Longevity and Anti-senescence Therapy Market Projected to Experience Major Revenue Boost During the Forecast Period Between 2020-2026 | Covid-19…

ReportsnReports recently added a detailed overview and industry professional survey report on the global Longevity and Anti-senescence Therapy Market. In this report, titled Longevity and Anti-senescence Therapy Market Size, Share and Industry Analysis by Technologies, By Product, By Application, By Distribution Channel, and Regional Forecast 2019-2026.

Download a Sample Copy of Report athttps://www.reportsnreports.com/contacts/requestsample.aspx?name=2255402

The scope of the report encompasses the major types of Longevity and Anti-senescence Therapy Market that have been used, as well as the major applications being developed by industry, academic researchers and their commercialization offices, and government agencies. It analyzes the current market status, examines future market drivers, and presents forecasts of growth over the next five years. Technology developments, including the latest trends, are discussed. Other influential factors such as screening strategies for pharmaceuticals have also been included.

The global Longevity and Anti-senescence Therapy Market is comprehensively profiled in the report, including a detailed study of the markets key drivers and restraints, major market players, and leading segments.

Report Scope:

The scope of this report is broad and covers various therapies currently under trials in the global longevity and anti-senescence therapy market. The market estimation has been performed with consideration for revenue generation in the forecast years 2018-2023 after the expected availability of products in the market by 2023. The global longevity and anti-senescence therapy market has been segmented by the following therapies: Senolytic drug therapy, Gene therapy, Immunotherapy and Other therapies which includes stem cell-based therapies, etc.

Revenue forecasts from 2028 to 2023 are given for each therapy and application, with estimated values derived from the expected revenue generation in the first year of launch.

The report also includes a discussion of the major players performing research or the potential players across each regional longevity and anti-senescence therapy market. Further, it explains the major drivers and regional dynamics of the global longevity and anti-senescence therapy market and current trends within the industry.

The report concludes with a special focus on the vendor landscape and includes detailed profiles of the major vendors and potential entrants in the global longevity and anti-senescence therapy market.

Any Query or Discount? Ask our Expert athttps://www.reportsnreports.com/contacts/discount.aspx?name=2255402

Report Includes:

71 data tables and 40 additional tables An overview of the global longevity and anti-senescence therapy market Analyses of global market trends, with data from 2017 and 2018, and projections of compound annual growth rates (CAGRs) through 2023 Country specific data and analysis for the United States, Canada, Japan, China, India, U.K., France, Germany, Spain, Australia, Middle East and Africa Detailed description of various anti-senescence therapies, such as senolytic drug therapy, gene therapy, immunotherapy and other stem cell therapies, and their influence in slowing down aging or reverse aging process Coverage of various therapeutic drugs, devices and technologies and information on compounds used for the development of anti-ageing therapeutics A look at the clinical trials and expected launch of anti-senescence products Detailed profiles of the market leading companies and potential entrants in the global longevity and anti-senescence therapy market, including AgeX Therapeutics, CohBar Inc., PowerVision Inc., T.A. Sciences and Unity Biotechnology

Summary:

Global longevity and anti-senescence therapy market deals in the adoption of different therapies and treatment options used to extend human longevity and lifespan. ?Human longevity is typically used to describe the length of an individuals lifetime and is sometimes used as a synonym for ?life expectancy in the demography. ?Anti-senescence is the process by which cells stop dividing irreversibly and enter a stage of permanent growth arrest, eliminating cell death. Anti-senescence therapy is used in the treatment of senescence induced through unrepaired DNA damage or other cellular stresses.

Global longevity and anti-senescence market will witness rapid growth over the forecast period (2018-2023) owing to an increasing emphasis on Stem Cell Research and an increasing demand for cell-based assays in research and development.

An increasing geriatric population across the globe and a rising awareness of antiaging products among generation Y and later generations are the major factors expected to promote the growth of global longevity and anti-senescence market. Factors such as a surging level of disposable income and increasing advancements in anti-senescence technologies are also providing traction to the global longevity and anti-senescence market growth over the forecast period (2018-2023).

Click Here & Get a Single User OR Corporate User License Key for This Report athttps://www.reportsnreports.com/purchase.aspx?name=2255402

According to the National Institutes of Health (NIH), the total geriatric population across the globe in 2016 was over REDACTED. By 2022, the global geriatric population (65 years and above) is anticipated to reach over REDACTED. An increasing geriatric population across the globe will generate huge growth prospectus to the market.

