Influences of Gender and Age on the Prevalence and Complications of Nonalcoholic Fatty Liver Disease.

Objective To investigate the effects of gender and age on the prevalence and complications of nonalcoholic fatty liver disease(NAFLD). Methods A total of 8429 NAFLD patients were selected from the Health Check-up Center and Outpatient Departments of Qilu Hospital of Shandong University(Qingdao).The questionnaire-based survey,physical examinations,biochemical tests,and liver ultrasonography were performed for all cases.Patients were divided into young group(<45 years),middle aged group(45 years≤age<60 years),and old group(≥60 years)according to age,and the clinical features and laboratory findings were analyzed. Results The proportion of male patients gradually decreased with age,while the proportion of female patients increased(P<0.01);The incidences of metabolic diseases showed significant difference among young group,middle aged group,and old group(P<0.01).Except for hyperlipidemia,the proportion of male patients with NAFLD-accompanied metabolic symdrome was significantly higher than that of female patients in all three age groups(all P<0.01). Conclusions The prevalence of NAFLD-accompanied metabolic syndrome disease is associated with age and gender.This finding is useful for the prevention and treatment of NAFLD.

53BP1 suppresses epithelial-mesenchymal transition by downregulating ZEB1 through microRNA-200b/429 in breast cancer.

Epithelial-mesenchymal transition (EMT) is an important mechanism of cancer invasion and metastasis. Although p53 binding protein 1 (53BP1) has been implicated in several biological processes, its function in EMT of human cancers has not yet been reported. Here, we show that 53BP1 negatively regulated EMT by modulating ZEB1 through targeting microRNA (miR)-200b and miR-429. Furthermore, 53BP1 promoted ZEB1-mediated upregulation of E-cadherin and also inhibited the expressions of mesenchymal markers, leading to increased migration and invasion in MDA-MB-231 breast cancer cells. Consistently, in MCF-7 breast cancer cells, low 53BP1 expression reduced E-cadherin expression, resulting in increased migration and invasion. These effects were reversed by miR-200b and miR-429 inhibition or overexpression. Sections of tumor xenograft model showed increased ZEB1 expression and decreased E-cadherin expression with the downregulation of 53BP1. In 18 clinical tissue samples, expression of 53BP1 was positively correlated with miR-200b and mir-429 and negatively correlated with ZEB1. It was also found that 53BP1 was associated with lymph node metastasis. Taken together, these results suggest that 53BP1 functioned as a tumor suppressor gene by its novel negative control of EMT through regulating the expression of miR-200b/429 and their target gene ZEB1.

A genetic polymorphism (rs17251221) in the calcium-sensing receptor is associated with breast cancer susceptibility and prognosis.

BACKGROUND: Calcium-sensing receptor (CaSR) is a typical G protein coupled receptor. The rs17251221 SNP is located in an intron of the CaSR gene, and the G allele is considered a gain of function mutation. Previous studies revealed that rs17251221 polymorphisms contribute to the risk of developing certain types of cancers. This study investigated the rs17251221 SNP in breast cancer by analyzing the correlation of the rs17251221 genotype with breast cancer susceptibility, clinicopathological features and prognosis. METHODS: A TaqMan assay was used to genotype the rs17251221 SNP in a case-control study. The expression levels of CaSR in breast cancer tissues were determined using quantitative reverse-transcription PCR (qRT-PCR) and western blot analysis. The association of the rs17251221 genotype and the clinicopathological characteristics, as well as the prognosis of the breast cancer patient, was assessed statistically. RESULTS: We found that the AG and GG genotypes were associated with lower mRNA and protein levels of CaSR compared to the AA genotype in breast cancer tissues. We also found that the AG and GG genotypes were associated with breast cancer susceptibility, the patient's age at diagnosis, tumor size, lymph node metastasis and estrogen receptor status of breast cancer tissue. More importantly, we found that the genotypes were prognostic markers for both disease-free survival and overall survival of breast cancer. CONCLUSION: The rs17251221 SNP is a risk factor associated with breast cancer susceptibility, as well as a prognostic indicator. Our data suggest that rs17251221 may be a potential therapeutic target in breast cancer.

