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The 4.2 nm α-CsPbI3 quantum dots - polymer composite films with 630 nm emission and high stability have been achieved, which are used for LED displays with color gamut to 96% of the Rec. 2020 standard.

Manganese doped perovskite nanocrystals (NCs) have been synthesized by a novel two-step hot injection strategy with an unprecedented Mn doping efficiency of 48.5%, bright orange emission under ultraviolet light and X-ray excitation and a photoluminesce (PL) quantum yield of 84.4%, making them excellent luminescent materials.

A novel quaternary ammonium antinomy halide was synthesized and used to construct bright orange LEDs with a luminous efficiency of 24.5 lm W−1, which can run continuously in air for more than 1200 minutes without performance degradation.

In order to achieve high color rendering index (CRI) and low correlated color temperature (CCT) indoor lighting, single component phosphors with broadband dual emission emission are high demanded for white light emitting diodes (WLEDs). However, phosphors with such fluorescent properties are rare at present. Herein, we report a facile solid-state chemical method for the synthesis of single-component phosphor with broadband emission and large Stokes shift that can meet the requirements of future white light sources. These new tetrabutylammonium copper halides phosphors have excellent warm white emission characteristics, and their luminescence peaks located at 494 nm and 654 nm, respectively. The optimized photoluminescence (PL) quantum yield can reach 93.7%. The typical CIE coordinate of the as-fabricated WLED is at (0.3620, 0.3731) with CRI of 89 and low CCT of 4516 K.

In recent years, two-dimensional (2D) layered tin halide perovskites have attracted much attention due to their excellent luminescence properties compared with their three-dimensional (3D) analogs. Here, we synthesized 2D perovskites of the form (RNH3)2SnBr4 through a facile hot-injection approach without the use of toxic tri-n-octylphosphine (TOP) as the solvent. We found that these compounds have strong photoluminescence (PL) emission with high PL quantum yields (QY) of 35% ((C6H13NH3)2SnBr4), 82% ((C8H17NH3)2SnBr4), 60% ((C12H25NH3)2SnBr4) and 50% ((C18H35NH3)2SnBr4). Among them, ((C6H13NH3)2SnBr4) was synthesized for the first time; however, (C18H36NH3)2SnBr4 perovskites showed the best stability with a PL QY decrease of less than 1% after 30 days under ambient air and humidity conditions. In addition, other 2D (C8H17NH3)2SnX4 (X = Br, I, or mixture) perovskites were prepared by adjusting the halide ratio, resulting in spectral tunability from yellow to red. Interestingly, through Zn2+ doping, the morphology became more uniform, and the PL stability was significantly improved. Finally, we used Zn2+-doped (C8H17NH3)2SnBr4 yellow phosphor to fabricate UV-pumped yellow LEDs. We expect these 2D perovskites to be promising phosphors in future solid-state lighting and display technologies.

Recently, two-dimensional (2D) metal halide perovskite materials with wide application in perovskite-based solar cells have attracted significant attention. Among them, 2D mixed lead–tin perovskites have not been systematically explored. Herein, we synthesize a 2D phenethylammonium (PEA) tin–lead bromide perovskite, PEA2SnxPb1−xBr4, via a simple solution-phase approach without toxic reagents and high temperatures. By tuning the ratio of Sn and Pb, the UV-vis absorption spectra showed unique bandgap bending behaviors. DFT calculations indicate the key effects of spin–orbital coupling (SOC) without the interference of lattice distortion. Moreover, we provided the standard equation with a correction term to introduce the influence of SOC. These results not only provide a step forward towards the bandgap engineering of perovskites, but also help to expand the application of 2D perovskite materials.