Senolytics, placenta stem cells and blood transfusions are some of the hot technologies picking up pace in the longevity and anti-anti-senescence market. Companies and start-ups across the globe such as Unity Biotechnology, Human Longevity Inc., Calico Life Sciences, Acorda Therapeutics, etc. are working extensively in this field for the extension of human longevity by focusing on study of genomics, microbiome, bioinformatics and stem cell therapies, etc. These factors are poised to drive market growth over the forecast period.

Global longevity and anti-senescence market is projected to rise at a CAGR of REDACTED during the forecast period of 2018 through 2023. In 2023, total revenues are expected to reach REDACTED, registering REDACTED in growth from REDACTED in 2018.

The report provides analysis based on each market segment including therapies and application. The therapies segment is further sub-segmented into Senolytic drug therapy, Gene therapy, Immunotherapy and Others. Senolytic drug therapy held the largest market revenue share of REDACTED in 2017. By 2023, total revenue from senolytic drug therapy is expected to reach REDACTED. Gene therapy segment is estimated to rise at the highest CAGR of REDACTED till 2023. The fastest growth of the gene therapy segment is due to the Large investments in genomics. For Instance; The National Human Genome Research Institute (U.S.) had a budget grant of REDACTED for REDACTED research projects in 2015, thus increasing funding to REDACTED for approximately REDACTED projects in 2016.

The latest Longevity and Anti-senescence Therapy Market report provides readers with a deeper understanding of potential target consumers to create a lucrative marketing strategy for the 2019-2026 forecast period. For entrepreneurs seeking information about potential customers, it will be particularly helpful. Selective statements provided by leading vendors would allow entrepreneurs to gain a deeper understanding of the local market and prospective customers.

Table of Contents:

Chapter 1 Introduction

Study Background

Study Goals and Objectives

Reasons for Doing This Study

Scope of Report

Methodology and Information Sources

Geographic Breakdown

Market Breakdown

Analysts Credentials

.Continued

About Us: ReportsnReports.com is your single source for all market research needs. Our database includes 500,000+ market research reports from over 95 leading global publishers & in-depth market research studies of over 5000 micro markets.We provide 24/7 online and offline support to our customers.

E-mail: [emailprotected]

Phone: +1 888 391 5441

See the original post here:
Longevity and Anti-senescence Therapy Market Projected to Experience Major Revenue Boost During the Forecast Period Between 2020-2026 | Covid-19...

Stem Cell Assay Market Growth by Top Companies, Trends by Types and Application, Forecast to 2026 – Bandera County Courier

Verified Market Research recently published a research report titled, Stem Cell Assay Market Study Report 2020. The research report is created based on historical and forecast data derived from researchers using primary and secondary methods. The Stem Cell Assay market is one of the fastest-growing markets and is expected to witness substantial growth in the forecast years. Reader are provided easy access to thorough analysis on the various aspects such as opportunities and restraints affecting the market. The report clearly explains the trajectory this market will take in the forecast years.

Global Stem Cell Assay market was valued at USD 536.53million in 2016 and is projected to reach USD 2858.95millionby 2025, growing at a CAGR of 20.43% from 2017 to 2025.

Get | Download Sample Copy @ https://www.verifiedmarketresearch.com/download-sample/?rid=24266&utm_source=BCC&utm_medium=002

Stem Cell Assay Market Leading Players:

Stem Cell Assay Market: Competitive Landscape

This section of the report provides complete information about the various manufacturers in the market. The major manufacturers to which the report refers hold a large proportion that require a microscopic appearance. It provides important information about the different strategies of these manufacturers to combat competition and to expand their presence in the market. In addition, the current trends of the manufacturers are checked in order to innovate their product for the future. This report is intended to help the reader understand the market and make business decisions accordingly.

Ask for Discount @ https://www.verifiedmarketresearch.com/ask-for-discount/?rid=24266&utm_source=BCC&utm_medium=002

Table of Contents :

Executive Summary: It includes key trends of the Stem Cell Assay market related to products, applications, and other crucial factors. It also provides analysis of the competitive landscape and CAGR and market size of the Stem Cell Assay market based on production and revenue.

Production and Consumption by Region: It covers all regional markets to which the research study relates. Prices and key players in addition to production and consumption in each regional market are discussed.

Key Players: Here, the report throws light on financial ratios, pricing structure, production cost, gross profit, sales volume, revenue, and gross margin of leading and prominent companies competing in the Stem Cell Assay market.

