The role of IFITM1 in promoting breast cancer aggression and aromatase-inhibitor resistance

Breast cancer remains the leading malignancy among women in the United States, affecting an estimated 246,660 women in 2016. Breast cancer can be separated into three groups known as estrogen receptor/ progesterone receptor positive (ER+/PR+), Her2/neu positive (HER2+), and triple negative (ER-/PR-/HER2-) subtypes. The majority of breast cancers rely on estrogen to stimulate their growth and survival. Estrogen is produced from precursor hormones by the aromatase enzyme, whose action can be blocked with aromatase inhibitors (AIs). Unfortunately ~40% of breast cancer patients are resistant to this treatment and their breast tumors either continue to grow or recur despite depletion of circulating estrogen. The precise cause of AI-resistance is not known. Our lab aims to determine the mechanisms that allow breast cancer cells to survive in estrogen-depleted conditions. We have previously reported the generation of an AI-resistant breast cancer cell line, MCF-7:5C, which was isolated under estrogen-free conditions from the estrogen-dependent breast cancer cell line MCF-7. The MCF-7:5C cell line is highly aggressive and overexpresses several interferon stimulated genes including, interferon inducible transmembrane protein 1 (IFITM1). IFITM1 is a type 1 interferon (IFN) stimulated gene (ISG) that is not expressed in normal breast tissue, and is only induced by the type1 IFNs (IFNα and β) to protect the host from viral infections. IFNα signals through a specific receptor, IFNAR, which uses JAK/STAT signaling to produce the ISGs. ISGs are known to drive the progression of other cancer types, to inhibit apoptosis and promote DNA damage resistance. However, the significance of constitutive overexpression of ISGs in AI-resistant breast cancer is not known. We hypothesize that IFITM1 overexpression contributes the AI-resistant phenotype and promotes breast cancer cell aggression and survival. In this thesis, we demonstrate that IFITM1 is overexpressed in breast tumors and is correlated with poor response to endocrine therapy using in silico analysis of breast tumor expression databases and a human tissue microarray. Gain and loss of function studies in an IFITM1-overexpressing AI-resistant breast cancer cell line, MCF-7:5C, and an IFITM1-null AI-sensitive breast cancer cell line, MCF-7, reveal that IFITM1 promotes the AI-resistant aggressive phenotype and estrogen-independent growth. Additionally, the orthotopic (mammary fat pad) and mouse mammary intraductal (MIND) models of breast cancer evaluate the role of IFITM1 in tumor growth and invasion respectively. We report that loss of IFITM1 induced cell death in AI-resistant MCF-7:5C cells results in marked increases in p21/Waf1/Cip1 transcription, expression and nuclear localization. Notably, p21 transcriptional upregulation was mediated by STAT1 activation. These findings suggest IFITM1 overexpression contributes directly to breast cancer progression and that it may be a therapeutically relevant target in the treatment of endocrine-resistant breast cancer. Mechanistic studies reveal that MCF-7:5C cells produce elevated levels of IFN as compared to MCF-7 cells and that this cytokine binds to the type 1 IFN receptor, IFNAR, and induces JAK/STAT signaling, ultimately resulting in the overexpression of IFITM1. Independently, we also find that mucin 1 (MUC1) associates with STAT1 and stabilizes its phosphorylated form, thereby contributing directly to IFITM1 expression. MUC1 expression is hormonally controlled and is normally enhanced by estrogen stimulation. We find that MUC1 expression is dysregulated in AI-resistant MCF-7:5C cells and is instead reduced by estrogen stimulation. MCF-7:5C cells are sensitive to apoptosis following exposure to estrogen, which can be enhanced by loss of IFITM1 expression. Loss of MUC1 expression similarly enhances estrogen-induced apoptosis, suggesting that the communication between MUC1 and STAT1 also influences estrogen signaling in AI-resistant breast cancer. In this thesis, we conduct investigations into the mechanisms and functional significance of IFITM1 expression in AI-resistant breast cancer and conclude that IFITM1 overexpression may be a targetable marker of AI-resistant disease

