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With the continuous innovation of digital technology in my country at this stage and the design of medical imaging technology systems, the depth and breadth of the development of digital medical imaging technology have been greatly expanded. This paper focus on application of medical images in breast milk smearing of the umbilical nursing for full-term newborns.To explore the effect of breast milk application in umbilical nursing of full-term newborns.596 full-term newborns were divided into three groups: Experimental Group, Control Group A and Control Group B, Experimental Group A treated with breast milk, control group a treated with 75% alcohol, and control group B treated with 37 ~ 42°C warm boiled water, the time of umbilical cord abscission, infection and other complications were compared among the three groups. The process was recorded by images.According to the images, compared with the Control Group A and B, the experimental group significantly shortened the time of umbilical cord shedding, the difference was statistically significant (The application of breast milk in umbilical region of full-term neonates can reduce the time of umbilical cord abscission without increasing the incidence of Omphalitis.

Blocking the interaction of MTDH/SND1 complex is an attractive strategy for cancer therapeutics. In this work, we designed and obtained a novel class of potent stabilized peptide inhibitors derived from MTDH sequence to disrupt MTDH/SND1 interaction. Through structure-based optimization and biological evaluation, stabilized peptides were obtained with tight binding affinity, improved cell penetration, and antitumor effects in the triple-negative breast cancer (TNBC) cells without nonspecific toxicity. To date, our study was the first report to demonstrate that stabilized peptides truncated from MTDH could serve as promising candidates to disrupt the MTDH/SND1 interaction for potential breast cancer treatment.

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Colorectal and lung cancers account for one-third of all cancer-related deaths worldwide. Previous studies suggested that metadherin (MTDH) is involved in the development of colorectal and lung cancers. However, how MTDH regulates the pathogenesis of these cancers remains largely unknown. Using genetically modified mouse models of spontaneous colorectal and lung cancers, we found that MTDH promotes cancer progression by facilitating Wnt activation and by inducing cytotoxic T-cell exhaustion, respectively. Moreover, we developed locked nucleic acid-modified (LNA) MTDH antisense oligonucleotides (ASO) that effectively and specifically suppress MTDH expression in vitro and in vivo. Treatments with MTDH ASOs in mouse models significantly attenuated progression and metastasis of colorectal, lung, and breast cancers. Our study opens a new avenue for developing therapies against colorectal and lung cancers by targeting MTDH using LNA-modified ASO.Significance:This study provides new insights into the mechanism of MTDH in promoting colorectal and lung cancers, as well as genetic and pharmacologic evidence supporting the development of MTDH-targeting therapeutics.

Metastatic breast cancer is a leading health burden worldwide. Previous studies have shown that metadherin (MTDH) promotes breast cancer initiation, metastasis and therapy resistance; however, the therapeutic potential of targeting MTDH remains largely unexplored. Here, we used genetically modified mice and demonstrate that genetic ablation of Mtdh inhibits breast cancer development through disrupting the interaction with staphylococcal nuclease domain-containing 1 (SND1), which is required to sustain breast cancer progression in established tumors. We performed a small-molecule compound screening to identify a class of specific inhibitors that disrupts the protein–protein interaction (PPI) between MTDH and SND1 and show that our lead candidate compounds C26-A2 and C26-A6 suppressed tumor growth and metastasis and enhanced chemotherapy sensitivity in preclinical models of triple-negative breast cancer (TNBC). Our results demonstrate a significant therapeutic potential in targeting the MTDH–SND1 complex and identify a new class of therapeutic agents for metastatic breast cancer. Kang and colleagues identify a specific compound blocking MTDH1–SND1 interaction, which prevents metastatic breast cancer progression, induces regression of established metastasis in preclinical models and restores chemosensitivity.