Chemotherapy resistance represents a major obstacle for the treatment of patients with breast cancer (BC) and greatly restricts the therapeutic effect of the first-line chemotherapeutic agent doxorubicin (DOX). The present study aimed to investigate the feasibility of the recombinant dual-target murine double minute 2 (MDM2) and murine double minute X (MDMX) inhibitor in reversing the DOX resistance of BC. Both DOX-resistant human breast carcinoma cell lines exhibited a multidrug resistance (MDR) phenotype. The ability of the dual-target MDM2/MDMX inhibitor in reversing doxorubicin resistance was subsequently verified, (9.15 and 13.92 - fold reversal indexes) respectively. We observed that the MDM2/MDMX inhibitor in combination with DOX could suppress proliferation, promote cell cycle arrest and induce apoptosis. In addition, it was capable of reducing rhodamine123 efflux in DOX-resistance BC cell lines and further played a key role in BC nude mice model. The groups that were treated with the combination of the drugs had decreased P-glycoprotein/multidrug resistance-associated protein/cdc 2/Bcl-2 expression and increased CyclinB1/Bax expression. These effects were caused due to activation of the transforming growth factor β-activated kinase 1 (TAK1)-binding protein 1 (TAB1)/TAK1/p38 mitogen-activated protein kinase (MAPK) signaling pathway, as shown by small interfering RNA (siRNA) silencing and immumohistochemical staining of BC tissue sections. Furthermore, high MDM2/MDMX expression was positively associated with weak TAB1 expression in BC patients. Therefore, the recombinant dual-target MDM2/MDMX inhibitor could reverse doxorubicin resistance via the activation of the TAB1/TAK1/p38 MAPK pathway in wild-type p53 multidrug-resistant BC.

Manganese-doped perovskite nanocrystals (NCs) have been synthesized by a novel two-step hot-injection strategy with an unprecedented Mn doping efficiency of 48.5%, bright orange emission under ultraviolet light and X-ray excitation and a photoluminescence quantum yield of 84.4%, making them excellent luminescent materials.

High rates of de novo lipid synthesis have been discovered in certain kinds of tumours, including gallbladder cancer (GBC). Unlike several other tumours, GBC is highly insensitive to standard adjuvant therapy, which makes its treatment even more challenging. Although several potential targets and signalling pathways underlying GBC chemoresistance have been revealed, the precise mechanisms are still elusive. In this study, we found that α‐Mangostin, as a dietary xanthone, repressed the proliferation and clone formation ability, induced cell cycle arrest and the apoptosis, and suppressed de novo lipogenesis of gallbladder cancer cells. The underlying mechanisms might involve the activation of AMPK and, therefore, the suppression of SREBP1 nuclear translocation to blunt de novo lipogenesis. Furthermore, SREBP1 silencing by siRNA or α‐mangostin enhanced the sensitivity of gemcitabine in gallbladder cancer cells. In vivo studies also displayed that MA or gemcitabine administration to nude mice harbouring NOZ tumours can reduce tumour growth, and moreover, MA administration can significantly potentiate gemcitabine‐induced inhibition of tumour growth. Corroborating in vitro findings, tumours from mice treated with MA or gemcitabine alone showed decreased levels of proliferation with reduced Ki‐67 expression and elevated apoptosis confirmed by TUNEL staining, furthermore, the proliferation inhibition and apoptosis up‐regulation were obviously observed in MA combined with gemcitabine treatment group. Therefore, inhibiting de novo lipogenesis via targeting the AMPK/SREBP1 signalling by MA might provide insights into a potential strategy for sensitizing GBC cells to chemotherapy.

Purpose: Functional loss of BRCA1 is associated with poorly differentiated and metastatic breast cancers that are enriched with cancer stem cells (CSCs). CSCs can be generated from carcinoma cells through an epithelial-mesenchymal transition (EMT) program. We and others have previously demonstrated that BRCA1 suppresses EMT and regulates the expression of multiple EMT-related transcription factors. However, the downstream mediators of BRCA1 function in EMT suppression remain elusive. Methods: Depletion of BRCA1 or GATA3 activates p18INK4C , a cell cycle inhibitor which inhibits mammary epithelial cell proliferation. We have therefore created genetically engineered mice with Brca1 or Gata3 loss in addition to deletion of p18INK4C , to rescue proliferative defects caused by deficiency of Brca1 or Gata3. By using these mutant mice along with human BRCA1 deficient as well as proficient breast cancer tissues and cells, we investigated and compared the role of Brca1 and Gata3 loss in the activation of EMT in breast cancers. Results: We discovered that BRCA1 and GATA3 expressions were positively correlated in human breast cancer. Depletion of BRCA1 stimulated methylation of GATA3 promoter thereby repressing GATA3 transcription. We developed Brca1 and Gata3 deficient mouse system. We found that Gata3 deficiency in mice induced poorly-differentiated mammary tumors with the activation of EMT and promoted tumor initiating and metastatic potential. Gata3 deficient mammary tumors phenocopied Brca1 deficient tumors in the induction of EMT under the same genetic background. Reconstitution of Gata3 in Brca1-deficient tumor cells activated mesenchymal-epithelial transition, suppressing tumor initiation and metastasis. Conclusions: Our finding, for the first time, demonstrates that GATA3 functions downstream of BRCA1 to suppress EMT in controlling mammary tumorigenesis and metastasis.