PENINGKATAN AKTIVITAS PESERTA DIDIK DALAM PEMBELAJARAN ILMU PENGETAHUAN ALAM MENGGUNAKAN METODE DEMONSTRASI DI SD

Abstrak:Tujuan penelitian ini adalah untuk mendeskripsikan peningkatan aktivitas peserta didik dalam pembelajaran Ilmu Pengetahuan Alam dengan menggunakan metode demonstrasi di kelas IV Sekolah Dasar Negeri 24 Sidas. Metode yang digunakan dalam penelitian ini adalah metode deskriptif, sedangkan bentuk penelitiannya adalah Penelitian Tindakan Kelas (PTK). Subjek dalam penelitian ini adalah guru dan peserta didik kelas IV Sekolah Dasar Negeri 24 Sidas yang berjumlah 16 orang, dengan setting penelitian yaitu setting dalam kelas. Teknik pengumpal data yang digunakan teknik observasi langsung. Sedangkan alat pengumpul datanya adalah lembar observasi. Hasil yang dicapai dalam penelitian ini adalah (1) Perencanaan pembelajaran telah disusun dengan baik sesuai dengan pedoman penyusunan RPP. ( 2 ) Proses pelaksanaan pembelajaran Ilmu Pengetahuan Alam menggunakan metode demonstrasi juga telah dilakasanakan sesuai dengan langkah-langkah metode demonstrasi 3) Aktivitas Fisik peserta didik dalam proses pembelajaran meningkat dari 46,87% di siklus 1 menjadi 84,37% di siklus 2, terjadi peningkatan sebesar 37,5% dengan kategori baik. ( 4 ) Aktifitas Mental meningkat dari  53,13% di siklus 1 menjadi 84,37% di siklus 2, terjadi peningkatan sebesar 31,24% dengan kategori baik. ( 5 ) Aktifitas Emosional meningkat dari 56,25% di siklus 1 menjadi 90,63% di siklus 2 terjadi peningkatan sebesar 36,38% dengan kategori baik.   Kata Kunci : aktivitas, Ilmu Pengetahuan Alam, demonstrasi Abstarct: The purpose of this study was to describe the increase in the activity of learners in the learning of Natural Sciences using demonstration in Public Elementary School fourth grade 24 Sidas. The method used in this research is descriptive method, while the form of research is the Classroom Action Research (CAR). Subjects in this study were teachers and students of State Elementary School fourth grade 24 Sidas totaling 16 people, with a research setting that is in a class setting. Techniques pengumpal data used direct observation techniques. While the data collection tool is the observation sheet. The results achieved in this study were (1) Planning of learning have been prepared properly in accordance with the guidelines for the preparation of lesson plans. (2) The process of implementation of the Natural Sciences learning methods also have dilakasanakan demonstration in accordance with the steps demonstration method 3) Physical Activity learners in the learning process increased from 46.87% in cycle 1 to 84.37% in cycle 2, occurs an increase of 37.5% in both categories. (4) Mental activity increased from 53.13% in cycle 1 to 84.37% in cycle 2, an increase of 31.24% in both categories. (5) Emotional activity increased from 56.25% in cycle 1 to 90.63% in cycle 2 an increase of 36.38% in both categories. Keywords: activity, Natural Sciences, demonstratio

A rare case of group A streptococcal toxic‐shock syndrome in a postpartum adolescent leading to multi‐organ failure

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Teenage pregnancy is not uncommon, but given the age of the patient, experience, and competency among medical providers varies. While toxic‐shock syndrome from group A streptococcus is rare in teenage pregnancy, observed is a gap in care of bridging.The University of Kansas (KU) One University Open Access Author Fund sponsored jointly by the KU ProvostKU Vice Chancellor for Research & Graduate StudiesKUMC Vice Chancellor for Research and managed jointly by the Libraries at the Medical Center and KU – Lawrenc