Market Segments: This part of the report discusses about product type and application segments of the Stem Cell Assay market based on market share, CAGR, market size, and various other factors.

Research Methodology: This section discusses about the research methodology and approach used to prepare the report. It covers data triangulation, market breakdown, market size estimation, and research design and/or programs.

Why to Buy this Report?

The report is a perfect example of a detailed and meticulously prepared research study on the Stem Cell Assay market. It can be customized as per the requirements of the client. It not only caters to market players but also stakeholders and key decision makers looking for extensive research and analysis on the Stem Cell Assay market.

Complete Report is Available @ https://www.verifiedmarketresearch.com/product/Stem-Cell-Assay-Market/?utm_source=BCC&utm_medium=002

About us:

Verified market research partners with the customer and offer an insight into strategic and growth analyzes; Data necessary to achieve corporate goals and objectives. Our core values are trust, integrity and authenticity for our customers.

Analysts with a high level of expertise in data collection and governance use industrial techniques to collect and analyze data in all phases. Our analysts are trained to combine modern data collection techniques, superior research methodology, expertise and years of collective experience to produce informative and accurate research reports.

Contact us:

Mr. Edwyne FernandesCall: +1 (650) 781 4080Email: sales@verifiedmarketresearch.com

Tags: Stem Cell Assay Market Size, Stem Cell Assay Market Trends, Stem Cell Assay Market Forecast, Stem Cell Assay Market Growth, Stem Cell Assay Market Analysis

Follow this link:
Stem Cell Assay Market Growth by Top Companies, Trends by Types and Application, Forecast to 2026 - Bandera County Courier

A Method for Assessing the Role of Long Non-protein Coding RNAs – Technology Networks

The discovery of a huge number of long non-protein coding RNAs, aka lncRNAs, inthe mammalian genome was a major surprise of the recent large-scale genomics projects. Aninternational team including a bioinformatician from the Research Center of Biotechnology of the Russian Academy of Sciences, and the Moscow Institute of Physics and Technology has developed areliablemethodfor assessing therole of such RNAs. Thenew technique and the data obtained with it allow generating important hypotheses on how chromatin is composed and regulated, aswell as identifying the specific functions of lncRNAs.

Presented inNature Communications, the technology is called RADICL-seq and enables comprehensive mapping of each RNA, captured while interacting with all thegenomic regions that it targets, where many RNAs are likely to be important forgenome regulation and structure maintenance.RNA and gene regulationIt was previously believed that RNA functions mostly as an intermediary in building proteins based on a DNA template, with very rare exceptions such as ribosomal RNAs. However, with the development of genomic analysis, it turned out that not all DNA regions encode RNA, and not all transcribed RNA encodes proteins.

Although the number of noncoding RNAs and those that encode proteins is about the same, the function of most noncoding RNA is still not entirely clear.

Every type of cell has its own set of active genes, resulting in the production ofspecific proteins. This makes a brain cell different from a blood cell of the same organism despite both sharing the same DNA. Scientists are now coming to theconclusion that RNA is one of the factors that determine which genes are expressed, or active.

Long noncoding RNAs are known to interact with chromatin DNA tightly packaged with proteins. Chromatin has the ability to change its conformation, or shape, so that certain genes are either exposed for transcription or concealed. Long noncoding RNAs contribute to this conformation change and the resulting change in gene activity by interacting with certain chromatin regions. To understand the regulatory potential of RNA in addition to it being a template for protein synthesis it is important to know which chromatin region any given RNA interacts with.

How it works

RNAs interact with chromatin inside the cell nucleus by binding tochromatin-associated proteins that fold a DNA molecule. There are several technologies that can map such RNA-chromatin interactions. However, all of them have significant limitations. They tend to miss interactions, or require a lot of input material, or disrupt the nuclear structure.

Toaddress these shortcomings, a RIKEN-led team has presented a new method: RNA and DNA Interacting Complexes Ligated and Sequenced, or RADICL-seq for short. The technique produces more accurate results and keeps the cells intact upuntil theRNA-chromatin contacts are ligated.

The main idea of the RADICL-seq method is the following. First, the RNA is crosslinked to proteins located close to it in the nucleus of cells with formaldehyde. Then, DNA is cut into pieces by digesting it with a special protein. After that, thetechnology employs RNaseH treatment to reduce ribosomal RNA content, thus increasing the accuracy of the result. Then, by using a bridge adapter (amolecule with single-stranded and double-stranded ends) the proximal DNA and RNA are ligated. After the reversal of crosslinks, the RNA-adapter-DNA chimera is converted to double-stranded DNA for sequencing, revealing the sequence of the ligated RNA and DNA.