Despite increased overall survival rates, curative options for metastatic breast cancer remain limited. We have previously shown that metadherin (MTDH) is frequently overexpressed in poor prognosis breast cancer, where it promotes metastasis and therapy resistance through its interaction with staphylococcal nuclease domain-containing 1 (SND1). Through genetic and pharmacological targeting of the MTDH–SND1 interaction, we reveal a key role for this complex in suppressing antitumor T cell responses in breast cancer. The MTDH–SND1 complex reduces tumor antigen presentation and inhibits T cell infiltration and activation by binding to and destabilizing Tap1/2 messenger RNAs, which encode key components of the antigen-presentation machinery. Following small-molecule compound C26-A6 treatment to disrupt the MTDH–SND1 complex, we showed enhanced immune surveillance and sensitivity to anti-programmed cell death protein 1 therapy in preclinical models of metastatic breast cancer, in support of this combination therapy as a viable approach to increase immune-checkpoint blockade therapy responses in metastatic breast cancer. Kang and colleagues demonstrate that pharmacological targeting of the MTDH1–SND1 axis prevents immune evasion during metastatic progression and provides a synergistic combination strategy with immune-checkpoint blockade to treat metastasis.

Development of cancer therapeutics has traditionally focused on targeting driver oncogenes. Such an approach is limited by toxicity to normal tissues and treatment resistance. A class of 'cancer fitness genes' with crucial roles in metastasis have been identified. Elevated or altered activities of these genes do not directly cause cancer; instead, they relieve the stresses that tumor cells encounter and help them adapt to a changing microenvironment, thus facilitating tumor progression and metastasis. Importantly, as normal cells do not experience high levels of stress under physiological conditions, targeting cancer fitness genes is less likely to cause toxicity to noncancerous tissues. Here, we summarize the key features and function of cancer fitness genes and discuss their therapeutic potential.

Colorectal and lung cancers account for one-third of all cancer-related deaths worldwide. Previous studies suggested that metadherin (MTDH) is involved in the development of colorectal and lung cancers. However, how MTDH regulates the pathogenesis of these cancers remains largely unknown. Using genetically modified mouse models of spontaneous colorectal and lung cancers, we found that MTDH promotes cancer progression by facilitating Wnt activation and by inducing cytotoxic T-cell exhaustion, respectively. Moreover, we developed locked nucleic acid-modified (LNA) MTDH antisense oligonucleotides (ASO) that effectively and specifically suppress MTDH expression in vitro and in vivo. Treatments with MTDH ASOs in mouse models significantly attenuated progression and metastasis of colorectal, lung, and breast cancers. Our study opens a new avenue for developing therapies against colorectal and lung cancers by targeting MTDH using LNA-modified ASO. Significance: This study provides new insights into the mechanism of MTDH in promoting colorectal and lung cancers, as well as genetic and pharmacologic evidence supporting the development of MTDH-targeting therapeutics.

Metastasis is the ultimate “survival of the fittest” test for cancer cells, as only a small fraction of disseminated tumor cells can overcome the numerous hurdles they encounter during the transition from the site of origin to a distinctly different distant organ in the face of immune and therapeutic attacks and various other stresses. During cancer progression, tumor cells develop a variety of mechanisms to cope with the stresses they encounter, and acquire the ability to form metastases. Restraining these stress-releasing pathways could serve as potentially effective strategies to prevent or reduce metastasis and improve the survival of cancer patients. Here, we provide an overview of the tumor-intrinsic, microenvironment- and treatment-induced stresses that tumor cells encounter in the metastatic cascade and the molecular pathways they develop to relieve these stresses. We also summarize the preclinical and clinical studies that evaluate the potential therapeutic benefit of targeting these stress-relieving pathways.

SNAI2/SLUG, a metastasis-promoting transcription factor, is a labile protein that is degraded through the ubiquitin proteasome degradation system. Here, we conducted comprehensive gain- and loss-of-function screens using a human DUB cDNA library of 65 genes and an siRNA library of 98 genes, and identified USP20 as a deubiquitinase (DUB) that regulates SNAI2 ubiquitination and stability. Further investigation of USP20 demonstrated its function in promoting migration, invasion, and metastasis of breast cancer. USP20 positively correlates with SNAI2 protein level in breast tumor samples, and higher USP20 expression is associated with poor prognosis in ER− breast cancer patients.