MTDH mediates estrogen-independent growth and tamoxifen resistance by down-regulating PTEN in MCF-7 breast cancer cells.

BACKGROUND: About 70% of human breast cancers express estrogen receptor α (ERα) and in this kind of breast cancer estrogen plays an important role. Estrogen independent growth has been reported to promote resistance to one of the selective estrogen receptor modulators (SERMs) tamoxifen which is clinically the first line treatment for patients with ERα-positive breast cancer. The resistance of tamoxifen is a major problem in the clinical management of breast cancer. METHODS: We used MCF-7 cells with ectopic expression of MDTH in this study. MTT, clone formation and tumor formation in nude mice methods were utilized to confirm the role of MTDH in estrogen-independent growth and tamoxifen resistance. Flow cytometry, western blot and siRNA were used to study the detailed mechanisms. RESULTS: We found that MTDH could mediate estrogen-independent growth and induce resistance to tamoxifen in ERα-positive breast cancer cells. MTDH could reduce the expression of PTEN, up-regulate AKT and BCL2 and inhibit the apoptosis induced by tamoxifen. CONCLUSION: Our study indicated that MTDH was a candidate marker to predict the clinical efficacy of tamoxifen and targeting MTDH would overcome the resistance to tamoxifen in breast cancer cells.

Aberrant BLID expression is associated with breast cancer progression.

In our previous study, we have found that BH3-like motif containing, cell death inducer (BLID) was a tumor suppressor in breast cancer, and its downregulation was correlated with both poor disease-free and overall survival. In the present study, we aimed to explore the possible role of BLID in breast cancer progression. We found that BLID was strongly expressed in all normal breast tissues, and it became lower and wreaker gradually in the progression from normal, UDH (usual ductal hyperplasia), ADH (atypical ductal hyperplasia), and DCIS (ductal carcinoma in situ) to breast cancer. Statistical analysis demonstrated significant different BLID expressions between proliferative and cancerous breast lesions. Our data suggested that loss of BLID may contribute to the progression of intraductal proliferation lesions to breast cancer. Our finding gives a new clue that BLID might be a potential indicator for progression of breast cancer in the future.

Prognostic significance of calcium-sensing receptor in breast cancer.

The calcium-sensing receptor (CaSR) is a G-protein coupled receptor that is involved in tumor suppression of cancers. However, its role in breast cancer remains largely unknown. The aim of the study was to investigate the expression of CaSR in breast cancers and to evaluate its prognostic significance. We found that the protein levels of CaSR were significantly reduced in cancer lesion compared with its paired non-tumor tissues. By analyzing the expression of CaSR in a 148 cases of breast cancer tissue microarray (TMA) by immunohistochemistry, we found that patients with lower expression of CaSR were significantly associated with poor overall survival, cause-specific survival, and distant metastasis-free survival. The Cox multivariate analysis showed that CaSR was an independent prognostic significance for both overall survival and cause-specific survival of breast cancer patients. Our data confirmed the tumor suppressor role of CaSR and suggested that CaSR is an independent prognostic indicator of breast cancer.

[Retracted] Progesterone induces cell apoptosis via the CACNA2D3/Ca2+/p38 MAPK pathway in endometrial cancer.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the immunohistochemical data shown in Fig. 5C were strikingly similar to data appearing in different form in another article written by different authors at different research institutes that had already been submitted for publication elsewhere prior to the submission of this paper to Oncology Reports [Wu X, Cai D, Zhang F, Li M and Wan Q: Long noncoding RNA TUSC7 inhibits cell proliferation, migration and invasion by regulating SOCS4 (SOCS5) expression through targeting miR­616 in endometrial carcinoma. Life Sci 231: 116549, 2019]. In addition, the CACNA203 western blot data shown in Fig. 2A­c and B­C respectively looked strikingly similar, even though different experiments were intended to have been shown in these figure parts. In view of the fact that the contentious data had already apparently been submitted for publication prior to the receipt of this paper at Oncology Reports, and owing to a overall lack of confidence in the presentation of the data, the Editor of has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 43: 121­132, 2020; DOI: 10.3892/or.2019.7396].

53BP1 is a novel regulator of angiogenesis in breast cancer.