Background Basal-like breast cancers (BLBCs) are a leading cause of cancer death due to their capacity to metastasize and lack of effective therapies. More than half of BLBCs have a dysfunctional BRCA1. Although most BRCA1-deficient cancers respond to DNA-damaging agents, resistance and tumor recurrence remain a challenge to survival outcomes for BLBC patients. Additional therapies targeting the pathways aberrantly activated by BRCA1 deficiency are urgently needed. Methods Most BRCA1-deficient BLBCs carry a dysfunctional INK4-RB pathway. Thus, we created genetically engineered mice with Brca1 loss and deletion of p16INK4A, or separately p18INK4C, to model the deficient INK4-RB signaling in human BLBC. By using these mutant mice and human BRCA1-deficient and proficient breast cancer tissues and cells, we tested if there exists a druggable target in BRCA1-deficient breast cancers. Results Heterozygous germline or epithelium-specific deletion of Brca1 in p18INK4C- or p16INK4A-deficient mice activated Pdgfrβ signaling, induced epithelial-to-mesenchymal transition, and led to BLBCs. Confirming this role, targeted deletion of Pdgfrβ in Brca1-deficient tumor cells promoted cell death, induced mesenchymal-to-epithelial transition, and suppressed tumorigenesis. Importantly, we also found that pharmaceutical inhibition of Pdgfrβ and its downstream target Pkcα suppressed Brca1-deficient tumor initiation and progression and effectively killed BRCA1-deficient cancer cells. Conclusions Our work offers the first genetic and biochemical evidence that PDGFRβ-PKCα signaling is repressed by BRCA1, which establishes PDGFRβ-PKCα signaling as a therapeutic target for BRCA1-deficient breast cancers.

Additional file 5. BRCA1 represses transcription of PDGFRβ and EMT-associated genes. SUM149 cells were transfected with pBabe-empty (Empty), pBabe-HA-BRCA1 (BRCA1-a), or pBabe-Myc-BRCA1 (BRCA1-b). Expression of genes indicated in the cells were determined by western blot (A) and qRT-PCR (B) 48 h after transfection.

Additional file 1. Primer sequence for accessing the occupancy of BRCA1 on the PDGFRβ locus.

Additional file 4 Loss of Brca1 activates Pdgfrβ-Pkcα signaling and EMT in mammary tumors. Mammary tumors spontaneously developed in p18-/- and p18-/-;Brca1MGKO mice were analyzed by western blot.

Additional file 6 Pharmaceutical inhibition of PDGFRβ or PKCα activity targets BRCA1 deficient human breast cancer cells. (A, B) HCC1937 (A) and T47D (B) cells treated with DMSO, PDGFR Inh III at 20 nM, or Ro-31-8220 at 35 nM for 24 h were analyzed by western blot. Due to the extremely low level of PDGFRβ and PKCα in T47D cells in comparison with that in HCC1937 cells (shown in Fig. 7b), longer exposure bands for T47D cells were shown in (B). N.S., non-specific band. (C) HCC1937 and T47D cells were treated with DMSO, PDGFR Inh III, or Ro-31-8220 at the indicated concentrations for 24 h, and the number of viable cells was determined. Data are represented as mean ± SD of triplicates. *p

Additional file 3 Brca1-deficient mouse mammary tumors express high level of Pdgfrβ and are metastatic. (A) Representative immunostaining of a p16-/-;Brca1MGKO mammary tumor and its lung metastasis (M) with antibodies against Pdgfrβ (Green) and Ck14 (Red). Note the widely expressed Pdgfrβ in primary and metastasized tumors that are Ck14 positive. (B) Representative immunostaining of an additional p18-/-;Brca1MGKO mammary tumor.

Additional file 7. Expression of BRCA1 is inversely related with that of PDGFRβ and PKCα in human breast cancers. (A) Representative immunostaining analysis for serial human breast cancer sections. Antibodies used were indicated. (B) Immunostaining results for individual tumor in (A). +/−, 70%.

