Factors for risk stratification of patients with actinic keratosis using integrated analysis of clinicopathological features and gene expression patterns.

BACKGROUND: Actinic keratosis (AK) is considered as precursor lesion of invasive squamous cell carcinoma. Molecular studies on AK are limited because of too small size of the biopsy specimen to obtain enough DNA or RNA. METHODS: Twenty biopsy cases of AK, followed by second same-sited biopsies, were included. Ten cases were diagnosed with total regression (regression group), while the other 10 were diagnosed with invasive carcinoma (progression group) in the follow-up biopsies. Using digital spatial profiling (DSP) technology, whole-gene expression analysis defined by specific regions of interest was performed for all 20 cases. After the clinicopathological features were assessed, separate and integrated analyses of these features and gene expression patterns were performed using machine-learning technology. All analyses were performed on both lesion keratinocytes (KT) and infiltrated stromal lymphocytes (LC). RESULTS: Among the 18,667 genes assessed, 33 and 72 differentially expressed genes (DEGs) between the regression and progression groups were found in KT and LC respectively. The primary genes distinguishing the two groups were KRT10 for KT and CARD18 for LC. Clinicopathological features were weaker in risk stratification of AK progression than the gene expression patterns. Pathways associated with various cancers were upregulated in the progression group of KT, whereas the nucleotide-binding oligomerization domain (NOD)-like receptor signalling pathway was upregulated in the progression of LC. CONCLUSION: Gene expression patterns were effective for risk stratification of AK progression, and their distinguishing power was higher than that of clinicopathological features.

Enhancement of Steel Sandwich Sheet Adhesion Using Mechanical Interlocking Structures Formed by Electrochemical Etching.

Steel sandwich sheets (steel-polymer-steel), which are composed of lightweight polymers bonded on both sides with rigid steel sheets, have recently been developed as functional lightweight materials. In this study, a steel sandwich sheet (electrogalvanized (EG) steel sheet-polypropylene (PP)-EG steel sheet) with improved normal adhesion is fabricated without adhesives. Instead, adhesion is achieved via mechanical interlocking between the etched EG steel sheets and PP. Hierarchical structures were formed on the EG steel sheet surface by electrochemical etching to attain effective mechanical interlocking for improving normal adhesion without any adhesives. In the case of the EG steel sheet etched at 6 V for 7 s, a high fraction (∼35%) of holes (size: <1 µm2) with nanoscale scalloped structures was formed on the EG steel sheet surface. The normal adhesion test result of the fabricated steel sandwich sheet showed that the adhesion strength increased from virtually 0 (bare) to 559.6 kPa as a result of mechanical interlocking. The results of the focused ion beam-scanning electron microscopy and energy-dispersive spectrometry analyses confirmed the cohesive failure of PP resulting from the successful mechanical interlocking of PP with the holes formed on the etched EG steel sheet. To examine the effect of hierarchical structures on the normal adhesion of the steel sandwich sheet, finite element analysis was implemented.

Late-Onset Inflammation in Asian Rhinoplasty Using Alloplastic Implants.

BACKGROUND: Late-onset inflammation is a rare complication that may occur several months to years after undergoing an uneventful rhinoplasty using alloplastic implants and an uneventful postoperative course. Studies to determine the pathophysiological mechanisms of late-onset inflammation related to implants used in rhinoplasty are limited. The purpose of the study was to analyze differences between non-healthy capsules (NHC) with late-onset inflammation and healthy capsules (HC) without inflammation as controls to determine the possible cause of the inflammation. METHODS: Between April 2009 and May 2018, 39 patients who underwent rhinoplasty with alloplastic implants underwent histological studies. Twenty-one patients in the NHC group showed late-onset inflammation, while 18 patients in the HC group did not display late-onset inflammation. Capsules around the alloplastic implants were harvested, and histological studies using hematoxylin and eosin, Masson's trichrome, colloidal iron, and CD31 staining were performed and compared between the NHC and HC groups. RESULTS: In hematoxylin and eosin and Masson's trichrome staining, edematous granulation tissues, inflammatory cellular contents, and a disorganized collagen layer were increased in the NHC group compared to the HC group. The colloidal iron staining revealed mucin deposition in the NHC group. CD31-positive cells were observed lining the capsule in both groups; however, the lining cells were damaged in the NHC group. CONCLUSION: Granulation tissues, inflammatory reaction, collagen degeneration, mucin deposition, and endothelial lining cell damage were greater in the NHC group compared to the HC group. Damaged capsules may play a crucial role in late-onset inflammation. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy.