Hydrodynamic Limit of the Boltzmann Equation with Contact Discontinuities

The hydrodynamic limit for the Boltzmann equation is studied in the case when the limit system, that is, the system of Euler equations contains contact discontinuities. When suitable initial data is chosen to avoid the initial layer, we prove that there exists a unique solution to the Boltzmann equation globally in time for any given Knudsen number. And this family of solutions converge to the local Maxwellian defined by the contact discontinuity of the Euler equations uniformly away from the discontinuity as the Knudsen number $\varepsilon$ tends to zero. The proof is obtained by an appropriately chosen scaling and the energy method through the micro-macro decomposition.Comment: 34 pages. submitte

The Evolving Landscape of B Cells in Cancer Metastasis.

Metastasis is the leading cause of cancer mortality. Functional and clinical studies have documented diverse B-cell and antibody responses in cancer metastasis. The presence of B cells in tumor microenvironments and metastatic sites has been associated with diverse effects that can promote or inhibit metastasis. Specifically, B cells can contribute to the spread of cancer cells by enhancing tumor cell motility, invasion, angiogenesis, lymphangiogenesis, and extracellular matrix remodeling. Moreover, they can promote metastatic colonization by triggering pathogenic immunoglobulin responses and recruiting immune suppressive cells. Contrastingly, B cells can also exhibit antimetastatic effects. For example, they aid in enhanced antigen presentation, which helps activate immune responses against cancer cells. In addition, B cells play a crucial role in preventing the dissemination of metastatic cells from the primary tumor and secrete antibodies that can aid in tumor recognition. Here, we review the complex roles of B cells in metastasis, delineating the heterogeneity of B-cell activity and subtypes by metastatic site, antibody class, antigen (if known), and molecular phenotype. These important attributes of B cells emphasize the need for a deeper understanding and characterization of B-cell phenotypes to define their effects in metastasis

HER2 and HER3 as Therapeutic Targets in Head and Neck Cancer.

Work over the past several decades has identified that aberrations in the ErbB signaling pathways are key drivers of oncogenesis, and concurrent efforts to discover targetable vulnerabilities to counter this aberrant oncogenic signaling offer tremendous promise in treating a host of human cancers. These efforts have been centered primarily on EGFR (also known as HER1), leading to the discovery of the first targeted therapies approved for head and neck cancer. More recently, HER2 and HER3 signaling pathways have been identified as highly dysregulated in head and neck cancer. This review highlights the HER2 and HER3 signaling pathways and clinical efforts to target these receptors and their aberrant signaling to treat head and neck squamous cell carcinomas and other head and neck malignancies, including salivary gland carcinomas. This includes the use of small molecule inhibitors and blocking antibodies, both as single agents or as part of multimodal precision targeted and immunotherapies

Utilization of mediation in the resolution of conflict within the framework of art schools in Prague in the school year 2012/2013

STAT1 and STAT2 knockdown in SUM149 using three different siRNAs. (PPT 185 kb

Additional file 2: Figure S2. of Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells

Everolimus targets the phosphorylation of the PI3K/mTOR/Akt pathway at 48 and 72 h. MCF-7, MCF-7:5C and MCF-7:2A cells were seeded in 6-well plates and treated with 25, 50 or 100 nM everolimus or vehicle. Cells were harvested at 48 and 72 h and protein expression analyzed by western blot. Image represents three independent experiments. (PPT 674 kb

Additional file 1: Figure S1. of Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells

Everolimus does not impact the proliferation or cycling of normal breast cells. (a) MCF10A cells were seeded in 24-well plates and treated with a range of everolimus doses in triplicate. The percentage of viable cells was determined after 72 h of everolimus treatment. (b) MCF10A cells were seeded in 6-well plates in single cell suspension and treated with 20 nM everolimus for 9 days. The number and size of clones was quantified and represents means from two independent experiments conducted in triplicate. (c) After 24, 48 and 72 h of 20 nM everolimus treatment in 6-well plates, MCF10A cells were subjected to cell cycle analysis. The percent of cells in G1 phase is highlighted. (PPT 507 kb