Objectives Preeclampsia is a common complication of pregnancy that causes health problems for both the mother and her fetus. This study aimed to develop and externally validate a model to predict adverse outcomes in preeclampsia in a trans-regional two-center retrospective cohort of Chinese women. Study design To generate a model for the risk of women with adverse outcomes, we incorporated candidate variables in the development set in univariate, least absolute shrinkage and selection operator analysis and multivariable logistic regression. The performance of the model was evaluated for the receiver operating characteristic (ROC) curve, calibration and decision curve analysis. Further, we externally validated the model in an independent dataset. Main outcome measures Composite adverse outcomes within 48 hours of admission. Results There were 1 783 and 116 preeclampsia women in the development and validation set, respectively. The model included 10 predictors: gestational age at admission, irregular prenatal care, number of symptoms, mean arterial pressure, hematocrit, platelet count, fibrinogen, albumin, total bilirubin, and serum urea. The area under the ROC curve of the model was 0.867 in the development set and 0.841 in the external validation set. The calibration plots for the probability of adverse outcomes demonstrated a good correlation. Decision curve analysis further showed that our model had clinical application value. The nomogram and a software-based calculator ( https://sdfyyfck.shinyapps.io/preeclampsia/ ) were constructed for convenient clinical use. Conclusions Such a model could be used as a useful tool for the assessment of hypertensive-related complications in Chinese preeclampsia patients.

Epithelial-mesenchymal transition (EMT) has been reported to be involved in adenomyosis by promoting cell invasion and fibrogenesis. But few studies have identified critical factors that regulate EMT process during adenomyosis. The eukaryotic translation initiation factor 3 subunit e (eIF3e) protein is a component of the multisubunit eIF3 complex essential for cap-dependent translation initiation. The aim of this study was to investigate whether eIF3e is involved in EMT in adenomyosis. Ectopic endometrial tissue samples were collected from 40 premenopausal women with ultrasonographically diagnosed and histologically confirmed adenomyosis. As controls, endometrial samples were obtained from 40 cycling premenopausal women patients who underwent surgery for benign gynecologic disorders or cervical intraepithelial neoplasia but without endometriosis, adenomyosis, nor uterine fibroids. All tissue samples were subjected to immunohistochemistry analysis of eIF3e, transforming growth factor-β1 (TGF-β1), E-cadherin, vimentin, Snail, and proliferating cell nuclear antigen (PCNA). The epithelial component of ectopic endometrium showed significantly reduced immunoreactivity against eIF3e and E-cadherin but elevated immunoreactivity against TGF-β1, Snail, vimentin, and PCNA as compared with that of control endometrium (all P values

Ligand-dependent corepressor (LCOR) mediates normal and malignant breast stem cell differentiation. Cancer stem cells (CSCs) generate phenotypic heterogeneity and drive therapy resistance, yet their role in immunotherapy is poorly understood. Here we show that immune-checkpoint blockade (ICB) therapy selects for LCORlow CSCs with reduced antigen processing/presentation machinery (APM) driving immune escape and ICB resistance in triple-negative breast cancer (TNBC). We unveil an unexpected function of LCOR as a master transcriptional activator of APM genes binding to IFN-stimulated response elements (ISREs) in an IFN signaling-independent manner. Through genetic modification of LCOR expression, we demonstrate its central role in modulation of tumor immunogenicity and ICB responsiveness. In TNBC, LCOR associates with ICB clinical response. Importantly, extracellular vesicle (EV) Lcor-messenger RNA therapy in combination with anti-PD-L1 overcame resistance and eradicated breast cancer metastasis in preclinical models. Collectively, these data support LCOR as a promising target for enhancement of ICB efficacy in TNBC, by boosting of tumor APM independently of IFN. This work was supported by the Instituto de Salud Carlos III-FSE (nos. MS17/00037 and PI18/00014) and the Cancer Research Institute, Clinic and Laboratory Integration Program (grant no. CRI2477 to T.C.-T). We also thank the AECC LAB (grant no. LABAE19007CELI) and the FERO foundation (to T.C.-T). This work was also supported by ISCIII (CIBERONC nos. CB16/12/00481, CB16/12/00241, PI18/00006 and PI21/00002), Generalitat de Catalunya (no. 2017 SGR 507) and the European Community through the Regional Development Funding Program to J. Albanell. Y.K. is supported by the Brewster Foundation, the Breast Cancer Research Foundation, the Susan G. Komen Foundation and the American Cancer Society. J. Arribas is funded by the Breast Cancer Research Foundation (no. BCRF-20-08), Instituto de Salud Carlos III (no. PI19/01181), Asociación Española Contra el Cáncer (no. GCAEC19017ARRI) and Fundación BBVA (no. CAIMI VHIO-FBBVA 2018-2021). M.M.A. is funded by MICINN and the Spanish Government (no. PGC2018-094091-B-I00). D.C. was funded by Instituto de Salud Carlos III (no. JR1800003). S.M. is funded by PERIS (no. SLT006/17/00040). The wotk of R.R.G. is funded by MICINN, the Spanish Government (no. PID2019-104948RB-I00) and the BBVA Foundation. S.B and J.P. acknowledge support from the Spanish Ministry of Science, the EMBL partnership and the CESO and CERCA Program.