BACKGROUND: Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative breast cancer have poor prognoses. The benefit of adjuvant chemotherapy in these patients remains unclear. METHODS: We randomly assigned 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease-free survival. Secondary end points included overall survival. RESULTS: The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval [CI], 0.53 to 0.92; P=0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01). Among patients with triple-negative disease, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90). The hand-foot syndrome, the most common adverse reaction to capecitabine, occurred in 73.4% of the patients in the capecitabine group. CONCLUSIONS: After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing. (Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE-X UMIN Clinical Trials Registry number, UMIN000000843 .).

Clinical Experience with Treatment of Aquafilling Filler-Associated Complications: A Retrospective Study of 146 Cases.

BACKGROUND: Aquafilling filler is used for breast and buttock augmentation, which are the most commonly performed cosmetic surgery procedures. However, complications after using Aquafilling filler for breast augmentation have been reported, and there are concerns regarding its use in large areas, such as the buttocks. We provide our experience with complications after breast augmentation and buttock augmentation using Aquafilling filler. METHODS: This observational cohort study analyzed the data of 399 patients treated for filler-related complications at our institutes from September 2015 to November 2019. Of these patients, 146 underwent surgery to remove Aquafilling filler from the breast or buttock. RESULTS: The mean time between Aquafilling filler use and complication onset was 38.5 ± 10.2 months. The average amount of filler material removed from one side of the breast or buttock was 285.5 ± 95.8 mL (range 150-750 mL). The most common complications were induration and masses (83.6%), followed by pain (52.1%), firmness (24.7%), asymmetry (10.3%), migration (8.2%), mastitis (6.8%), dimpling (6.2%), fever (3.4%), and sepsis (n = 1). After treatment, there was no recurrence of infection, and the patient satisfaction level based on the visual analogue scale was 8.0 ± 0.9. CONCLUSIONS: Although Aquafilling filler is easily injectable and has long-term clinical effects, complications can occur. Furthermore, there are concerns regarding its toxicity and influence on the surrounding tissues. Hence, further research studies on Aquafilling filler and evidence regarding its long-term safety are needed. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Recurrence prediction using microRNA expression in hormone receptor positive breast cancer during tamoxifen treatment.

PURPOSE: To identify miRNAs associated with distant recurrence during tamoxifen treatment and build a recurrence prediction model. MATERIALS AND METHODS: We measured the expression of five miRNAs (miR-134, miR-125b-5P, miRNA-30a, miR-10a-5p and miR-222). A total of 176 tumour tissues from 176 patients who had hormone receptor positive breast cancer with tamoxifen treatment were used to measure miRNA expression using quantitative real-time PCR (qRT-PCR). RESULTS: The five miRNAs were all up-regulated in distant recurrence cases within 5 years after surgery and during tamoxifen treatment. Kaplan-Meier survival analyses based on expression cut-offs determined by receiver characteristics curves (ROC) showed that high expression of miR-134, miR-125b-5P, miRNA-30a, miR-10a-5p and miR-222 were significantly (log-rank p-value =0.006, p-value <0.0001, p-value <0.0001, p-value <0.0001 and p-value <0.0001, respectively) associated with short relapse-free time. Our results were used to build a combined 3 miRNAs expression model. It could be used to categorize high-risk subset of patients with short relapse-free survival (AUC =0.891, p-value <0.0001). CONCLUSIONS: Distant recurrence during tamoxifen treatment of hormone positive breast cancer might be affected by tamoxifen resistance related miRNAs. Such distant recurrence can be predicted using miRNA measurement.