In this study, we reported the one-step synthesis of chitosan-Fe(OH)3 beads without the use of acid solvent, which could be used as effective adsorbents for anionic dyes removal. The preparation process was easy and green. The as-prepared beads were characterized for structural and morphological analysis in detail using several techniques, such as Scanning Electron Microscope, Fourier Transform Infrared Spectroscopy, X-Ray Diffraction, X-ray photoelectron spectroscopy and Thermogravimetric analysis. The content of Fe(OH)3 in chitosan-Fe(OH)3 beads was 54.64 wt%. The removal efficiencies toward anionic dyes: congo red (CR) and methyl orange (MO) by chitosan-Fe(OH)3 beads were higher than pure chitosan beads. Moreover, the incorporation of Fe(OH)3 into chitosan beads could overcome the obstacle that powdery Fe(OH)3 particles are difficult to be separated from the adsorption solutions. The maximum adsorption capacities from Langmuir model for CR and MO by chitosan-Fe(OH)3 beads were 445.32 and 314.45 mg/g, respectively. The thermodynamic data indicated that the adsorption processes were spontaneous and endothermic. In addition, chitosan-Fe(OH)3 beads also showed good reusability and the removal efficiencies for both dyes retained above 95% after five cycles. From this work, it suggests that chitosan-Fe(OH)3 beads have great potential as low-cost and effective adsorbents for the removal of anionic dyes.

This communication describes a facile hot-injection method for the synthesis of novel micrometer-size formamidinium lead bromide perovskite (FAPbBr3) nanosheets of monolayer thickness (around 2.4 nm). Due to the strong quantum confinement effect, the as-synthesized large-sized perovskite nanosheets displayed an unprecedented extremely blue-shifted first sharp excitonic absorption peak at 435 nm and an emission peak at 437 nm, as compared to that of bulk FAPbBr3 crystals at 551 nm.

Lead halide perovskites with well-defined morphology have attracted attention for their unique properties as a promising new class of semiconductor materials in photovoltaics and optoelectronics. However, controlling morphologies and compositions of perovskite nanostructures with improved stability, especially for double cation lead halide perovskite, still remains a challenge. Here, we demonstrate a colloidal synthetic approach for direct synthesis of stable single-crystal formamidinium (FA) cesium double cation lead halide FA0.33Cs0.67PbBr3–xIx (0 ≤ x ≤ 3) perovskite nanostructures with controllable morphology over a wide range of halide compositions, without using a previous anion-exchange process. The presence of FA alloyed in the A site for the pure cesium lead halide perovskite structure can stabilize the nanocrystals while delivering a better balance between structure and composition. On the basis of the FA0.33Cs0.67PbBr3–xIx alloy perovskite system, we achieved nanowires and nanosheets with high y...

Recently, electrically conductive biomaterial scaffolds have shown great potential in tissue regeneration. Herein, we reported an electrically conductive polyaniline (PANI) coated poly(e-caprolactone) (PCL) electrospun micron-fiber scaffold for the enhanced attachment and proliferation of human umbilical vein endothelial cells (HUVECs) under electrical stimulation conditions. After the O2 plasma treatment toward PCL electrospun fiber, PANI could be polymerized onto their surfaces successfully. The obtained PANI-PCL fibers were characterized by SEM observations, FT-IR spectra, XPS analysis, and water contact angle measurement. The mechanical tests indicated that the fibers could satisfy the practical vascular scaffold requirements. The conductivity of the PANI-PCL fibers was 6.71×10-3S/cm which could provide a conductive in-vitro platform to study the effect of electrical stimulation on HUVECs proliferation. When PANI-coated PCL fibers were compared with PCL fibers, HUVECs exhibited highly enhanced adhesion and viability, especially under electrical stimulation (ES) of 200, 300, and 400mV/cm. Proliferation of HUVECs on PANI-PCL fibers was strongly dependent on electrical stimulation intensity. The results showed new insights into conductive scaffolds for vascular tissue engineering.