Decoding the noncoding

Incomparison with other existing methods, RADICL-seq mapped RNA-chromatin interactions with a higher accuracy. Moreover, the superior resolution ofthetechnology allowed the team to detect chromatin interactions not only with thenoncoding but also with the coding RNAs, including those found far from their transcription locus. The research confirmed that long noncoding RNAs play animportant role in the regulation of gene expression occurring at a considerable distance from the regulated gene.

This technology can also be used to study cell type-specific RNA-chromatin interactions. The scientists proved it by looking at two noncoding RNAs in a mouse cell, one of them possibly associated with schizophrenia. They found that aninteraction pattern between chromatin and those RNAs in two different cells theembryonic stem cell and the oligodendrocyte progenitor cell correlated with preferential gene expression in those cell types.

The new methods flexibility means scientists can gather additional biological information by modifying the experiment. In particular, this technology can make it possible to identify direct RNA-DNA interactions not mediated by chromatin proteins. The analysis performed by bioinformaticians from the Research Center ofBiotechnology and MIPT showed that not only the standard double helix interactions between DNA and RNA but also those involving RNA-DNA triplexes could participate in gene regulation. Also, such interactions highlight the significance of noncoding RNA in protein targeting to particular gene loci.

We are planning to conduct further research on the role of RNA in the regulation ofgene expression, chromatin remodeling, and ultimately, cell identity. Hopefully, we will be able to regulate genes by using these noncoding RNAs in the near future. This can be especially helpful for treating diseases, saysYulia Medvedeva, who leads the Regulatory Transcriptomics and Epigenomics group at the Research Center of Biotechnology, RAS, and heads the Lab of Bioinformatics for Cell Technologies at MIPT. She also manages the grant project supported by the Russian Science Foundation, which co-funded the study.

Reference:Bonetti, A., Agostini, F., Suzuki, A.M. et al. RADICL-seq identifies general and cell typespecific principles of genome-wide RNA-chromatin interactions. Nat Commun 11, 1018 (2020). https://doi.org/10.1038/s41467-020-14337-6.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

Here is the original post:
A Method for Assessing the Role of Long Non-protein Coding RNAs - Technology Networks

Adult Stem Cells Market with Coronavirus (Covid-19) Impact Analysis | Industry Strong Development By Major Eminent Players, New Innovations, Key…

Adult Stem Cells Market 2020 this report is including with the COVID19 Outbreak Impact analysis of key points influencing the growth of the market. Also, report providing market data derived from primary as well as secondary research techniques. The report aims to deliver premium insights, quality data figures and information in relevance with aspects such as market scope, size, share, segments including types of products and services, application, geographies as well. It presents the 360-degree overview of the competitive landscape of the industries. SWOT analysis has been used to understand the strength, weaknesses, opportunities, and threats in front of the businesses. Thus, helping the companies to understand the threats and challenges in front of the businesses. Adult Stem Cells market is showing steady growth and CAGR is expected to improve during the forecast period.

This Adult Stem Cells Market Report That Is Imagines That the Length of This Market Will Develop during The Time System While the Compound Annual Growth Rate (CAGR) Development. The Adult Stem Cells Business Report Point Would Be the Economic Situations and Relating Orders and Takes the Market Players in Driving Fields Over the World.

The Major Players in the Adult Stem Cells Market.GlobalstemJuventas Therapeutics Inc.Epistem Ltd.Hybrid Organ GmbhCellerix SaMesoblast Ltd.Intellicell Biosciences Inc.NeuralstemCelyadCapricor Inc.ClontechCellerant Therapeutics Inc.Cellular Dynamics InternationalBiotime Inc.Beike Biotechnology Co. Ltd.Brainstorm Cell Therapeutics Inc.NeurogenerationInternational Stem Cell Corp.Gamida Cell Ltd.Caladrius Biosciences Inc.Cytori Therapeutics Inc.

Key Businesses Segmentation of Adult Stem Cells Market

Most important types of Adult Stem Cells products covered in this report are:Epithelial stem cellsHematopoietic stem cells

Most widely used downstream fields of Adult Stem Cells market covered in this report are:Neurodegenerative diseasesHeart diseaseBone diseaseOthers

Which prime data figures are included in the Adult Stem Cells market report?