In our previous study, we found that 53BP1 was a tumor suppressor and was associated with prognosis in breast cancer. However, little is known about its role in angiogenesis. In the present study, we aimed to reveal the role of 53BP1 in angiogenesis of breast cancer. With RNA interference and ectopic expression strategies to elucidate the detailed function of 53BP1 in angiogenesis, we observed that ectopic expression of 53BP1 inhibited cellular angiogenesis and 53BP1 RNA interference led to an increase in angiogenesis both in vitro and in vivo. In clinical breast cancer samples, 53BP1 was inversely correlated with CD31, MMP-2 and MMP-9 by immunohistochemistry analysis. Furthermore, we showed that the Akt pathway was involved in the antiangiogenesis function of 53BP1. Overall, our findings demonstrate that 53BP1 plays a vital role in inhibiting angiogenesis. These findings suggest that 53BP1 might provide a viable target therapy for breast cancer.

Testin is a tumor suppressor and prognostic marker in breast cancer.

The testin (TES) gene was previously identified in the fragile chromosomal region FRA7G at 7q31.2. In the present study, we aimed to investigate the candidate tumor suppressor function of TES and explore its correlations to clinicopathologic features and prognosis in breast cancer. In clinical samples, we showed that the expression of TES decreased gradually from normal through ductal hyperplasia without atypia, atypical ductal hyperplasia, and ductal carcinoma in situ, to invasive ductal carcinoma. To explore the possible tumor suppressing function of TES, the expression of TES in breast cancer cells was manipulated by ectopic expression or by RNAi. We revealed that ectopic TES expression significantly inhibited cell proliferation, invasive ability, and angiogenesis, whereas knockdown of TES by RNAi enhanced cell proliferation, invasive ability, and angiogenesis. In an animal model, TES markedly inhibited breast cancer cell xenograft formation in athymic nude mice and reduced breast cancer cell metastasis to lung. Moreover, we revealed that TES inhibited the invasion and angiogenesis of breast cancer partially through miR-29b-mediated MMP-2 inhibition. Using the tissue microarray of breast cancer from Yale University, we found that lower TES expression was an independent prognostic factor for shorter overall survival and disease-free survival with univariate and multivariate analyses. Taken together, these data suggest that TES, as a valuable marker of breast cancer prognosis, plays an important role in the development and progression of breast cancer. TES may be an effective novel target in breast cancer prevention and treatment.

Antioxidative properties of bayberry tannins with different mean degrees of polymerization: Controlled degradation based on hydroxyl radicals.

The antioxidant properties of condensed tannins (CTs) are closely related to the mean degree of polymerization (mDP), and CTs with low mDP show stronger antioxidant effects. Therefore, obtaining CTs with a low mDP are very meaningful in improving their antioxidant properties and utilization. In this study, hydroxyl radicals generated by the decomposition of hydrogen peroxide under UV irradiation were used to degrade bayberry tannins in a clean and controllable manner. Taking the formaldehyde reactivity as an index to control the mDP of the degradation product, the changes in antioxidant properties of bayberry tannins with different mDP were studied by the method of 1,1-diphenyl-2-trinitrophenylhydrazine (DPPH), and 2,2-azido-di(3-ethyl-benzothiazole-6-sulfonic acid)diammonium salt (ABTS). Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), gel permeation chromatography (GPC), carbon nuclear magnetic resonance (13C NMR), and reversed-phase HPLC-ESI-MS were used to characterize the mDP, molecular weight (Mw), and chemical structure of the degradation products of bayberry tannins in different degradation stages. Results showed that hydroxyl radicals could cause significant degradation of bayberry tannins, and the controllable degradation of bayberry tannins could be achieved with the formaldehyde reactivity as an index. At the degradation times of 0, 2, 4, 6, and 8 h, the mDP (Mw) of the degradation products were as follows: 5.22 (2457), 4.36 (1895), 3.36 (1534), 2.87 (1153), and 1.78 (813), respectively. The antioxidant activity of the degraded product increased with the decrease in the mDP, and the degraded products had the largest formaldehyde reactivity and the best oxidation resistance when degraded for 6 h. This study provided a new method to achieve clean and controllable degradation of tannins and supported those tannins with low mDP could provide higher antioxidant activity.