Tetramethylpyrazine (TMP) and astragaloside IV (AGS-IV) are herbal ingredients that have been demonstrated in animal models to limit infarct size and protect cardiomyocytes in the acute phase of myocardial infarction (MI), yet their long-term cardioprotective effects have not been evaluated. In this study, TMP and/or AGS-IV were administrated to rats for 14 days after MI. Echocardiography revealed that the left ventricular (LV) dimensions and cardiac function were preserved in the MI rats with TMP and AGS-IV treatment, compared with untreated MI rats. Moreover, the LV dimensions and cardiac function in the MI rats with TMP and AGS-IV cotreatment were comparable with the sham-operated rats. In addition, TMP and AGS-IV synergistically inhibited LV fibrosis by attenuating MI-induced collagen deposition and elevation of transforming growth factor β1. TMP and AGS-IV, alone or in synergy, enhanced angiogenesis in the infarcted myocardium and reduced cardiac hypertrophy of the remote myocardium after MI. Furthermore, TMP and AGS-IV mutually upregulated the expression of Sonic hedgehog (Shh), Smoothened, and Glioblastoma-2, the receptor and signal transducer of Shh signaling pathway, in the infarcted myocardium. In summary, in the circumstance of the irreversible ischemic injury, the antifibrotic, and pro-angiogenic properties of TMP and AGS-IV on the nonaffected tissues contribute to the cardioprotection in the healing phase post MI, and the cardioprotective effects are likely to be mediated through the Shh pathway.

This study examined the tumor expression of programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) in patients with GEP-NEN. This study aims to reveal the relationship of their expression with clinicopathological characteristics and prognosis.PD1 and PD-L1 expression in tumors from 120 GEP-MEN patients was evaluated using immunohistochemistry. The correlations of the expression of PDL1/PD1 and clinicopathological features were assessed.Immunohistochemical staining indicated that PD-L1 was expressed in the tumor cells of 52.5% patients with GEP-NENs, and PD-L1 expression was positively correlated with the World Health Organization (WHO) classification, American Joint Committee on Cancer (AJCC) stage, lymphatic metastasis and prognosis. Meanwhile, PD-1 was expressed in tumor infiltrating lymphocytes within 55.8% tumor samples, and PD-1 expression was positively correlated with AJCC stage and GEP-NENs prognosis. Moreover, survival analysis indicated that the overall median survival of patients with PD-L1/PD-1-positive tumors significantly differed from that of patients with PD-L1/PD-1-negative tumors. Multivariate analysis confirmed that AJCC stage and Chromogranin A expression in tumor tissues were independent prognostic factors for overall survival. In conclusion, PDL1 was an independent prognostic factor for patients with GEP-NENs. Our results suggested that patients with GEP-NENs might be appropriate for PD1/PDL1-targeted therapy.Our findings show that the expression of PD-L1 and PD-1 correlates with patient prognosis, and may thus serve as potential pathological prognostic markers of GEP-NENs. Immunotherapy using PD-1/PD-L1 inhibitors may be a promising strategy for GEP-NENs patients with PD-L1/PD-1 positively expressed.

Highly efficient lead halide perovskites with tunable emission performance have become new candidate materials for light‐emitting devices and displays; however, the toxicity of lead and instability of halide perovskites greatly limits their application. Herein, rapid and large‐scale synthesis of highly emissive organic–inorganic manganese halide perovskites, (C5H6N)2MnBr4 and C5H6NMnCl3, are presented by a one‐pot solution‐based method, of which (C5H6N)2MnBr4 displays a high absolute photoluminescence quantum yield (95%) in the solid‐state. The developed (C5H6N)2MnBr4 perovskite noticeably exhibits high stability. Therefore both as‐synthesized green and red emissive manganese‐based phosphors with superior optical properties are used to fabricate blue light pumped white light‐emitting diodes (WLEDs), displaying excellent quality white light with a high color rendering index value of 91 and a correlated color temperature of 5331 K. This study not only presents the robust large‐scale production synthetic approach for organic–inorganic manganese halide perovskites, but also facilitates the development of high‐performance phosphors for future lighting and display technologies.

Yangwei Fan,1,* Ke Ma,1,* Chuying Wang,1 Jing Ning,1 Yuan Hu,1 Danfeng Dong,1 Xuyuan Dong,1 Qianqian Geng,2 Enxiao Li,1 Yinying Wu1 1Department of Medical Oncology, 2Department of Nuclear Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China *These authors contributed equally tothis work Purpose: Programmed death 1 (PD-1) receptor and its ligand, programmed death ligand-1 (PD-L1), play critical roles in the immune invasion of various tumors. This study aimed to explore the clinical significance of PD-L1/PD-1 expression in the progression of pulmonary neuroendocrine tumors (PNETs). Methods: The expression of PD-L1 and PD-1 in 80 patients diagnosed with PNETs were investigated. Immunohistochemical analysis was performed on 80 formalin-fixed paraffin-embedded tissue specimens from PNETs and 20 corresponding cancer-adjacent tissue specimens. Results: Tissues from PNETs had higher levels of PD-L1 (58.8%) and PD-1 (51.3%) compared to the cancer-adjacent tissues (25% and 20%, respectively). Meanwhile, PD-L1 expression was associated with PD-1 expression (P=0.007). PD-L1 expression was significantly associated with histological type (P=0.014) and tumor stage (P=0.014). Univariate analyses showed that the overall survival time of PNETs patients was significantly associated with PD-L1 expression in cancer cells (P=0.003), PD-1 expression in tumor-infiltrating lymphocytes (P=0.001), tumor node metastasis stage (P

