INPP4B suppresses HER2-induced mesenchymal transition in HER2+ breast cancer and enhances sensitivity to Lapatinib.

Human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) tends to metastasize and has a bad prognosis due to its high malignancy and rapid progression. Inositol polyphosphate 4-phosphatase isoenzymes type II (INPP4B) plays unequal roles in the development of various cancers. However, the function of INPP4B in HER2+ BC has not been elucidated. Here we found that INPP4B expression was significantly lower in HER2+ BC and positively correlated with the prognosis by bioinformatics and tissue immunofluorescence analyses. Overexpression of INPP4B inhibited cell proliferation, migration, and growth of xenografts in HER2+ BC cells. Conversely, depletion of INPP4B reversed these effects and activated the PDK1/AKT and Wnt/ß-catenin signaling pathways to promote epithelial-mesenchymal transition (EMT) progression. Moreover, INPP4B overexpression blocked epidermal growth factor (EGF) -induced cell proliferation, migration and EMT progression, whereas INPP4B depletion antagonized HER2 depletion in reduction of cell proliferation and migration of HER2+ BC cells. Additionally, Lapatinib (LAP) inhibited HER2+ BC cell survival, proliferation and migration, and its effect was further enhanced by overexpression of INPP4B. In summary, our results illustrate that INPP4B suppresses HER2+ BC growth, migration and EMT, and its expression level affects patient outcome, further providing new insights into clinical practice.

Potential Implications of Hyperoside on Oxidative Stress-Induced Human Diseases: A Comprehensive Review.

Hyperoside is a flavonol glycoside mainly found in plants of the genera Hypericum and Crataegus, and also detected in many plant species such as Abelmoschus manihot, Ribes nigrum, Rosa rugosa, Agrostis stolonifera, Apocynum venetum and Nelumbo nucifera. This compound exhibits a multitude of biological functions including anti-inflammatory, antidepressant, antioxidative, vascular protective effects and neuroprotective effects, etc. This review summarizes the quantification, original plant, chemical structure and property, structure-activity relationship, pharmacologic effect, pharmacokinetics, toxicity and clinical application of hyperoside, which will be significant for the exploitation for new drug and full utilization of this compound.

N76-1, a novel CDK7 inhibitor, exhibits potent anti-cancer effects in triple negative breast cancer.

Emerging evidence suggests that genetically highly specific triple-negative breast cancer (TNBC) possesses a relatively uniform transcriptional program that is abnormally dependent on cyclin-dependent kinase 7 (CDK7). In this study, we obtained an inhibitor of CDK7, N76-1, by attaching the side chain of the covalent CDK7 inhibitor THZ1 to the core of the anaplastic lymphoma kinase inhibitor ceritinib. This study aimed to elucidate the role and underlying mechanism of N76-1 in TNBC and evaluate its potential value as an anti-TNBC drug. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays showed that N76-1 inhibited the viability of TNBC cells. Kinase activity and cellular thermal shift assays showed that N76-1 directly targeted CDK7. Flow cytometry results revealed that N76-1 induced apoptosis and cell cycle arrest in the G2/M phase. N76-1 also effectively inhibited the migration of TNBC cells by high-content detection. The RNA-seq analysis showed that the transcription of genes, especially those related to transcriptional regulation and cell cycle, was suppressed after N76-1 treatment. Moreover, N76-1 markedly inhibited the growth of TNBC xenografts and phosphorylation of RNAPII in tumor tissues. In summary, N76-1 exerts potent anticancer effects in TNBC by inhibiting CDK7 and provides a new strategy and research basis for the development of new drugs for TNBC.

VPS34-IN1 induces apoptosis of ER+ breast cancer cells via activating PERK/ATF4/CHOP pathway.

VPS34-IN1 is a specific selective inhibitor of Class III Phosphatidylinositol 3-kinase (PI3K) and has been shown to exhibit a significant antitumor effect in leukemia and liver cancer. In current study, we focused on the anticancer effect and potential mechanism of VPS34-IN1 in estrogen receptor positive (ER+ ) breast cancer. Our results revealed that VPS34-IN1 inhibited the viability of ER+ breast cancer cells in vitro and in vivo. Flow cytometry and western blot analyses showed that VPS34-IN1 treatment induced breast cancer cell apopotosis. Interestingly, VPS34-IN1 treatment activated protein kinase R (PKR)-like ER kinase (PERK) branch of endoplasmic reticulum (ER) stress. Furthermore, knockdown of PERK by siRNA or inhibition of PERK activity by chemical inhibitor GSK2656157 could attenuate VPS34-IN1-mediated apoptosis in ER+ breast cancer cells. Collectively, VPS34-IN1 has an antitumor effect in breast cancer, and it may result from activating PERK/ATF4/CHOP pathway of ER stress to induce cell apoptosis. These findings broaden our understanding of the anti-breast cancer effects and mechanisms of VPS34-IN1 and provide new ideas and reference directions for the treatment of ER+ breast cancer.