Anti-cancer effect of metformin by suppressing signaling pathway of HER2 and HER3 in tamoxifen-resistant breast cancer cells.

Development of new therapeutic strategies is becoming increasingly important to overcome tamoxifen resistance. Recently, much interest has been focused on anti-tumor effects of metformin commonly used to treat type II diabetes. Increased protein expression and signaling of epidermal growth factor receptor (EGFR) family is a possible mechanism involved in tamoxifen resistance. Since HER2/HER3 heterodimers are able to induce strong downstream signaling and activate various biological responses such as cellular proliferation and growth, we investigated the anti-cancer effect of metformin by inhibition of signaling pathway via downregulation of HER2 and HER3 using tamoxifen-resistant MCF-7 (TR MCF-7) cells. Compared to MCF-7 cells, TR MCF-7 cells showed increased expression of EGFR, HER2, and HER3, and metformin inhibited the expression of these proteins in a dose- and time-dependent manner. Metformin inhibited activation of HER2 (Tyr1248)/HER3 (Tyr1289)/Akt (Ser473) as well as cell proliferation and colony formation by estrogenic promotion in MCF-7 and TR MCF-7 cells. Known as a HER3 ligand, heregulin (HRG)-ß1-induced phosphorylation of HER2, HER3 and Akt, and protein interaction of HER2/HER3 and colony formation were inhibited by metformin in both cells. Consistent with the results in the two cell lines, we identified that metformin inhibited HER2/HER3/Akt signaling axis activated by HRG-ß1 using the HER2 and HER3-overexpressing breast cancer cell line SK-BR-3. Lastly, lapatinib-induced HER3 upregulation was significantly inhibited by treatment of metformin in HER3 siRNA-transfected TR MCF-7 cells. These data suggest that metformin might overcome tamoxifen resistance through the inhibition of expression and signaling of receptor tyrosine kinase HER2 and HER3.

Expression of ROR1, pAkt, and pCREB in gastric adenocarcinoma.

The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transmembrane protein of receptor tyrosine kinase family. High expression of ROR1 is reported in many types of malignancies and is thought to be involved in tumor growth, apoptosis, and epithelial-mesenchymal transition. In this study, we examined the expression of ROR1, pAkt, and pCREB in gastric adenocarcinoma and analyzed with clinicopathologic factors and tumor proliferation. Tissue microarray blocks containing 424 gastric adenocarcinomas were used for immunohistochemical staining. Ki-67 labeling index was used for tumor proliferation activity. High expression of ROR1 (63%), pAkt (36%), and pCREB (20%) was observed in gastric adenocarcinomas, and expression of these proteins was well intercorrelated. ROR1 and pCREB expression was associated with Ki-67 labeling index (P < .001). Expression of pAkt and pCREB group showed longer survival in univariate analysis (P = .007 and P < .001, respectively). This is the first study that analyzed ROR1 expression in gastric adenocarcinoma tissue samples. We revealed that gastric adenocarcinomas highly express ROR1 and related proteins and its prognostic significance. ROR1 in gastric adenocarcinoma could be possible candidate of therapeutic target, and more comprehensive study is required.

YKL-40 expression could be a poor prognostic marker in the breast cancer tissue.

YKL-40 is a glycoprotein involved in cellular growth, migration, and the inflammatory process. Elevation in serum levels of YKL-40 has been associated with worse prognosis in various cancers, including breast cancer. Given that the clinical significance of YKL-40 expression in breast cancer tissue is unclear, we aimed to determine the prognostic value of YKL-40 expression in breast cancer tissue using immunohistochemistry. We performed tissue microarray (TMA) analysis of 425 breast cancer tissues collected during operation. Immunohistochemical staining was performed to measure expression of YKL-40 and several breast cancer biomarkers, such as aldehyde dehyadrogenase1, TGF-beta, and Gli-1 as well as hormonal receptor and Her-2/neu status. Statistical analysis of the relationship of YKL-40 expression with clinicopathological characteristics was performed for 390 TMA samples. YKL-40 was expressed to varying degrees in 84.9% of breast cancer tissues. YKL-40 expression was correlated with estrogen receptor and progesterone receptor negativity and was positively correlated with TGF-beta and Gli-1 expression. Strong YKL-40 expression was associated with a larger proportion of Her-2/neu-enriched and basal-like tumors. The results of this study demonstrate that YKL-40 expression in breast cancer tissues is associated with hormone receptor negativity and Her-2/neu-enriched molecular subtypes of breast cancer, and therefore could be considered a poor prognostic predictor.