Anginex is an artificial synthetic small molecule β-sheet-forming peptide shown to have anti-angiogenesis and antitumor effects in various solid tumors. However, its molecular mechanism remains largely unclear and efficient delivery methods for anginex remains to be developed. We report on the development of recombinant adeno-associated virus (rAAV2)-delivered anginex and the underlying mechanism of anti-angiogenesis and antitumor effects of anginex. We have successfully developed the rAAV2 vector to efficiently express anginex (rAAV2‑anginex). Transduction of rAAV2-anginex significantly induced apoptosis, and inhibited the proliferation, migration, invasion and tube formation of human umbilical vein endothelial cells in vitro. Western blot analysis revealed that rAAV2‑anginex inhibited the phosphorylation of Akt, while inducing the phosphorylation of JNK and activation of the NF-κB signaling pathway. In an in vivo CAM assay and xenograft model of SKOV3, rAAV2-anginex significantly reduced microvessel density (MVD) and vascular endothelial growth factor 165 (VEGF165), as demonstrated by immunohistochemistry analysis. Importantly, rAAV2-anginex inhibited tumor growth in an ovarian cancer SKOV3 cell nude mouse xenograft model. Our results suggest that rAAV2-anginex may inhibit tumor angiogenesis and growth through regulating Akt, JNK and NF-κB signaling pathways.

Impaired mitochondrial function and activation of NLRP3 inflammasome cascade has a significant role in the pathogenesis of myocardial ischemia–reperfusion (IR) injury. The current study investigated whether eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or their corresponding CYP epoxygenase metabolites 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) protect against IR injury. Isolated mouse hearts were perfused in the Langendorff mode with vehicle, DHA, 19,20-EDP, EPA, or 17,18-EEQ and subjected to 30 min of ischemia and followed by 40 min of reperfusion. In contrast with EPA and 17,18-EEQ, DHA and 19,20-EDP exerted cardioprotection, as shown by a significant improvement in postischemic functional recovery associated with significant attenuation of NLRP3 inflammasome complex activation and preserved mitochondrial function. Hearts perfused with DHA or 19,20-EDP displayed a marked reduction in localization of mitochondrial Drp-1 and Mfn-2 as well as maintained Opa-1 levels. DHA and 19,20-EDP preserved the activities of both the cytosolic Trx-1 and mitochondrial Trx-2. DHA cardioprotective effect was attenuated by the CYP epoxygenase inhibitor N-(methysulfonyl)-2-(2-propynyloxy)-benzenehexanamide. In conclusion, our data indicate a differential cardioprotective response between DHA, EPA, and their active metabolites toward IR injury. Interestingly, 19,20-EDP provided the best protection against IR injury via maintaining mitochondrial function and thereby reducing the detrimental NLRP3 inflammasome responses.

Background Estrogen promotes breast cancer development and progression mainly through estrogen receptor (ER). However, blockage of estrogen production or action prevents development of and suppresses progression of ER-negative breast cancers. How estrogen promotes ER-negative breast cancer development and progression is poorly understood. We previously discovered that deletion of cell cycle inhibitors p16Ink4a (p16) or p18Ink4c (p18) is required for development of Brca1-deficient basal-like mammary tumors, and that mice lacking p18 develop luminal-type mammary tumors. Methods A genetic model system with three mouse strains, one that develops ER-positive mammary tumors (p18 single deletion) and the others that develop ER-negative tumors (p16;Brca1 and p18;Brca1 compound deletion), human BRCA1 mutant breast cancer patient-derived xenografts, and human BRCA1-deficient and BRCA1-proficient breast cancer cells were used to determine the role of estrogen in activating epithelial-mesenchymal transition (EMT), stimulating cell proliferation, and promoting ER-negative mammary tumor initiation and metastasis. Results Estrogen stimulated the proliferation and tumor-initiating potential of both ER-positive Brca1-proficient and ER-negative Brca1-deficient tumor cells. Estrogen activated EMT in a subset of Brca1-deficient mammary tumor cells that maintained epithelial features, and enhanced the number of cancer stem cells, promoting tumor progression and metastasis. Estrogen activated EMT independent of ER in Brca1-deficient, but not Brca1-proficient, tumor cells. Estrogen activated the AKT pathway in BRCA1-deficient tumor cells independent of ER, and pharmaceutical inhibition of AKT activity suppressed EMT and cell proliferation preventing BRCA1 deficient tumor progression. Conclusions This study reveals for the first time that estrogen promotes BRCA1-deficient tumor initiation and progression by stimulation of cell proliferation and activation of EMT, which are dependent on AKT activation and independent of ER. Electronic supplementary material The online version of this article (10.1186/s13058-018-0996-9) contains supplementary material, which is available to authorized users.