Metastatic breast cancer is a leading health burden worldwide. Previous studies have shown that metadherin (MTDH) promotes breast cancer initiation, metastasis and therapy resistance; however, the therapeutic potential of targeting MTDH remains largely unexplored. Here, we used genetically modified mice and demonstrate that genetic ablation of Mtdh inhibits breast cancer development through disrupting the interaction with staphylococcal nuclease domain-containing 1 (SND1), which is required to sustain breast cancer progression in established tumors. We performed a small-molecule compound screening to identify a class of specific inhibitors that disrupts the protein-protein interaction (PPI) between MTDH and SND1 and show that our lead candidate compounds C26-A2 and C26-A6 suppressed tumor growth and metastasis and enhanced chemotherapy sensitivity in preclinical models of triple-negative breast cancer (TNBC). Our results demonstrate a significant therapeutic potential in targeting the MTDH-SND1 complex and identify a new class of therapeutic agents for metastatic breast cancer.

Background: Cesarean delivery after failure of trial of labor is associated with adverse maternal and perinatal outcomes. A prediction algorithm to identify women with high risk of an emergency cesarean could help reduce morbidity and mortality associated with labor. The objective of the present study was to derive and validate a simple model to predict cesarean delivery for low-risk nulliparous women in Chinese population.Methods: This retrospective study analyzed the low-risk nulliparous women with singleton cephalic full-term fetus delivered in two medical centers. After the clinical data of the women who delivered at the tertiary referral center (n=6 551) was collected and was used univariate and multivariable logistic regression analysis, the prediction model was fitted. We performed external validation using data from nulliparous who delivered from another hospital(secondary referral center, n=7 657). A new nomogram was established based on the development cohort to predict the cesarean. The ROC curve, calibration plot and decision curve analysis were used to assess the predictive performance. Results: The cesarean delivery rates in the development cohort and the external validation cohort were 8.79% (576/6 551) and 7.82% (599/7 657). Multivariable logistic regression analysis showed that maternal age, height, BMI, weight gained during pregnancy, gestational age, induction method, meconium-stained amniotic fluid and neonatal sex were independent factors affecting cesarean outcome. Because sex of the fetuses were unknown until they born(China's Fertility Policy), we established two prediction models according to fetal sex was involved or not. The AUC was 0.782 and 0.774, respectively. The Hosmer-Lemeshow goodness-of-fit test showed that these two models fitted well. Decision curve analysis demonstrated that the models were clinically useful. And internal validation using Bootstrap method showed that these prediction models perform well. On the external validation set, the AUC were 0.775 and 0.775, respectively. The calibration plots for the probability of cesarean showed a good correlation. The online web server was constructed based on the nomogram for convenient clinical use.Conclusions: Both two models established by these factors have good prediction efficiency and high accuracy, which can provide the reference for clinicians to guide pregnant women to choose an appropriate delivery mode.

Epithelial-mesenchymal transition (EMT) is now well documented to be involved in the development of endometriosis through the promotion of invasion and fibrogenesis. To date, several factors have been reported to be involved in EMT in endometriosis. The eukaryotic translation initiation factor 3 subunit e (eIF3e) protein is a component of the multisubunit eIF3 complex essential for cap-dependent translation initiation. The aim of this study was to investigate whether eIF3e is involved in EMT in endometriosis. We recruited 40 premenopausal women (34.7 [6.8] years) with laparoscopically and histologically diagnosed ovarian endometriomas, and their ectopic endometrial tissue samples were collected after informed consent. As controls, endometrial tissue samples were obtained after informed consent from 40 premenopausal women, roughly age-matched (36.9 [6.4] years) and menstrual phase-matched with endometriosis group, who underwent surgery for benign gynecologic disorders or cervical intraepithelial neoplasia but without endometriosis, adenomyosis, or uterine fibroids. All tissue samples were subjected to immunohistochemistry analysis of eIF3e, transforming growth factor (TGF-β1), Snail, E-cadherin, vimentin, and proliferating cell nuclear antigen (PCNA). We found significantly reduced immunoreactivity against eIF3e and E-cadherin but elevated immunoreactivity against TGF-β1, Snail, vimentin, and PCNA in endometriotic epithelial cells when compared to that of control endometrium (all P values