What are the crucial aspects incorporated in the Adult Stem Cells market report?

Who all can be benefitted out of this Adult Stem Cells market report?

Research Goals:

The Report on Global Adult Stem Cells Market Studies the Strategy Pattern Adopted by Prominent International Players. Additionally, The Report Also Evaluates the Market Size in Terms of Revenue (USD MN) For the Forecast Period. All Data and Figures Involving Percentage Shares Splits, And Breakdowns Are Determined Using Secondary Sources and Verified Through Primary Sources.

Purchase FULL Report Now! https://www.qurateresearch.com/report/buy/HnM/global-adult-stem-cells-industry/QBI-MR-HnM-517105

A free report data (as a form of Excel Datasheet) will also be provided upon request along with a new purchase.

Contact Us:Web: http://www.qurateresearch.comE-mail: [emailprotected]Ph: US +13393375221, IN +919881074592

Go here to read the rest:
Adult Stem Cells Market with Coronavirus (Covid-19) Impact Analysis | Industry Strong Development By Major Eminent Players, New Innovations, Key...

Stem Cell and Regenerative Therapy Market Covid-19 Impact Analysis, Size, Share & Trends Analysis Report by Component, By Enterprise Size, By End…

ReportsnReports recently added a detailed overview and industry professional survey report on the global Stem Cell and Regenerative Therapy Market. In this report, titled Stem Cell and Regenerative Therapy Market Size, Share and Industry Analysis by Technologies, By Product, By Application, By Distribution Channel, and Regional Forecast 2019-2026.

Download a Sample Copy of Report athttps://www.reportsnreports.com/contacts/requestsample.aspx?name=2351731

The scope of the report encompasses the major types of Stem Cell and Regenerative Therapy Market that have been used, as well as the major applications being developed by industry, academic researchers and their commercialization offices, and government agencies. It analyzes the current market status, examines future market drivers, and presents forecasts of growth over the next five years. Technology developments, including the latest trends, are discussed. Other influential factors such as screening strategies for pharmaceuticals have also been included.

The global Stem Cell and Regenerative Therapy Market is comprehensively profiled in the report, including a detailed study of the markets key drivers and restraints, major market players, and leading segments.

Report Scope:

The scope of this report is broad and covers various type of product available in the stem cell and regenerative medicines market and potential application sectors across various industries. The current report offers a detailed analysis of the stem cell and regenerative medicines market.

The report highlights the current and future market potential of stem cell and regenerative medicines and provides a detailed analysis of the competitive environment, recent development, merger and acquisition, drivers, restraints, and technology background in the market. The report also covers market projections through 2024.

The report details market shares of stem cell and regenerative medicines based on products, application, and geography. Based on product the market is segmented into therapeutic products, cell banking, tools and reagents. The therapeutics products segments include cell therapy, tissue engineering and gene therapy. By application, the market is segmented into oncology, cardiovascular disorders, dermatology, orthopedic applications, central nervous system disorders, diabetes, others

The market is segmented by geography into the following regions: North America, Europe, Asia-Pacific, South America, and the Middle East and Africa. The report presents detailed analyses of major countries such as the U.S., Canada, Mexico, Germany, the U.K. France, Japan, China and India. For market estimates, data is provided for 2018 as the base year, with forecasts for 2019 through 2024. Estimated values are based on product manufacturers total revenues. Projected and forecasted revenue values are in constant U.S. dollars, unadjusted for inflation.

Report Includes:

28 data tables An overview of global markets for stem cell and regenerative medicines Analyses of global market trends, with data from 2018, estimates for 2019, and projections of compound annual growth rates (CAGRs) through 2024 Details of historic background and description of embryonic and adult stem cells Information on stem cell banking and stem cell research A look at the growing research & development activities in regenerative medicine Coverage of ethical issues in stem cell research & regulatory constraints on biopharmaceuticals Comprehensive company profiles of key players in the market, including Aldagen Inc., Caladrius Biosciences Inc., Daiichi Sankyo Co. Ltd., Gamida Cell Ltd. and Novartis AG

Any Query or Discount? Ask our Expert athttps://www.reportsnreports.com/contacts/discount.aspx?name=2351731

Summary:

The global market for stem cell and regenerative medicines was valued at REDACTED billion in 2018. The market is expected to grow at a compound annual growth rate (CAGR) of REDACTED to reach approximately REDACTED billion by 2024. Growth of the global market is attributed to the factors such as growingprevalence of cancer, technological advancement in product, growing adoption of novel therapeuticssuch as cell therapy, gene therapy in treatment of chronic diseases and increasing investment fromprivate players in cell-based therapies.