In this study, we reported the one-step synthesis of chitosan-Fe(OH)

Figure S1. Characterization of mammary tumors developed in mutant mice in Balb/cB6 mixed background. Representative mammary tumors spontaneously developed in p18-/-;Brca1MGKO, p16-/-;Brca1MGKO and p18-/- mice were immunostained with the antibodies indicated. The representative cells are enlarged in the insets.

Figure S4. Estrogen promotes lung metastasis of Brca1-deficient mammary tumors. (A, B) Metastatic p18-/-;Brca1MGKO tumor cells were inoculated into the MFPs of NSG mice with either E2 or placebo supplement. When newly generated tumors reached maximum size allowed by the IACUC in 3â 6Â weeks, or the mice became moribund, lungs were dissected for analysis. Representative gross pictures (A) and H.E. staining (B) of lungs are shown.

Figure S6. Estrogen promotes EMT in Brca1-deficient tumor cells (A, B) p18-/-;Brca1MGKO type 1 (A) and p18-/- tumor cells (B) were treated with DMSO or E2 for the indicated time and analyzed by western blot. (C, D) p18-/-;Brca1MGKO type 2 tumor cells were treated with DMSO or 50 nM E2 for 2 h or 72 h, and then analyzed by FACS (C) and western blot (D). (E) SUM149 cells were treated with DMSO or 50 nM E2 for 72 h and analyzed by western blot.

Figure S3. Estrogen promotes Brca1-proficient and deficient mammary tumor initiation (A)Â Western blot analysis of mammary tumors regenerated by p18-/- or p18-/-;Brca1MGKO tumor cells with E2 supplement. (B) Representative gross pictures of p18-/- and p16-/-;Brca1MGKO tumors generated by transplantation. We transplanted 1 x 107 p18-/- or 6 x 104 p16-/-;Brca1MGKO tumor cells into MFPs of NSG mice with or without E2 supplement. Gross pictures were taken 6-7 weeks post-transplantation. (C) Representative H.E. staining of primary p18-/- tumors and tumors generated by p18-/- tumor cells with E2 supplement. Note the well-differentiated cells with glandular structure in both primary and regenerated tumors. (D) Representative H.E. staining of p16-/-;Brca1MGKO tumors generated in the presence or absence of E2 supplement. Note the poorly differentiated cells with increased fibroblast-like cells in the tumors with E2 treatment. Spindle cells (black arrows), cells with high nuclear-cytoplasm ratio (green arrows), mitotic cells (red arrows), and necrosis (yellow arrows) are indicated.

Figure S5. IHC analysis of ERa and EMT markers for tumors with or without E2 treatment. (A-C) Representative p18-/-;Brca1MGKO and p18-/- mammary tumors treated with E2 or placebo were immunostained with the antibodies indicated. Note the negative ERa staining in E2-treated p18-/-;Brca1MGKO tumors (B) and positive ERa staining in E2-treated p18-/- tumors (C).

Figure S7. Estrogen stimulates ER-positive cell proliferation that is blocked by 4OHT. MCF-7 cells were treated with DMSO and 5 nM E2 with or without 5 µM 4OHT. The number of viable cells was determined on day 1, day 3, and day 5 (A). Cells treated for 72 h were collected and analyzed by western blot (B); *p?