Carcinoma cells often acquire mobility and invasiveness by undergoing epithelial-to-mesenchymal transition, and yet most metastatic lesions remain epithelial in nature. Recently, in Nature, Padmanaban et al. (2019) demonstrated that the quintessential epithelial marker E-cadherin promotes metastasis of invasive ductal breast carcinoma by enhancing the survival of tumor cells.

The tumor microenvironment contains heterogeneous populations of stromal cells with important roles in cancer progression and metastasis. In a recent study published in Nature Medicine, pSTAT3+ reactive astrocytes were found to promote brain metastasis by altering the tumor microenvironment, and represent a promising target for the treatment of brain metastasis.

The tumor microenvironment contains heterogeneous populations of stromal cells with important roles in cancer progression and metastasis. In a recent study published in Nature Medicine, pSTAT3

Tumor microenvironment (TME) is comprised of cellular and non-cellular components that exist within and around the tumor mass. The TME is highly dynamic and its importance in different stages of cancer progression has been well recognized. A growing body of evidence suggests that TME also plays pivotal roles in cancer treatment responses. TME is significantly remodeled upon cancer therapies, and such change either enhances the responses or induces drug resistance. Given the importance of TME in tumor progression and therapy resistance, strategies that remodel TME to improve therapeutic responses are under developing. In this review, we provide an overview of the essential components in TME and the remodeling of TME in response to anti-cancer treatments. We also summarize the strategies that aim to enhance therapeutic efficacy by modulating TME.

Supplemental Material, Fig_S2 for The Possible Role of Eukaryotic Translation Initiation Factor 3 Subunit e (eIF3e) in the Epithelial–Mesenchymal Transition in Adenomyosis by Xianjun Cai, Minhong Shen, Xishi Liu, and Jichan Nie in Reproductive Sciences

Bone metastasis is a major health threat to breast cancer patients. Tumor-derived Jagged1 represents a central node in mediating tumor-stromal interactions that promote osteolytic bone metastasis. Here, we report the development of a highly effective fully human monoclonal antibody against Jagged1 (clone 15D11). In addition to its inhibitory effect on bone metastasis of Jagged1-expressing tumor cells, 15D11 dramatically sensitizes bone metastasis to chemotherapy, which induces Jagged1 expression in osteoblasts to provide a survival niche for cancer cells. We further confirm the bone metastasis-promoting function of osteoblast-derived Jagged1 using osteoblast-specific Jagged1 transgenic mouse model. These findings establish 15D11 as a potential therapeutic agent for the prevention or treatment of bone metastasis.

Microtubules are highly dynamic filaments assembled from αβ-tubulin heterodimers and play important roles in many cellular processes, including cell division and migration. Microtubule dynamics is tightly regulated by microtubule-associated proteins (MAPs) that function by binding to microtubules or free tubulin dimers. Here, we report that FOR20 (FOP-related protein of 20 kDa), a conserved protein critical for ciliogenesis and cell cycle progression, is a previously uncharacterized MAP that facilitates microtubule depolymerization and promotes cell migration. FOR20 not only directly binds to microtubules but also regulates microtubule dynamics in vitro by decreasing the microtubule growth rate and increasing the depolymerization rate and catastrophe frequency. In the in vitro microtubule dynamics assays, FOR20 appears to preferentially interact with free tubulin dimers over microtubules. Depletion of FOR20 inhibits microtubule depolymerization and promotes microtubule regrowth after the nocodazole treatment in HeLa cells. In addition, FOR20 knockdown significantly inhibits both individual and collective migration of mammalian cells. Taken together, these data suggest that FOR20 functions as a MAP to promote microtubule depolymerization and cell migration.