Antioxidant Properties of Larch Tannins with Different Mean Polymerization Degrees: Controlled Degradation Based on Hydroxyl Radical Degradation.

Hydroxyl radical produced by hydrogen peroxide decomposition under UV radiation was used to degrade larch tannins in an environmentally friendly manner. The formaldehyde reactivity of the degraded products was used as an index to control the mean degree of polymerization (mDP) of the degraded products, and the effects of different mDP on the antioxidant activity of tannins were studied. Results showed that hydroxyl radical could significantly reduce the degree of polymerization (DP) and molecular weight (Mw) of larch tannins, and the mDP and Mw of degraded products could be controlled by considering the formaldehyde reactivity as the index. The antioxidant activity of larch tannins increased with the decrease in mDP. When the degradation time was 6 h, the formaldehyde reactivity was the highest at 0.823. The antioxidant activity of the degraded product was excellent, and the free radical scavenging rate was more than 98%.

Progesterone induces cell apoptosis via the CACNA2D3/Ca2+/p38 MAPK pathway in endometrial cancer.

Endometrial cancer (EC) is one of the most common malignant gynecological tumors in women. The main treatments for EC (surgery, chemotherapy and radiation therapy) produce significant side effects. Thus, it is urgent to identify promising therapeutic targets and prognostic markers. CACNA2D3, as a member of the calcium channel regulatory α2δ subunit family, is reported to exert a tumor suppressive effect in numerous cancers. However, the function of CACNA2D3 in EC is not well known. In the present study, CACNA2D3 was lowly expressed in EC tissues and cells. The overexpression of CACNA2D3 via lentiviral particle injection significantly blocked the tumor growth in an in vivo xenograft model. In vitro, the overexpression of CACNA2D3 markedly inhibited cell proliferation and migration, and promoted cell apoptosis and calcium influx. These data revealed that CACNA2D3 functions as a tumor suppressor in EC. It was also revealed that the addition of progesterone (P4) blocked tumor growth in Ishikawa­injected nude mice. P4 induced the expression of CACNA2D3 in vivo and in vitro, and the silencing of CACNA2D3 affected P4­inhibited cell proliferation and P4­induced cell apoptosis and calcium influx. In Ishikawa cells, P4 enhanced the expression of phosphorylated (p)­p38 MAPK and PTEN, but blocked the levels of p­PI3K and p­AKT. The knockdown of CACNA2D3 blocked the function of P4. These data revealed that P4 promoted cell apoptosis via the activation of the CACNA2D3/Ca2+/p38 MAPK pathway, and blocked cell proliferation via suppression of the PI3K/AKT pathway. Collectively, these findings indicated the antitumor role of CACNA2D3 in EC, and revealed the mechanism of P4 inhibition of EC progression, which provided a new target for EC therapy and new evidence for P4 in EC therapy.

Locally Weighted Fusion of Structural and Attribute Information in Graph Clustering.

Attributed graphs have attracted much attention in recent years. Different from conventional graphs, attributed graphs involve two different types of heterogeneous information, i.e., structural information, which represents the links between the nodes, and attribute information on each of the nodes. Clustering on attributed graphs usually requires the fusion of both types of information in order to identify meaningful clusters. However, most of existing works implement the combination of these two types of information in a "global" manner by treating all nodes equally and learning a global weight for the information fusion. To address this issue, this paper proposed a novel weighted K -means algorithm with "local" learning for attributed graph clustering, called adaptive fusion of structural and attribute information (Adapt-SA) and analyzed the convergence property of the algorithm. The key advantage of this model is to automatically balance the structural connections and attribute information of each node to learn a fusion weight, and get densely connected clusters with high attribute semantic similarity. Experimental study of weights on both synthetic and real-world data sets showed that the weights learned by Adapt-SA were reasonable, and they reflected which one of these two types of information was more important to decide the membership of a node. We also compared Adapt-SA with the state-of-the-art algorithms on the real-world networks with varieties of characteristics. The experimental results demonstrated that our method outperformed the other algorithms in partitioning an attributed graph into a community structure or other general structures.

Heterogeneous network embedding enabling accurate disease association predictions.