In the global market, North America held the highest market share in 2018. The Asia-Pacific region is anticipated to grow at the highest CAGR during the forecast period. The growing government funding for regenerative medicines in research institutes along with the growing number of clinical trials based on cell-based therapy and investment in R&D activities is expected to supplement the growth of the stem cell and regenerative market in Asia-Pacific region during the forecast period.

Reasons for Doing This Study

Global stem cell and regenerative medicines market comprises of various products for novel therapeutics that are adopted across various applications. New advancement and product launches have influenced the stem cell and regenerative medicines market and it is expected to grow in the near future. The biopharmaceutical companies are investing significantly in cell-based therapeutics. The government organizations are funding research and development activities related to stem cell research. These factors are impacting the stem cell and regenerative medicines market positively and augmenting the demand of stem cell and regenerative therapy among different application segments. The market is impacted through adoption of stem cell therapy. The key players in the market are investing in development of innovative products. The stem cell therapy market is likely to grow during the forecast period owing to growing investment from private companies, increasing in regulatory approval of stem cell-based therapeutics for treatment of chronic diseases and growth in commercial applications of regenerative medicine.

Products based on stem cells do not yet form an established market, but unlike some other potential applications of bioscience, stem cell technology has already produced many significant products in important therapeutic areas. The potential scope of the stem cell market is now becoming clear, and it is appropriate to review the technology, see its current practical applications, evaluate the participating companies and look to its future.

The report provides the reader with a background on stem cell and regenerative therapy, analyzes the current factors influencing the market, provides decision-makers the tools that inform decisions about expansion and penetration in this market.

Click Here & Get a Single User OR Corporate User License Key for This Report athttps://www.reportsnreports.com/purchase.aspx?name=2351731

The latest Stem Cell and Regenerative Therapy Market report provides readers with a deeper understanding of potential target consumers to create a lucrative marketing strategy for the 2019-2026 forecast period. For entrepreneurs seeking information about potential customers, it will be particularly helpful. Selective statements provided by leading vendors would allow entrepreneurs to gain a deeper understanding of the local market and prospective customers.

Table of Contents:

Chapter 1 Introduction

Study Background

Study Goals and Objectives

Reasons for Doing This Study

Scope of Report

Methodology and Information Sources

Geographic Breakdown

Market Breakdown

Analysts Credentials

.Continued

About Us: ReportsnReports.com is your single source for all market research needs. Our database includes 500,000+ market research reports from over 95 leading global publishers & in-depth market research studies of over 5000 micro markets.We provide 24/7 online and offline support to our customers.

E-mail: [emailprotected]

Phone: +1 888 391 5441

Visit link:
Stem Cell and Regenerative Therapy Market Covid-19 Impact Analysis, Size, Share & Trends Analysis Report by Component, By Enterprise Size, By End...

The RNA binding protein CPEB2 regulates hormone sensing in mammary gland development and luminal breast cancer – Science Advances

INTRODUCTION

The mammary gland develops postnatally and is subjected to marked remodeling in every oestrus cycle and during pregnancy. The mature mammary duct consists of an outer layer of basal myoepithelial cells and a polarized inner layer of luminal epithelial cells, which surround a hollow lumen and include hormone-sensing cells. During lactation, the lobuloalveolar units contain the luminal milk-producing alveolar cells (1, 2). This epithelial ductal tree is embedded within the mammary fat pad, which comprises fibroblasts, adipocytes, blood vessels, nerves, and immune cells (1). The development and remodeling of mammary ducts, through ductal branching and elongation, require epithelial cell proliferation to be coordinated with specification and maintenance of cell differentiation, as well as with tissue and cell polarity. These events are governed by ovarian steroid hormones, which control normal mammary development and lead to the neoplastic conversion of mammary tissue when misregulated. Estrogen is the most potent mitogenic stimulus for mammary ductal elongation during puberty, and it also directs the transcription of progesterone receptor (PR), which, in turn, induces ductal side branching and luminal lineage differentiation (35). Hormone-sensing cells, which are positive for estrogen receptor (ER) and PR, account for only a small fraction (7 to 30%) of the luminal epithelium. These hormone receptorpositive (HR+) cells integrate hormonal cues to signal to adjacent HR-negative (HR) cells via paracrine communication, which trigger the major proliferative response at the adult stage, mainly through the receptor activator of nuclear factor B (NFB) ligand (RANKL) (68).