Role of erbB3 receptors in cancer therapeutic resistance.

ErbB3 receptors are unique members of the erbB receptor tyrosine kinases (RTKs), which are often aberrantly expressed and/or activated in human cancers. Unlike other members in the family, erbB3 lacks or has impaired kinase activity. To transduce cell signaling, erbB3 has to interact with other RTKs and to be phosphorylated by its interactive partners, of those, erbB2 is the most important one. ErbB3 is frequently co-expressed with other RTKs in cancer cells to activate oncogenic signaling, such as phosphoinositide-3-kinase/protein kinase B (Akt) pathway, mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) pathway, Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway, etc. and thereby promote tumorigenesis. Numerous studies have demonstrated that activation of erbB3 signaling plays an important role in the progression of a variety of tumor types, such as erbB2-overexpressing breast cancer, castration-resistant prostate cancer, platinum refractory/resistant ovarian cancer, epidermal growth factor receptor TKI-resistant non-small-cell lung cancer, and others. Basic research on the underlying mechanisms implicated the functions of erbB3 as a major cause of treatment failure in cancer therapy. Thus, concomitant inhibition of erbB3 is thought to be required to overcome the resistance and to effectively treat human cancers. This review focuses on the latest advances in our understanding of erbB3-initiated signaling in the development of resistance to cancer treatments.

Nipple Schwannoma: A Case Report and Literature Review on Nipple Mass.

Schwannomas are slow-growing benign tumors originating from the Schwann cells of the peripheral nerve sheaths. Herein, we report the first documented case of a schwannoma presenting as a painful nipple mass in a 32-year-old woman. This mass initially developed six years ago following a period of breastfeeding. Breast magnetic resonance imaging (MRI) scans revealed an iso-intense mass, with an approximate size of 2.2 cm, on a T1-weighted image with internal cystic changes. The mass exhibited heterogeneously delayed enhancement and restricted diffusion. Surgical excision was performed, and the diagnosis of cutaneous plexiform nipple schwannoma was confirmed histopathologically. A literature review revealed that the MRI findings of the nipple mass in our case were consistent with the common features of a schwannoma.

Molecular Classification of Breast Cancer Using Weakly Supervised Learning.

Purpose: The molecular classification of breast cancer is crucial for effective treatment. The emergence of digital pathology has ushered in a new era in which weakly supervised learning leveraging whole-slide images has gained prominence in developing deep learning models because this approach alleviates the need for extensive manual annotation. Weakly supervised learning was employed to classify the molecular subtypes of breast cancer. Methods: Our approach capitalizes on two whole-slide image datasets: one consisting of breast cancer cases from the Korea University Guro Hospital (KG) and the other originating from The Cancer Genomic Atlas dataset (TCGA). Furthermore, we visualized the inferred results using an attention-based heat map and reviewed the histomorphological features of the most attentive patches. Results: The KG+TCGA-trained model achieved an area under the receiver operating characteristics value of 0.749. An inherent challenge lies in the imbalance among subtypes. Additionally, discrepancies between the two datasets resulted in different molecular subtype proportions. To mitigate this imbalance, we merged the two datasets, and the resulting model exhibited improved performance. The attentive patches correlated well with widely recognized histomorphologic features. The triple-negative subtype has a high incidence of high-grade nuclei, tumor necrosis, and intratumoral tumor-infiltrating lymphocytes. The luminal A subtype showed a high incidence of collagen fibers. Conclusions: The artificial intelligence (AI) model based on weakly supervised learning showed promising performance. A review of the most attentive patches provided insights into the predictions of the AI model. AI models can become invaluable screening tools that reduce costs and workloads in practice.