Figure S2. p18-/-;Brca1MGKO and p16-/-;Brca1MGKO tumor cells generate reproducible ER-negative Brca1-deficient mammary tumors. (A) A primary mammary tumor (donor tumor A) developed in a 15-month-old p16-/-;Brca1MGKO mouse was analyzed by FACS. As a control, tumor-free mammary glands from age-matched p16-/- mice were analyzed. Note a predominant CD24?+?CD29high population in the tumor. (B, C) We transplanted 6?Ă ?104 FACS-sorted Lin- cells from a p16-/-;Brca1MGKO tumor (donor tumor B) into MFPs of four NSG mice. Representative tumors generated were analyzed by IHC (B) and western blot (C). (D, E) Representative p18-/- and p18-/-;Brca1MGKO tumor cells were cultured and analyzed. MCF7 cells were used as a positive control of ERa expression. (F, G) We transplanted 1?Ă ?106 cultured p18-/-;Brca1MGKO tumor (donor tumor A) cells into MFPs of four NSG mice. Representative tumors generated were analyzed by IHC (F) and western blot (G). p18-/- tumors were used as control in (C) and (G).

HOXD10, a key regulator of cell-differentiated phenotype maintainence, has been demonstrated to be involved in the tumorigenesis of many human malignacies. However, the status of HOXD10 expression and its biological function in cholangiocellular carcinoma (CCC) remain to be clarified. In the present study, we investigated the clinical significance and biological functions of HOXD10 in CCC and found that the expression of HOXD10 and its downstream effector RHOC was significantly different in well-differentiated CCC tissues compared with poorly-differentiated lesions. We also observed a significant correlation between low HOXD10 and high RHOC expression levels and worse prognosis. The stable overexpression of HOXD10 by lentivirus vector significantly inhibited cell invasion partly by downregulating the expression of MMP2 and MMP9, and significantly increased early apoptosis in CCC cell lines and induced G1 phase cell cycle arrest, contributing to the inhibition of cell proliferation in vitro. Additionally, we demonstrated that the inactivation of the RHOC/AKT/MAPK pathway was involved in the tumor-suppressive functions of HOXD10 in CCC. These results suggested that HOXD10 may be a putative suppressor gene and can act as a prognostic marker and potentially a novel therapeutic target for CCC.

// Ke Ma 1, * , Yangwei Fan 1, * , Xuyuan Dong 1 , Danfeng Dong 1 , Yuyan Guo 2 , Xin Wei 3 , Jing Ning 4 , Qianqian Geng 5 , Chuying Wang 1 , Yuan Hu 1 , Mengya Li 1 , Wenxia Niu 1 , Enxiao Li 1 and Yinying Wu 1 1 Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, P.R. China 2 Department of Medical Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, P.R. China 3 Department of Medical Oncology, Shaanxi Province People’s Hospital, Xi’an, Shaanxi 710068, P.R. China 4 Department of Obstetrics and Gynecology, Xi’an Third Hospital, Xi’an, Shaanxi 710068, P.R. China 5 Department of Nuclear Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, P.R. China * These authors have contributed equally to this work Correspondence to: Yinying Wu, email: shadowless_111@163.com , makeyfly@126.com Enxiao Li, email: doclienxiao@sina.com Keywords: MTA1, metastasis, epithelial to mesenchymal transition, NSCLC, AKT Received: August 10, 2016 Accepted: February 27, 2017 Published: March 21, 2017 ABSTRACT The present study assessed the role of metastasis-associated protein 1 (MTA1) in epithelial to mesenchymal transition (EMT) and metastasis in non-small-cell lung cancer (NSCLC) cells using a normal lung epithelium cell line, three NSCLC cell lines, a mouse NSCLC model, and 56 clinical NSCLC samples. We observed that MTA1 overexpression decreased cellular adhesion, promoted migration and invasion, and changed cytoskeletal polarity. MTA1 knockdown had the opposite effects. MTA1 overexpression decreased E-cadherin, Claudin-1, and ZO-1 levels and increased Vimentin expression in vitro and in vivo , through activation of AKT/GSK3β/β-catenin signaling. However, treatment with the AKT inhibitor MK2206 did not completely rescue effects associated with MTA1 expression changes, indicating that pathways other than the AKT/GSK3β/β-catenin pathway could be involved in MTA1-induced EMT. Compared with normal lung tissues, MTA1 expression was elevated in NSCLC patient tissues and was correlated with American Joint Committee on Cancer stage, T stage, lymphatic metastasis, and patient overall survival. Additionally, MTA1 expression was positively associated with p-AKT and cytoplasmic β-catenin levels. These findings indicate MTA1 promotes NSCLC cell EMT and metastasis via AKT/GSK3β/β-catenin signaling, which suggests MTA1 may be an effective anti-NSCLC therapeutic target.