Investigating the Role of Muscleblind-Like 1 in the Suppression of Breast Cancer Progression

Breast cancer is a prevalent disease. Metastatic disease accounts for the majority of deaths from breast cancer, as patients with distant metastatic disease have a much worse prognosis than those with localized disease. In order to better understand why some breast cancers metastasize and others do not, it is critical to identify and elucidate the determinants of breast cancer progression. Post-transcriptional control of gene expression plays a central role in modulating transcriptional output. The interactions between messenger RNA cis-regulatory elements and trans-factors control coordinated gene expression states. Posttranscriptional regulatory programs that enhance metastatic capacity are selected for during cancer progression. In this study, the RNA binding protein Muscleblind-like 1 (MBNL1) is identified as a novel suppressor of breast cancer metastasis. MBNL1 loss-of-function contributes to the pathogenesis of myotonic dystrophy, a human genetic disease, but has no reported role in tumorigenesis or cancer progression. In this study, MBNL1 is identified as a suppressor of breast cancer metastasis. MBNL1 was found to suppress metastasis of human breast cancer cells in a xenograft mouse model. Additionally, MBNL1 transcript levels are significantly correlated with metastasis-free survival of breast cancer patients. MBNL1 depletion was also found to enhance the invasion and trans-endothelial migration capacity of breast cancer cells. Identification of endogenous MBNL1 protein-RNA interactions in breast cancer cells was carried out using HITS-CLIP. Transcriptome-wide analysis of MBNL1-dependent transcript stability and MBNL1 HITS-CLIP data revealed that globally, transcripts directly bound by MBNL1 are stabilized by MBNL1. Two transcripts, DBNL and TACC1, were identified as transcripts that were bound by MBNL1 and also destabilized upon MBNL1 depletion. Both DBNL and TACC1, when overexpressed in breast cancer cells depleted of MBNL1, were found to reverse the pro-invasive and metastatic colonization phenotypes observed upon MBNL1 depletion. Therefore, DBNL and TACC1 were identified as modulators of the metastasis suppressive effect of MBNL1 in breast cancer

Inference of RNA decay rate from transcriptional profiling highlights the regulatory programs of Alzheimer's disease.

The abundance of mRNA is mainly determined by the rates of RNA transcription and decay. Here, we present a method for unbiased estimation of differential mRNA decay rate from RNA-sequencing data by modeling the kinetics of mRNA metabolism. We show that in all primary human tissues tested, and particularly in the central nervous system, many pathways are regulated at the mRNA stability level. We present a parsimonious regulatory model consisting of two RNA-binding proteins and four microRNAs that modulate the mRNA stability landscape of the brain, which suggests a new link between RBFOX proteins and Alzheimer's disease. We show that downregulation of RBFOX1 leads to destabilization of mRNAs encoding for synaptic transmission proteins, which may contribute to the loss of synaptic function in Alzheimer's disease. RBFOX1 downregulation is more likely to occur in older and female individuals, consistent with the association of Alzheimer's disease with age and gender."mRNA abundance is determined by the rates of transcription and decay. Here, the authors propose a method for estimating the rate of differential mRNA decay from RNA-seq data and model mRNA stability in the brain, suggesting a link between mRNA stability and Alzheimer's disease.

Systematic discovery of structural elements governing stability of mammalian messenger RNAs.

Decoding post-transcriptional regulatory programs in RNA is a critical step towards the larger goal of developing predictive dynamical models of cellular behaviour. Despite recent efforts, the vast landscape of RNA regulatory elements remains largely uncharacterized. A long-standing obstacle is the contribution of local RNA secondary structure to the definition of interaction partners in a variety of regulatory contexts, including--but not limited to--transcript stability, alternative splicing and localization. There are many documented instances where the presence of a structural regulatory element dictates alternative splicing patterns (for example, human cardiac troponin T) or affects other aspects of RNA biology. Thus, a full characterization of post-transcriptional regulatory programs requires capturing information provided by both local secondary structures and the underlying sequence. Here we present a computational framework based on context-free grammars and mutual information that systematically explores the immense space of small structural elements and reveals motifs that are significantly informative of genome-wide measurements of RNA behaviour. By applying this framework to genome-wide human mRNA stability data, we reveal eight highly significant elements with substantial structural information, for the strongest of which we show a major role in global mRNA regulation. Through biochemistry, mass spectrometry and in vivo binding studies, we identified human HNRPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1, also known as HNRNPA2B1) as the key regulator that binds this element and stabilizes a large number of its target genes. We created a global post-transcriptional regulatory map based on the identity of the discovered linear and structural cis-regulatory elements, their regulatory interactions and their target pathways. This approach could also be used to reveal the structural elements that modulate other aspects of RNA behaviour

Primary Cutaneous Melanoma Arising in a Long-Standing Irradiated Keloid

Ionizing radiation has been used therapeutically for a variety of clinical conditions, including treatment of hypertrophic keloids. Keloids may rarely be associated with malignancy, but the use of low-dose ionizing radiation is associated with an increased risk of cutaneous malignancies. We describe a case in which a primary desmoplastic melanoma arose in a long-standing, previously irradiated keloid

Cancer cells exploit an orphan RNA to drive metastatic progression.