Reprogramming of mouse fibroblasts into induced pluripotent stem cells with Nanog.

Oct4-Sox2-Nanog transcriptional networks are critical for the maintenance of embryonic stem (ES) cell self-renewal and induction of pluripotency. However, in transcription factor-induced reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), Nanog is initially dispensable and Oct4 remains the sole factor that could not be substituted/omitted. Here, we show that mouse fibroblasts could be reprogrammed into iPSCs by Nanog and Bmi1, which replaces Sox2, Klf4, and c-Myc, in the absence of Oct4. Furthermore, we show that in the presence of shh agonists (oxysterol and purmophamine), which replaces the function of Bmi1, a single transcription factor, Nanog is sufficient to reprogram mouse fibroblasts into iPSCs. Nanog-induced iPSCs resemble mESCs in terms of morphology, global gene expression profiles, epigenetic status and pluripotency both in vitro and in vivo. These findings support that Nanog can replace the Oct4 for the somatic cell reprogramming and underlie the mechanisms of Nanog in reprogramming process.

Expression of moesin and CD44 is associated with poor prognosis in gastric adenocarcinoma.

AIMS: CD44 has been reported as a negative prognostic marker in gastric cancer. It interacts with moesin in epithelial-mesenchymal transition. To date, to our knowledge, there has been no clinical study dealing with the relationship between moesin and gastric adenocarcinoma. We analysed the expression of moesin and CD44 in gastric adenocarcinoma tissue, and correlations with clinicopathological factors. METHODS AND RESULTS: A retrospective analysis was made of 430 patients who had undergone gastrectomy at the Korea University Guro Hospital between 2002 and 2005 for gastric adenocarcinoma. Using tissue microarray and immunohistochemical staining, moesin expression was observed in 192 (44.7%) cases; it was associated significantly with poorly differentiated histology, invasion depth, lymph node metastasis, lymphatic invasion and advanced pathological TNM stage. CD44 expression was not correlated with clinicopathological features or moesin expression. Moesin expression was a strong predictor of lymph node metastasis in logistic regression analysis. Both moesin expression and CD44 expression were associated significantly with poor overall survival in univariate analysis. Furthermore, in multivariate analysis, moesin and CD44 were independent markers of poor prognosis, along with pathological TNM stage and older patient age. CONCLUSION: Moesin expression and CD44 expression might be useful markers of poor prognosis in gastric adenocarcinoma.

HRG-ß1-driven ErbB3 signaling induces epithelial-mesenchymal transition in breast cancer cells.

BACKGROUND: Heregulin (HRG; also known as neuregulin) is a ligand for ErbB3. One of its isotypes, HRG-ß1, binds to ErbB3 and forms heterodimers with other ErbB family members, thereby enhancing the proliferation and tumorigenesis of breast cancer cells. HRG stimulation may contribute to the progression of epithelial-mesenchymal transition (EMT) and tumor metastasis in breast cancer. Majority of studies regarding EMT has been concentrated on TGF-ß signaling. Therefore, we investigated whether the HRG-ß1 and ErbB3 activate Smad2 signaling during process of EMT in breast cancer cells. METHODS: The SK-BR-3 and MCF7 breast cancer cell lines were used. The expressions of phospho-Smad2 and EMT markers were observed by western blotting and immunofluorescence assays after treatment with HRG-ß1. The cell motility and invasiveness were determined by wound healing and matrigel invasion assays. Smad2 and ErbB3 small interfering RNA (siRNA) transfections were performed to assess the involvement of ErbB3 and Smad2 in HRG-ß1-induced EMT. RESULTS: HRG-ß1 induced EMT through activation of Smad2. The expression of E-cadherin was decreased after HRG-ß1 treatment, while the expressions of Snail, vimentin, and fibronectin were increased. The HRG-ß1-induced expressions of Snail, vimentin, and fibronectin, and nuclear colocalization of phospho-Smad2 and Snail were inhibited by pretreatment with a PI3k inhibitor, LY294002, or two phospho-Smad2 inhibitors, PD169316 or SB203580 and cancer cell migration by HRG-ß1 was inhibited. Knockdown of Smad2 by siRNA transfection suppressed the expressions of Snail and fibronectin in response to HRG-ß1 stimulation and knockdown of ErbB3 suppressed the expressions of phospho-Smad2, Snail, and fibronectin induced by HRG-ß1, whereas E-cadherin was increased compared with control siRNA-transfected cells. Knockdown of ErbB3 and Smad2 also decreased SK-BR-3 and MCF7 cell invasion. CONCLUSIONS: Our data suggest that HRG-ß1 and ErbB3 induce EMT, cancer cell migration and invasion through the PI3k/Akt-phospho-Smad2-Snail signaling pathway in SK-BR-3 and MCF7 breast cancer cells.