Temporal and spatial control of mRNA translation, coupled to regulation of mRNA stability and localization, link cell proliferation, polarity, and differentiation (912). These gene regulation responses and the integration of external signals are coordinated through RNA binding proteins and cognate cis-acting elements to assemble specific ribonucleoprotein complexes. The cytoplasmic polyadenylation element (CPE)binding (CPEB) family of RNA binding proteins regulates mRNA stability and translation through dynamic changes in their poly(A) tail length (13, 14). The four family members (CPEB1 to CPEB4) competitively recognize the same CPE in the 3 untranslated region (3UTR) of target mRNAs (15). CPEs interact with other cis-elements in a CPE combinatorial code to define spatiotemporal gene expression patterns (11, 1619). In turn, individual pairs of CPE/CPEBs assemble into complexes that either repress or activate translation; repressor complexes shorten the poly(A) tail and mediate subcellular localization of repressed mRNAs, while activator complexes elongate the poly(A) tail (13). The switch from repression to activation is regulated by coordinated CPEB-specific posttranslational modifications of all four CPEBs (20). Although most CPEB functions have been studied during early development, CPEB1 in the mammary gland regulates the translation of milk protein transcripts, such as -casein mRNA (21), and the localizationbut not the translational activationof ZO-1 (Zona Occludens Protein 1) mRNA to the apical surface of epithelial cells for tight junction assembly (22). Changes in poly(A) tail length regulate gene expression, integrating extracellular signals into cellular outcomes, including mitotic cell division and steroid hormone responses (17, 23, 24). Here, we show that the RNA binding protein CPEB2, which regulates the poly(A) tail length of CPE-containing mRNAs, contributes to mammary gland development and luminal breast carcinogenesis by regulating the translation of mRNAs downstream of steroid hormone signaling.

To address how CPEBs could contribute to postnatal mammary gland development, we first determined the relative expression levels of all four CPEB mRNAs in pubertal, adult, pregnant, lactating, and involuted mouse mammary glands (Fig. 1A). Cpeb2 mRNA was the most abundant of the four Cpeb mRNAs in adult virgin mice, and it also peaked at lactation. After cell sorting of mammary epithelial cells (MECs) (fig. S1A), we found that Cpeb2 mRNA was expressed mainly in luminal cells, whereas Cpeb1 was predominant in myoepithelial cells (Fig. 1B). A similar distribution was observed at the protein level (fig. S1B). We next determined the consequences in mammary gland morphogenesis of total loss-of-function mouse models for CPEBs in postpubertal adult nulliparous mice. To this end, we determined the elongation and branching of the epithelial ductal tree in mammary gland whole mounts. We used previously described knockout (KO) mice for CPEB1 and CPEB4 (19, 25) and generated KO mice for CPEB2 and CPEB3 (figs. S2 and S3). CPEB2 and CPEB3 KO mice were viable and fertile and did not show any overt phenotype. While ductal morphogenesis was not affected in CPEB3 KO or CPEB4 KO mice, CPEB1 KO and CPEB2 KO animals displayed reduced branching through the fat pad (Fig. 1C and fig. S4A). Branching was quantified using AngioTool software (fig. S4B). Because of a defect in oogenesis, ovaries from CPEB1 KO females are rudimentary and do not secrete normal levels of reproductive hormones (26). This deficiency, which can be partially rescued by injection of 17-estradiol (22), limits mammary duct proliferation. Accordingly, we observed reduced ductal expansion through the fat pad only in adult CPEB1-deficient mammary glands (fig. S4). To better define cell-autonomous defects in mammary duct development, we generated CK14-specific KO mice for CPEB1 and CPEB2 (KOCK14), where the CK14 promoter is expressed by all MECs during embryonic development (27). When the KO was restricted to the CK14 lineage, loss of CPEB2 (but not of CPEB1) resulted in reduced number of junctions (Fig. 1D). At earlier developmental times, we also observed a delayed ductal expansion in CPEB2 KO mice, as shown by diminished pubertal invasion of the epithelial tree through the fat pad that was recovered in adulthood (Fig. 1E and fig. S4B). CPEB2 KO mice also showed an increased luminal/myoepithelial cell ratio (Fig. 1F and fig. S4D). Thus, deletion of CPEB2 results in delayed ductal extension and reduced branching, two events sequentially regulated by ER and PR.