SummaryMetastatic dissemination is often initiated by the reactivation of an embryonic development program referred to as epithelial-mesenchymal transition (EMT). The transcription factor SNAIL promotes EMT and elicits associated pathological characteristics such as invasion, metastasis, and stemness. To better understand the posttranslational regulation of SNAIL, we performed a luciferase-based, genome-wide E3 ligase siRNA library screen and identified SCF-FBXO11 as an important E3 that targets SNAIL for ubiquitylation and degradation. Furthermore, we discovered that SNAIL degradation by FBXO11 is dependent on Ser-11 phosphorylation of SNAIL by protein kinase D1 (PKD1). FBXO11 blocks SNAIL-induced EMT, tumor initiation, and metastasis in multiple breast cancer models. These findings establish the PKD1-FBXO11-SNAIL axis as a mechanism of posttranslational regulation of EMT and cancer metastasis.

SummaryMetadherin (MTDH) and Staphylococcal nuclease domain containing 1 (SND1) are overexpressed and interact in diverse cancer types. The structural mechanism of their interaction remains unclear. Here, we determined the high-resolution crystal structure of MTDH-SND1 complex, which reveals an 11-residue MTDH peptide motif occupying an extended protein groove between two SN domains (SN1/2), with two MTDH tryptophan residues nestled into two well-defined pockets in SND1. At the opposite side of the MTDH-SND1 binding interface, SND1 possesses long protruding arms and deep surface valleys that are prone to binding with other partners. Despite the simple binding mode, interactions at both tryptophan-binding pockets are important for MTDH and SND1’s roles in breast cancer and for SND1 stability under stress. Our study reveals a unique mode of interaction with SN domains that dictates cancer-promoting activity and provides a structural basis for mechanistic understanding of MTDH-SND1-mediated signaling and for exploring therapeutic targeting of this complex.

Growing evidence indicates that miRNAs play critical roles in tumorigenesis and cancer progression. Here, we report that miR-215 is significantly up-regulated in gastric cancer tissues from either gastrectomy or gastroscopy. Receiver Operator Characteristic (ROC) curve analysis indicated that miR-215 may be a candidate biomarker for gastric cancer diagnosis. Inhibition of miR-215 significantly suppressed gastric cancer cell proliferation possibly via G1 arrest. Further analyses indicated that miR-215 was able to target retinoblastoma tumor-suppressor gene 1 (RB1) through its 3'-UTR in gastric cancer cells. These data suggest that frequently up-regulated miR-215 in gastric cancer may influence cell proliferation by targeting RB1.

Metastasis is responsible for the majority of cancer-related deaths. The transcription factor SNAI2 promotes metastasis by facilitating tumor cell invasion and tumor initiating activity. However, its post-translational regulation is less studied. We performed a dual luciferase-based, genome-wide E3 ligase siRNA library screening and identified ASB13 as an E3 ubiquitin ligase that targets SNAI2 for ubiquitination and degradation. ASB13 knockout in breast cancer cells leads to increased cell migration and decreased F-actin polymerization; while overexpression of ASB13 suppresses lung metastasis formed by LM2 cells. Furthermore, we discovered that ASB13 knockout decreases YAP expression, which is dependent on increased SNAI2 protein level. YAP functions as a tumor suppressor gene in breast cancer, as YAP knockout increases tumorsphere formation, anchorage-independent colony formation, and cell migration. Clinical data analysis reveals that ASB13 expression is positively correlated with overall survival in breast cancer patients. These findings establish the ASB13-SNAI2-YAP axis as a regulatory mechanism for breast cancer migration and metastasis. Citation Format: Huijuan Fan, Xuxiang Wang, Wenyang Li, Minhong Shen, Yong Wei, Hanqiu Zheng, Yibin Kang. ASB13 inhibits breast cancer progression and metastasis through SNAI2 degradation and transcriptional regulation of YAP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 162.