Here we performed a systematic search to identify breast-cancer-specific small noncoding RNAs, which we have collectively termed orphan noncoding RNAs (oncRNAs). We subsequently discovered that one of these oncRNAs, which originates from the 3' end of TERC, acts as a regulator of gene expression and is a robust promoter of breast cancer metastasis. This oncRNA, which we have named T3p, exerts its prometastatic effects by acting as an inhibitor of RISC complex activity and increasing the expression of the prometastatic genes NUPR1 and PANX2. Furthermore, we have shown that oncRNAs are present in cancer-cell-derived extracellular vesicles, raising the possibility that these circulating oncRNAs may also have a role in non-cell autonomous disease pathogenesis. Additionally, these circulating oncRNAs present a novel avenue for cancer fingerprinting using liquid biopsies

Exile Vol. XXVI No. 1

Photo: Untitled by Jamie Bailey 3 Poem: Hi, My Name Is by Kathy Andrews 4 Poem: Untitled by Willi Haworth 5 Photo: Stratified Snow by Jim Lundy 6 Poem: Untitled by A. Pence 7 Poem: Akua\u27ba by Tona Dickerson 8 Photo: Untitled by Jim Lundy 9 Story: The Dogcatchers of Portimao by Debora Papierski 10-13 Photo: Untitled by Holly Hall 14 Poem: Tocopold Bloom: A Working Class Hero by Mary Ladky 15 Photo: Untitled by Cory Easter 16 Poem: A Mortal Wound by Peter Fish 17 Poem: Let Me Sleep by R. G. Trub 18-19 Photo: Modified Cube by Jim Lundy 20 Story: Untitled by Kathy Desmond 21-23 Photo: Untitled by Holly Hall 24 Poem: Untitled by Sharon McCartney 25 Photo: Untitled by Him Lundy 26 Poem: Every Morning I Wake by Peter Fish 27 Photo: Untitled by Rof Smith 28 Poem: For Mark Some Words by Bonny Lowe 29 Photo: Untitled by Jim Lundy 30 Poem: A Flash of Crooked Light by Lisa Minacci 31 Photo: Untitled by Jim Lundy 32 Poem: Paper Hearts by W. Dulles 33 Drawing: Untitled by Roger Weisman 34 Story: Untitled by Dane Lavin 35-42 Photo: Untitled by Jim Lundy 43 Special Thanks To Laurie Howard -

Randomized trial of DVD, telephone, and usual care for increasing mammography adherence

The purpose of this study was to test an intervention to increase mammography screening in women 51-75 years of age who had not received a mammogram in the last 15 months. A total of 1681 women were randomized to (1) a mailed tailored interactive DVD, (2) a computer-tailored telephone counseling, or (3) usual care. Women with income below US$75,000 who were in the interactive DVD group had significantly more mammograms than women in usual care. Women with income above US$75,000 had significantly fewer mammograms than women with income less than US$75,000 regardless of group. Further investigation is needed to understand why women with income above US$75,000 did not show the same benefit of the intervention

Report of the 2020-2021 Professional Affairs Standing Committee: Pharmacists Unique Role and Integration in Healthcare Settings

EXECUTIVE SUMMARY The 2020-21 Professional Affairs Committee was charged to (1) Read all six reports from the 2019-20 AACP standing committees to identify elements of these reports that are relevant to the committee’s work this year; (2) Identify opportunities and models of integration of pharmacist care services in physician and other health provider practices beyond primary care; (3) Differentiate and make the case for the integration of pharmacist care services from that of other mid-level providers; and (4) From the work on the aforementioned charges, identify salient activities for the Center To Accelerate Pharmacy Practice Transformation and Academic Innovation (CTAP) for consideration by the AACP Strategic Planning Committee and AACP staff. This report provides information on the committee’s process to address the committee charges, describes the rationale for and the results from a call to colleges and schools of pharmacy to provide information on their integrating pharmacist care services in physician and other health provider practices beyond primary care practice, and discusses how pharmacist-provided patient care services differ from those provided by other healthcare providers. The committee offers a revision to a current association policy statement, a proposed policy statement as well as recommendations to CTAP and AACP and suggestions to colleges and schools of pharmacy pertaining to the committee charges