Prognostic implications for high expression of oncogenic microRNAs in advanced gastric carcinoma.

BACKGROUND: Aberrant expressions of specific microRNAs are recently known in many malignancies, including gastric carcinoma. The prognostic implication of oncogenic microRNA dysregulation was investigated in advanced gastric carcinomas undergoing radical resection and adjuvant systemic chemotherapy, and observed on long-term follow-up. METHODS: The expression levels of miR-20a, miR-21, miR-25, miR-93, miR-103, miR-106a, miR-106b, miR-130b, miR-155, miR-221, and miR-222 were analyzed in formalin-fixed paraffin-embedded (FFPE) cancer tissues of 91 patients, using reverse transcription real-time PCR. RESULTS: The high expression of miR-20a, miR-25, miR-93, miR-103, miR-106a, miR-106b, miR-130 was associated with lymph node metastasis (P < 0.05), and high expression of miR-155 was related to tumor penetration through serosa and lymph node metastasis (P < 0.05). Cases with high expression of miR-222 (P = 0.014) showed reduced 5-year survival rates. The high expression of miR-222 and miR-221 showed correlation with shorter metastasis-free survival (P = 0.039 and 0.033, respectively), and miR-222 high expression was related to reduced overall survival (P = 0.012). CONCLUSIONS: The high expression of miR-20a, miR-25, miR-93, miR-103, miR-106a, miR-106b, miR-130, miR-155, miR-221, and miR-222 in AGC tissues may be a high risk factor associated with tumor penetration through serosa, lymph node metastasis, distant metastasis, and poor long-term survival in patients undergoing radical resection and adjuvant systemic chemotherapy.

The relationship between preeclampsia, pregnancy-induced hypertension and maternal risk of breast cancer: a meta-analysis.

BACKGROUND: It has long been recognized that some human breast cancers are hormone dependent. Preeclampsia is a syndrome of pregnancy defined by the onset of hypertension and proteinuria and characterized by dysfunction of the maternal endothelium. Many hormonal changes occur with preeclampsia, and we hypothesize that these changes may influence the risk of maternal breast cancer. We also analyzed the relation between pregnancy-induced hypertension (PIH) and maternal risk of breast cancer. METHODS: Among 13 relevant publications about preeclampsia and six relevant publications about PIH, some studies find preeclampsia associated with a lower risk of breast cancer, but others did not. Therefore, these results are inconclusive. We conducted meta-analysis to evaluate more precisely the relationship between preeclampsia, PIH and maternal risk of breast cancer. RESULTS: The pooled estimate of the hazard ratio (HR) associated with preeclampsia was 0.86 (95% CI 0.73-1.01), and that associated with PIH was 0.83 (0.66-1.06), both based on the random effects model. CONCLUSION: Some suggestive but not entirely consistent nor conclusive evidence was found on the association between the history of preeclampsia or PIH with the subsequent risk of breast cancer.

The relationship between twin births and maternal risk of breast cancer: a meta-analysis.