Triple-negative breast cancer (TNBC) patients have the worst prognosis and distant metastasis-free survival among all major subtypes of breast cancer. The poor clinical outlook is further exacerbated by a lack of effective targeted therapies for TNBC. Here we show that ectopic expression and therapeutic delivery of the secreted protein Tubulointerstitial nephritis antigen-like 1 (Tinagl1) suppresses TNBC progression and metastasis through direct binding to integrin α5β1, αvβ1, and epidermal growth factor receptor (EGFR), and subsequent simultaneous inhibition of focal adhesion kinase (FAK) and EGFR signaling pathways. Moreover, Tinagl1 protein level is associated with good prognosis and reversely correlates with FAK and EGFR activation status in TNBC. Our results suggest Tinagl1 as a candidate therapeutic agent for TNBC by dual inhibition of integrin/FAK and EGFR signaling pathways.

Study question Do platelets have any role in the development of adenomyosis? Summary answer Activated platelets coincide with the release of transforming growth factor (TGF)-β1 and induction of the TGF-β/Smad signaling pathway as well as evidence of epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT) in a mouse model of adenomyosis, resulting ultimately in fibrosis, as in adenomyosis. What is known already Both EMT and FMT are known to play vital roles in fibrogenesis in general and in endometriosis in particular. EMT has been implicated in the development of adenomyosis, but this was based primarily on cross-sectional observation. It is unclear as to whether adenomyotic lesions and their microenvironment have the machinery to promote EMT and FMT, resulting ultimately in fibrosis. There has not been any published study on the role of platelets in the development of adenomyosis, even though adenomyotic lesions undergo repeated cycles of tissue injury and repair, which implicates the involvement of platelets and constitutes an environment conducive for fibrogenesis. Study design, size, duration Adenomyosis was induced in 28 female ICR mice by neonatal dosing of tamoxifen. Another 32 were neonatally dosed without tamoxifen. These mice were sacrificed serially and their tissue samples were subsequently evaluated. Participants/materials, setting, methods Female ICR mice with and without induced adenomyosis were sacrificed in batch at 5, 10, 15, 42 and 60 days of age. The depth of myometrial infiltration of endometrial tissues was assessed and immunohistochemistry analysis of biomarkers of EMT and FMT, as well as TGF-β1, phosphorylated Smad3 (p-Smad3) and markers of proliferation, angiogenesis and extracellular matrix (ECM) deposits was performed in ectopic (for adenomyotic mice) and eutopic (controls) endometrial tissue samples. Masson trichrome and Van Gieson stainings were performed to quantify the extent of fibrosis in lesions. Progesterone receptor isoform B (PR-B) staining also was performed. Main results and the role of chance While TGF-β1 immunoreactivity was consistently low in control endometrium, its level was increased dramatically starting from Day 10, along with the extent of platelet aggregation. Staining for TGF-β1 and p-Smad3 increased progressively as adenomyosis progressed, along with markers for proliferation, angiogenesis and ECM deposits. Consistently, staining of vimentin (a marker for stromal or mesenchymal cells) was also increased while that of E-cadherin (a marker for epithelial cells) was reduced. PR-B staining also decreased progressively. Starting from Day 42, α-SMA staining, a marker for myofibroblasts, was elevated in lesions, while in control endometrium, it was negative. Concomitantly, the extent of fibrosis also was increased. Limitations, reasons for caution This study is limited by the use of histochemistry and immunohistochemistry analyses only and the lack of intervention. Wider implications of the findings Like their endometriotic counterpart, adenomyotic lesions and their microenvironment may contain all the necessary molecular machinery to promote fibrogenesis. Platelet-induced activation of the TGF-β/Smad signaling pathway may be a driving force in EMT and FMT in the development of adenomyosis, leading to fibrosis. This study provides the first piece of evidence that adenomyotic lesions are wounds that undergo repeated injury and healing, and as such, platelets play critical roles in the development of adenomyosis. It suggests the potential for the use of anti-platelet therapy in the treatment of adenomyosis, and also opens a new venue for developing novel biomarkers for diagnostic or prognostic purposes. Study funding/competing interests Support for data collection and analysis was provided by grants from the National Science Foundation of China. None of the authors has anything to disclose.

