This study aims to investigate the clinical significance and biological function of RASSF6 in human breast cancers. RASSF6 protein was found to be downregulated in 42 of 95 human breast cancer tissues by immunohistochemistry, which was associated with advanced TNM stage and nodal metastasis. The rate of RASSF6 downregulation was higher in Triple-negative breast cancer (TNBC). Downregulation of RASSF6 protein was also found in breast cancer cell lines, especially in TNBC cell lines. Overexpression RASSF6 inhibited cell growth rate and colony formation ability in MDA-MB-231 cell line. Depletion of RASSF6 promoted proliferation rate and colony formation ability in T47D cell line. Flow cytometry/PI staining demonstrated that RASSF6 inhibited cell cycle transition. AnnxinV/PI analysis showed that RASSF6 overexpression upregulated apoptosis induced by cisplatin (CDDP) while RASSF6 depletion inhibited apoptosis. JC-1 staining showed that RASSF6 overexpression inhibited mitochondrial membrane potential. Western blot analysis demonstrated that RASSF6 repressed cyclin D1, YAP while upregulated p21, cleaved caspase 3 and cytochrome c expression. In addition, RASSF6 activated Hippo signaling pathway by upregulating MST1/2 and LATS1 phosphorylation. Restoration of YAP inhibited cleaved caspase 3 and cytochrome c which were induced by RASSF6. Restoration of YAP also reduced the rate of CDDP induced apoptosis. In conclusion, this study provided evidence that RASSF6 functions as a potential tumor suppressor in human breast cancer through activation of Hippo pathway.

TRIM32 promotes proliferation and confers chemoresistance to breast cancer cells through activation of the NF-κB pathway.

Dysregulation of TRIM32 has been implicated in several human cancers, however, its clinical significance and biological function in breast cancer have not been investigated. Using immunohistochemistry, we found that TRIM32 expression is upregulated in breast cancer tissues and that it correlates with advanced stage and poor prognosis. TRIM32 is also overexpressed in 4/7 breast cancer cell lines. CCK8 and colony formation assays showed that TRIM32 depletion inhibited proliferation and colony formation in the T47D cell line, while TRIM32 overexpression promoted MCF-7 cell growth and colony formation. Cell viability and Annexin V/PI staining demonstrated that TRIM32 maintained breast cancer cell survival and reduced apoptosis rate when cells were treated with cisplatin. Western blot analysis demonstrated that TRIM32 overexpression resulted in an upregulation of p-IκB, p-p65, cIAP1, and cIAP2 and a downregulation of p21 and p27 in MCF-7 cells. TRIM32 depletion in T47D cells demonstrated the opposite results, suggesting that TRIM32 may activate the NF-κB pathway. The NF-κB inhibitor BAY 11-7082 blocked the effects of TRIM32 on cisplatin resistance and cIAP1/2 protein regulation. Taken together, the present study demonstrates that TRIM32 downregulates p21/p27 and upregulates IAP family proteins to facilitate breast cancer cell growth and inhibit drug-induced apoptosis, possibly through the NF-κB signaling pathway.

Impact of persistence on survival of patients with breast cancer treated with endocrine therapy in Northeast China: a prospective study.

The purpose of this prospective study is to investigate the impact of endocrine treatment persistence on the survival of patients with estrogen receptor-positive breast cancer treated with endocrine therapy and identify the risk factors influencing the treatment persistence. We enrolled 1085 patients from Northeast China who were diagnosed as stage I-III, estrogen receptor-positive breast cancer between January 2007 and December 2010. The prognostic factors for disease-free survival (DFS) and overall survival (OS) of patients were identified using univariate and multivariate Cox proportional hazards regression models. Multiple logistic regression analysis was done to determine the possible risk factors for non-endocrine treatment and treatment discontinuation. Among the patients enrolled, 598 (55.1%) underwent 5 years of endocrine therapy, 278 (25.6%) less than 5 years, and 209 (19.3%) non-endocrine therapy. OS rates in the continuation, discontinuation, and non-endocrine treatment groups were 97.8%, 92.6% and 74.3%, and DFS 97.5%, 86.2% and 69.9%, respectively. After adjusting for pathological and socioeconomic factors, non-endocrine therapy and discontinuation were independent predictors for DFS and OS. Elderly patients (≥ 65 years), those living in suburban and rural areas, locally advanced patients, and receiving no radiotherapy and/or chemotherapy were more likely to receive non-endocrine therapy and discontinue endocrine treatment. In conclusion, the prospective study demonstrate that the persistence of endocrine treatment is low in estrogen receptor-positive breast cancer patients in Northeast China. Non-endocrine treatment and early discontinuation serve as independent prognostic factors for both DFS and OS of breast cancer patients treated with endocrine therapy.