Women who undergo a greater number of menstrual cycles may be at increased risk of breast cancer, possibly due to cumulative exposure to ovarian hormones. Pregnancy reduces the lifetime number of menstrual cycles and also influences the levels of ovarian hormones. Twin pregnancies differ from singleton pregnancies in both hormone levels and perinatal changes. To date, a meta-analysis on the effects of twin birth on the risk of maternal breast cancer has not been conducted. Among 17 relevant publications identified in a systematic search, some suggest that twin births may be associated with lower breast cancer risk but others do not; therefore, the results are inconclusive. Although our pooled results of all 17 published studies did not show a reduced maternal risk of breast cancer for twin births (HR 0.94; 95% CI = 0.87-1.02; P = 0.127), a trend toward reduced maternal risk of breast cancer was identified in a subgroup analysis of cohort studies (HR 0.91; 95% CI = 0.83-1.01; P = 0.068). The results of this meta-analysis suggest that twin pregnancy does not significantly decrease the maternal risk of breast cancer.

Epithelial-mesenchymal transition in breast cancer correlates with high histological grade and triple-negative phenotype.

AIMS: Epithelial-mesenchymal transition (EMT) is characterized by a loss of epithelial nature and the acquisition of a mesenchymal form. The aim of this study was to assess the role of EMT in human mammary carcinogenesis, by performing immunohistochemical studies of EMT markers with tissue microarrays. METHODS AND RESULTS: A total of 492 cases were evaluated and classified as hormone receptor (HR)-positive type, HER2 type and triple-negative (TN) type by the use of immunohistochemistry and in-situ hybridization. We compared these groups in terms of epithelial and mesenchymal marker expression patterns. Of the 102 cases of TN-type breast cancer, 24.5% expressed vimentin, 13.7% expressed N-cadherin, and 9.8% expressed smooth muscle actin (SMA). Of the 221 cases of HR-type breast cancer, 4.1% expressed vimentin, 5.9% expressed N-cadherin, and 0.4% expressed SMA. Regarding epithelial markers, decreased expression was seen in 16.7% of cases for E-cadherin, in 45.1% for cytokeratin (CK)19 and in 60.8% for CK8 and CK18 (CAM5.2) in TN-type breast cancer cases. Decreased expression was seen in 11.8% of cases for E-cadherin, in 6.8% for CK19 and in 3.2% for CAM5.2 in HR-type cases. CONCLUSIONS: EMT features were particularly seen in TN-type breast cancer (P < 0.001). EMT was also significantly associated with high histological grade (P < 0.001).

Repair of rabbit ulna segmental bone defect using freshly isolated adipose-derived stromal vascular fraction.

BACKGROUND AIMS: Stromal vascular fractions (SVF) from adipose tissue have heterogeneous cell populations, and include multipotent adipose-derived stem cells. The advantages of using of SVF include the avoidance of an additional culture period, a reduced risk of extensive cell contamination, and cost-effectiveness. METHODS: Unilateral 20-mm mid-diaphyseal segmental defects in rabbit ulna were treated with one of the following: polylactic glycolic acid (PLGA) scaffold alone (group 1, control), a PLGA scaffold with undifferentiated SVF cells (group 2), or a PLGA scaffold with osteogenically differentiated SVF cells (group 3). At 8 weeks after implantation, five rabbits in each treatment group were killed to assess bone defect healing by plain radiography, quantitative microcomputed tomography and histology. RESULTS: The SVF cells were well grown on PLGA scaffolds and expressed type I collagen and alkaline phosphatase (ALP). The intensity of ALP and OPN gene expressions in osteogenic medium culture were increased from 14 days to 28 days. In vivo evaluations at 8 weeks showed that treatment of SVF cells with or without osteogenic differentiation resulted in more bone formation in the critically sized segmental defects than PLGA scaffold alone. Osteogenically differentiated SVF cells significantly enhanced bone healing compared with undifferentiated SVF cells. CONCLUSIONS: Adipose-derived stromal SVF showed osteogenic potential in vitro. Accordingly, SVF could provide a cell source for bone tissue engineering. However, treatment with uncultured SVF cells on bone healing was not satisfactory in the in vivo animal model.