STUDY QUESTION Do platelets play any role in the development of adenomyosis? SUMMARY ANSWER As in endometriosis, adenomyotic lesions show significantly increased platelet aggregation, increased expression of transforming growth factor (TGF)-β1, phosphorylated Smad3, markers of epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT), and smooth muscle metaplasia (SMM), in conjunction with increased fibrosis as compared with normal endometrium. WHAT IS KNOWN ALREADY Both EMT and FMT are known to play vital roles in fibrogenesis in general and in endometriosis in particular. EMT has been implicated in the development of adenomyosis. SMM is universally seen in endometriosis and also in adenomyosis, and is correlated positively with the extent of fibrosis. However, there has been no published study on the role of platelets in fibrogenesis in adenomyosis, even though adenomyotic lesions undergo repeated cycles of tissue injury and repair, which suggests the involvement of platelets and their possible roles in fibrogenesis. STUDY DESIGN, SIZE, DURATION Cross-sectional studies of ectopic endometrial and control endometrial tissue samples from three sets of women with and without adenomyosis (n= 34 and 20, 12 and 10, and 8 and 8, respectively) were carried out from 2014 to 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS Immunohistochemistry analysis of ectopic endometrial tissues from women with (n= 34) and without (n= 20) adenomyosis with respect to biomarkers of EMT, FMT and highly differentiated smooth muscle cells as well as TGF-β1, phosphorylated Smad3, markers of proliferation, angiogenesis and extracellular matrix (ECM) deposits. Masson trichrome staining, Van Gieson staining and Pico-Sirius staining were performed to evaluate and quantify the extent of fibrosis in lesions. Progesterone receptor isoform B (PR-B) staining also was performed. In addition, CD42b-positive platelets in ectopic (n= 12) and control (n= 10) endometrium were counted by confocal microscopy and compared. The protein expression levels of TGF-β1 and phosphorylated Smad3 in both ectopic (n= 8) and control (n= 8) endometrium were measured by western blot analysis. Immunofluorescent staining of both platelets and hepatocyte growth factor (HGF) was also performed for adenomyotic tissue samples (n= 10). MAIN RESULTS AND THE ROLE OF CHANCE Adenomyotic lesions had a significantly higher extent of platelet aggregation and increased staining for TGF-β1 and phosphorylated Smad3 (both P-values

This study was undertaken to test the hypotheses that, due to gradual accumulation of dead erythrocytes and their ingested products resulting from repeated hemorrhage, older endometriomas (whitish in color) contain chocolate fluid with higher iron content than younger (brownish/blackish in color) ones with concomitant higher collagen content and more adhesions. We recruited 30 premenopausal women with histologically confirmed ovarian endometriomas and collected samples of their endometriotic lesions and chocolate fluid and measured the viscosity, density, and the concentration of total bilirubin, ferritin, and free iron of the chocolate fluid. We also evaluated the lesion color and adhesion scores. In addition, we performed Masson trichrome and Picro-Sirius red staining on all endometriotic cysts and evaluated the extent of fibrosis in the lesions. We found that fluids taken from white-colored endometriomas had significantly higher concentration of total bilirubin, ferritin, and free iron, respectively, than black/brown-colored ones. In addition, older cysts had fluids that had significantly higher density and viscosity. Fluid density correlated positively with the concentrations of total bilirubin, ferritin, and free iron. Older lesions had significantly more collagen content and higher adhesion scores. Taken together, these data supports the notion that older cysts, having experienced more bleeding episodes, contain chocolate fluid that is higher in viscosity, density, and iron content and higher fibrotic content than younger ones. This provides another piece of evidence that endometriotic lesions are wounds that undergo repeated injury and repair, resulting ultimately fibrotic lesions that are resistant to hormonal treatment.

Inhibition of cytokinesis by overexpression of NudCL that is localized to the centrosome and midbody

SummaryThe Metadherin gene (MTDH) is prevalently amplified in breast cancer and associated with poor prognosis; however, its functional contribution to tumorigenesis is poorly understood. Using mouse models representing different subtypes of breast cancer, we demonstrated that MTDH plays a critical role in mammary tumorigenesis by regulating oncogene-induced expansion and activities of tumor-initiating cells (TICs), whereas it is largely dispensable for normal development. Mechanistically, MTDH supports the survival of mammary epithelial cells under oncogenic/stress conditions by interacting with and stabilizing Staphylococcal nuclease domain-containing 1 (SND1). Silencing MTDH or SND1 individually or disrupting their interaction compromises tumorigenenic potential of TICs in vivo. This functional significance of MTDH-SND1 interaction is further supported by clinical analysis of human breast cancer samples.