Promoting Apoptosis, a Promising Way to Treat Breast Cancer With Natural Products: A Comprehensive Review.

Breast cancer is one of the top-ranked malignant carcinomas associated with morbidity and mortality in women worldwide. Chemotherapy is one of the main approaches to breast cancer treatment. Breast cancer initially responds to traditional first- and second-line drugs (aromatase inhibitor, tamoxifen, and carboplatin), but eventually acquires resistance, and certain patients relapse within 5 years. Chemotherapeutic drugs also have obvious toxic effects. In recent years, natural products have been widely used in breast cancer research because of their low side effects, low toxicity, and good efficacy based on their multitarget therapy. Apoptosis, a programmed cell death, occurs as a normal and controlled process that promotes cell growth and death. Inducing apoptosis is an important strategy to control excessive breast cancer cell proliferation. Accumulating evidence has revealed that natural products become increasingly important in breast cancer treatment by suppressing cell apoptosis. In this study, we reviewed current studies on natural product-induced breast cancer cell apoptosis and summarized the proapoptosis mechanisms including mitochondrial, FasL/Fas, PI3K/AKT, reactive oxygen species, and mitogen-activated protein kinase-mediated pathway. We hope that our review can provide direction in the search for candidate drugs derived from natural products to treat breast cancer by promoting cell apoptosis.

Quasi-phase-matched second harmonic generation of long-range surface plasmon polaritons.

In this paper, we experimentally demonstrate the second harmonic generation of long-range surface plasmon polaritons via quasi-phase matching in lithium niobate. After depositing a 9/13 nm thick Au film on periodically poled lithium niobate, TiO2 of about 2.3 µm in thickness is evaporated on the sample as a refractive-index-matching material. This dielectric (periodically poled lithium niobate)-metal(Au)-dielectric(TiO2) sandwich structure can support the transmission of long-range surface plasmon polaritons through it. By designing a moderate ferroelectric domain period of periodically poled lithium niobate, the phase mismatch between the fundamental wave and second harmonic wave of the long-range surface plasmon polaritons can be compensated and a second harmonic wave can be generated effectively. This can be used to provide integrated plasmonic devices with attractive applications in quantum and classic information processing.

Response surface methodology investigation into optimization of the removal condition and mechanism of Cr(â ¥) by Na2SO3/CaO.

The removal of Cr(Ⅵ) by chemical reduction-precipitation is widely applied in wastewater treatment plants. Nevertheless, the formation of Cr(OH)3 with gel properties has weak settlement performance, making it necessary to add a coagulant aid to reduce the settling time and improve the settling effect. In this investigation, a high concentration of Cr(Ⅵ) was removed using Na2SO3 as a reducing agent and CaO as a coagulant. An improved reduction and precipitation experiment was modeled by applying a three-factor central composite experimental design (CCD). To reveal as many mechanisms as possible for CrT removal, other verification experiments were performed. The CrT removal efficiency decreased, which can be explained by the following three reasons: dissolution of Cr(Ⅲ), competition for adsorption between Ca2+ and Cr(Ⅲ) at different coagulation times, and formation of a solubility complex with Cr(Ⅲ) due to the surplus SO32- in solution. The increasing CrT removal efficiency can be explained by the following two reasons: dissolved Ca2+ from CaO can neutralize CrO2- that is produced by the dissolution of Cr(OH)3 in alkaline solution and can broaden the optimal final pH range of coagulation. Ca2+ could also strengthen the CrT removal through adsorption bridging and co-precipitation with CaO as the core of flocs.

Towards an all-in fiber photodetector by directly bonding few-layer molybdenum disulfide to a fiber facet.

Although photodetectors based on two dimensional (2D) materials have been intensively studied, there are few reports of optical fiber compatible devices. Herein we successfully fabricated an all-in fiber photodetector (FPD) based on an end-face bonded with few-layer molybdenum disulfide (MoS2). Our FPD has a considerably high photo-responsivity of ∼0.6 A W-1 at a bias voltage of 4 V and 0.01 A W-1 under the bias-free conditions. We believe that the proposed platform may provide a new strategy for the integration of 2D materials in fibers and realization of optoelectronic and sensing applications.

MRS algorithm: a new method for searching myocardial region in SPECT myocardial perfusion images.

First, the necessity of automatically segmenting myocardium from myocardial SPECT image is discussed in Section 1. To eliminate the influence of the background, the optimal threshold segmentation method modified for the MRS algorithm is explained in Section 2. Then, the image erosion structure is applied to identify the myocardium region and the liver region. The contour tracing method is introduced to extract the myocardial contour. To locate the centriod of the myocardium, the myocardial centriod searching method is developed. The protocol of the MRS algorithm is summarized in Section 6. The performance of the MRS algorithm is investigated and the conclusion is drawn in Section 7. Finally, the importance of the MRS algorithm and the improvement of the MRS algorithm are discussed.