BACKGROUND: It is significant to identificate complex biological mechanisms of various diseases in biomedical research. Recently, the growing generation of tremendous amount of data in genomics, epigenomics, metagenomics, proteomics, metabolomics, nutriomics, etc., has resulted in the rise of systematic biological means of exploring complex diseases. However, the disparity between the production of the multiple data and our capability of analyzing data has been broaden gradually. Furthermore, we observe that networks can represent many of the above-mentioned data, and founded on the vector representations learned by network embedding methods, entities which are in close proximity but at present do not actually possess direct links are very likely to be related, therefore they are promising candidate subjects for biological investigation. RESULTS: We incorporate six public biological databases to construct a heterogeneous biological network containing three categories of entities (i.e., genes, diseases, miRNAs) and multiple types of edges (i.e., the known relationships). To tackle the inherent heterogeneity, we develop a heterogeneous network embedding model for mapping the network into a low dimensional vector space in which the relationships between entities are preserved well. And in order to assess the effectiveness of our method, we conduct gene-disease as well as miRNA-disease associations predictions, results of which show the superiority of our novel method over several state-of-the-arts. Furthermore, many associations predicted by our method are verified in the latest real-world dataset. CONCLUSIONS: We propose a novel heterogeneous network embedding method which can adequately take advantage of the abundant contextual information and structures of heterogeneous network. Moreover, we illustrate the performance of the proposed method on directing studies in biology, which can assist in identifying new hypotheses in biological investigation.

Adverse Drug Event Detection from Electronic Health Records Using Hierarchical Recurrent Neural Networks with Dual-Level Embedding.

INTRODUCTION: Adverse drug event (ADE) detection is a vital step towards effective pharmacovigilance and prevention of future incidents caused by potentially harmful ADEs. The electronic health records (EHRs) of patients in hospitals contain valuable information regarding ADEs and hence are an important source for detecting ADE signals. However, EHR texts tend to be noisy. Yet applying off-the-shelf tools for EHR text preprocessing jeopardizes the subsequent ADE detection performance, which depends on a well tokenized text input. OBJECTIVE: In this paper, we report our experience with the NLP Challenges for Detecting Medication and Adverse Drug Events from Electronic Health Records (MADE1.0), which aims to promote deep innovations on this subject. In particular, we have developed rule-based sentence and word tokenization techniques to deal with the noise in the EHR text. METHODS: We propose a detection methodology by adapting a three-layered, deep learning architecture of (1) recurrent neural network [bi-directional long short-term memory (Bi-LSTM)] for character-level word representation to encode the morphological features of the medical terminology, (2) Bi-LSTM for capturing the contextual information of each word within a sentence, and (3) conditional random fields for the final label prediction by also considering the surrounding words. We experiment with different word embedding methods commonly used in word-level classification tasks and demonstrate the impact of an integrated usage of both domain-specific and general-purpose pre-trained word embedding for detecting ADEs from EHRs. RESULTS: Our system was ranked first for the named entity recognition task in the MADE1.0 challenge, with a micro-averaged F1-score of 0.8290 (official score). CONCLUSION: Our results indicate that the integration of two widely used sequence labeling techniques that complement each other along with dual-level embedding (character level and word level) to represent words in the input layer results in a deep learning architecture that achieves excellent information extraction accuracy for EHR notes.

Correction: Trail Resistance Induces Epithelial-Mesenchymal Transition and Enhances Invasiveness by Suppressing PTEN via miR-221 in Breast Cancer.

[This corrects the article DOI: 10.1371/journal.pone.0099067.].

RING domain of zinc finger protein like 1 is essential for cell proliferation in endometrial cancer cell line RL95-2.