Acquired melanocytic naevus phenotypes and MC1R genotypes in Han Chinese: a cross-sectional study.

BACKGROUND: Early detection and treatment are the most important elements in reducing the incidence of melanoma deaths. Acquired melanocytic naevi (AMN) are well-known precursors of melanoma but most of our knowledge on the clinico-dermoscopic phenotypes of AMN is based on studies in European-background populations, particularly American and Australian populations. There has been little research in Chinese Han populations on clinico-dermoscopic variability of naevi or how naevi are affected by melanoma-linked variants of the melanocortin 1 receptor (MC1R) gene. METHODS: Clinical and dermoscopic features of 448 AMN in 115 patients from the Han ethnic group in mainland China were described. Germline polymorphisms in MC1R were determined for 98 of these patients. RESULTS: AMN were predominantly found on the head and neck. Dermoscopic patterns observed were nonspecific, reticular, globular, and parallel furrow, with most AMN having a nonspecific pattern. There were no associations between MC1R polymorphisms and clinical or dermoscopic features of AMN. DISCUSSION: Our results provide evidence that AMN in the Han population in China have similar dermoscopic patterns to those in European populations, but are present in much lower numbers. As there were no associations between clinical or dermoscopic features of AMN and MC1R polymorphisms, further studies should focus on candidate gene associations with AMN features and the risk of melanoma, with larger sample sizes and comparisons to AMN in other populations.

Upregulation of transmembrane 4 L6 family member 1 predicts poor prognosis in invasive breast cancer: A STROBE-compliant article.

Transmembrane 4 L6 family member 1 (TM4SF1) belongs to the 4-transmembrane-domain family and functions as an oncogene in multiple human cancers. In this work, we aim to determine TM4SF1 expression and its prognostic impact on patients with invasive breast cancer.Overall, we enrolled 209 invasive breast cancer patients and immunohistochemically examined the expression of TM4SF1 in tumor specimens. The relationship between TM4SF1 expression and clinicopathological parameter and patient survival of breast cancer patients was analyzed.Among the 209 cases, 137 (65.6%) exhibited high expression of TM4SF1. High TM4SF1 expression was significantly associated with advanced histological grade and negative estrogen receptor and progesterone receptor status. Triple-negative breast cancer (TNBC) tumors were more likely to express high levels of TM4SF1 than non-TNBC cases. Patients with high tumoral expression of TM4SF1 had a significantly shorter disease-free survival (DFS; P = .00) and overall survival (OS; P = .01) than those with low expression of TM4SF1. When survival analysis was restricted to the 167 patients (79.9%) receiving adjuvant chemotherapy, TM4SF1 expression was also correlated with poorer DFS and OS (P = .00). In multiple Cox regression analysis TM4SF1 expression remained an independent prognostic indicator for OS and DFS.TM4SF1 is upregulated and serves as an independent poor prognostic indicator in invasive breast cancer.

The value of substratified combined imaging assessment with mammography and ultrasonography for Chinese women with palpable breast masses.

A 5-point breast imaging classification modified from the seven-category Breast Imaging-Reporting and Data System has been applied for mammographic and ultrasonographic examinations in patients with palpable breast masses. The aim of this study was to confirm the value of combined imaging assessment. We included 5,296 cases (3,002 benign and 2,294 cancer) from January 2004 to December 2011. Ultrasonography showed a significantly (P < 0.01) higher sensitivity and specificity and lower false-negative rate and false-negative predictive value (false-NPV) than mammography. The sensitivity of combined imaging was significantly (P < 0.01) increased and the false-negative rate and false-NPV were significantly (P < 0.01) reduced compared to mammography or ultrasonography alone. However, the specificity was significantly (P < 0.01) declined for combined imaging versus mammography or ultrasonography alone. Compared with combined imaging assessment, a significant (P < 0.01) improvement was noted with substratified scoring, with increased specificity and false-negative rate and decreased sensitivity. In conclusion, the substratified combined imaging score has the potential to provide additional value in the workup of palpable breast lesions.