Endometrial cancer (EC) is the fourth most common cancer in women and exhibits increasing incidence and mortality. Some reports showed that the 5-year survival rate of EC was closely associated with the diagnosed stage. It is urgent to screen for sensitive and specific targets to improve early detection and EC therapy. In our study, we found that zinc finger protein like 1 (ZFPL1) was highly expressed in EC tissues and the EC cell line RL95-2, as detected via RT-qPCR and western blot analysis. Immunocytochemistry results showed that ZFPL1 was localized in the Golgi complex dependent on the C-terminal transmembrane domain. The MTT and EdU stains were employed to examine the effect of ZFPL1 on cell proliferation. We found that the silencing of ZFPL1 blocked cell proliferation and the expression of p-Akt308 and p-Akt473 but improved the protein level of PTEN. The overexpression of ZFPL1 and ZFPL1ΔTMD (deletion of the transmembrane domain) promoted cell proliferation and induced the expression of p-Akt308 and p-Akt473. However, the overexpression of ZFPL1ΔRING (deletion of the RING domain) caused loss of the function of ZFPL1 in cell proliferation and the PI3K/Akt pathway. In summary, ZFPL1 induced RL95-2 cell proliferation and was involved in PI3K/Akt pathway, suggesting the oncogenic role of ZFPL1 during EC development. Additionally, the RING domain was essential for the function of ZFPL1. These findings provided a new biomarker for EC diagnosis and therapy.

Risk assessment of genotoxic and carcinogenic alkenylbenzenes in botanical containing products present on the Chinese market.

In the present study, a risk assessment of plant food supplements (PFS), traditional Chinese medicines (TCM) and herbal teas containing alkenylbenzenes was performed using the Margin of Exposure (MOE) approach. The levels of alkenylbenzenes in botanical preparations collected on the Chinese market were quantified and the combined estimated daily intake (EDI) was determined using dose additivity. The combined EDI values obtained assuming equal potency of all alkenylbenzenes detected in the PFS, TCM and herbal teas were 0.3 to 14.3, 0.05 to 539.4 and 0.04 to 42.5 µg/kg bw/day, respectively. Calculating combined EDI values taking into account the toxic equivalency (TEQ) approach, the values for PFS, TCM and herbal teas were 0.3 to 7.7, 0.05 to 278.0 and 0.02 to 16.5 µg estragole equivalents/kg bw/day, respectively. The MOE values resulting from consumption of these PFS, TCM and one cup of herbal tea per day during life-time were generally lower than 10 000, suggesting a potential priority for risk management. For short-term exposure such as two weeks consumption, applying Haber's rule, only one TCM 6 () still had an MOE value below 10 000. It is concluded that selected consumption of Chinese botanical preparations raise a concern because of exposure to alkenylbenzenes, especially when exposure is for longer periods of time.

Immunization with Toxoplasma gondii aspartic protease 3 increases survival time of infected mice.

Aspartic proteases in the Toxoplasma gondii, called TgASP1, 2, 3, and 5, play essential roles in the life cycle. In a previous study, we have demonstrated that TgASP1 is an antigen that prolongs survival time of infected mice. As an in-depth study, we have investigated the protective immunity of TgSAP3. A bioinformatic analysis was used to predict the linear B-cell epitopes and potential Th-cell epitopes on TgASP3, the results suggested that it has a large number of excellent epitopes. Mice were inoculated with a recombinant eukaryotic expression vector to evaluate the immune protection against an infection with the virulent RH strain of T. gondii. The enhanced immune response and increased survival time (up to 18days) were observed for vaccinated mice, showing that the TgASP3 antigen can provides partial protection.

Periareolar incision for the management of benign breast tumors.

Benign breast tumors (BBTs) are common in women. The traditional surgical resection method for the various types of BBT leaves obvious scars and affects the appearance of the breast. The present study introduces the experience of a single institution in the treatment of BBT by periareolar incision. The clinical data of 153 patients (182 breasts) with BBT who had undergone a resection via a periareolar incision between January 2010 and December 2012 in Qilu Hospital, Shandong University (Jinan, Shandong, China), was retrospectively analyzed. All incisions were primary healing. Of the 153 patients, 1 (0.7%) developed a hematoma and 2 (1.3%) developed slight nipple ischemia. No infections or other complications were observed. During 1 month to 3 years of follow-up, the cosmetic effects were assessed. Periareolar incision is not only suitable for all types of breast surgery for benign tumor resection, but also has the advantage of a hidden incision, a small scar, no ischemic necrosis of the nipple areola, high patient satisfaction and good post-operative cosmetic effect. The technique is therefore a good surgical incision choice that is worthy of note.