(A) mRNA levels of Cpeb1 to Cpeb4 normalized to Gapdh in whole tissue mammary gland (n = 2; n = 7 for adult nulliparous). Tissue was obtained from mice at puberty (5 weeks old), adult nulliparous (10 weeks old), midpregnancy (day 12 of gestation), lactation (2 weeks of lactation), or involution (6 days after weaning). Gapdh expression is also shown. Statistics were determined using two-way analysis of variance (ANOVA), **P < 0.01, ***P < 0.001, and ****P < 0.0001. (B) mRNA levels of Cpeb1 to Cpeb4 normalized to Gapdh in sorted cells from adult virgin mammary gland (n = 3). Statistics using two-way ANOVA, ****P < 0.0001. Myo, myoepithelial. (C) Representative carmine-stained mammary gland whole mounts and automatic quantification of the number junctions in virgin 10- to 12-week-old WT (n = 11) and constitutive CPEB1 KO (n = 4), CPEB2 KO (n = 10), CPEB3 KO (n = 5), and CPEB4 KO (n = 4) mice. Statistics were determined using the Mann-Whitney test, *P < 0.05 and **P < 0.01. (D) Representative mammary whole mounts and automatic quantification of the number of junctions in virgin 10- to 12-week-old epithelial-specific WTCK14 (n = 4), CPEB1 KOCK14 (n = 6), and CPEB2 KO CK14 (n = 8) mice. Statistics were determined using the Mann-Whitney test, *P < 0.05. (E) Representative mammary whole mounts and quantification of the area of the fat pad filled with epithelial ducts at puberty in WT and CPEB2 KO females (5 weeks old) (n = 5). Statistics were determined using the Mann-Whitney test, *P < 0.05. (F) Ratio between the percentage of luminal and myoepithelial cells gated on lineage-negative (WT, n = 7; CPEB1 KO, n = 4; CPEB2 KO, n = 6; CPEB3 KO, n = 4; and CPEB4 KO, n = 4). Statistics were determined using the Mann-Whitney test, *P < 0.05.

To further determine the cell-of-origin of the mammary CPEB2 KO phenotype and given that CPEB2 was mostly expressed in the luminal compartment of the mammary gland (Fig. 1B and fig. S1B), we sorted luminal cell types from adult virgin mammary glands (28). We distinguished the following three cell types [as defined in (28, 29)]: ductal progenitor (DP; Sca1+CD49b+), ductal differentiated (DD; Sca1+CD49b), and alveolar progenitor (AP; Sca1CD49b) (Fig. 2A). We observed a general increase in Sca1 levels in CPEB2 KO mammary glands and increased cell number in the gate for the Sca1+CD49b+ population, concomitant with a reduction in the Sca1+CD49b window (Fig. 2, A to E). The AP population, on the other hand, did not change significantly upon CPEB2 depletion. To further characterize the effect of CPEB2 loss-of-function in MECs, we studied the transcriptomes of all four wild-type (WT) and CPEB2 KO epithelial populations using DNA microarrays. First, we confirmed our gating strategy through the expression of well-known markers in the expected populations (fig. S5A). Principal components analysis of gene expression profiles further confirmed clustering by populations and showed that the main differences between WT and CPEB2 KO cells affected the Sca1+CD49b+ population, with DPKO placed between DPWT and DDWT (fig. S5B). This was calculated by comparing the distance between centroids of different genotypes on a given population versus the dispersion within the population (see Methods and fig. S5B). Next, on the basis of the genes differentially expressed in the DPWT versus DDWT populations, we generated a WT progenitor signature by selecting candidate genes with the highest and lowest fold change (FC) percentiles and P < 0.01 (1% most up- and down-regulated genes, n = 181 and n = 101, respectively). We found a clear negative enrichment for the WT progenitor signature in DPKO cells, with the genes up-regulated being negatively enriched and vice versa (Fig. 2F nd fig. S5C). Similarly, further filtering using a false discovery rate (FDR) of 0.1 as a threshold (instead of P value) resulted in a more stringent signature with 24 up-regulated and no down-regulated genes (WT DP versus WT DD) that was also negatively enriched in DPKO cells (fig. S5D) (see Methods). These observations suggest that the DPKO cells contained a partially differentiated population. mRNA expression of the luminal progenitor markers Elf5, Kit, Cd14, and Rspo1 (29) was reduced in DPKO cells as compared with the DPWT population (Fig. 2G). Conversely, these luminal progenitor markers were unaffected in APKO cells, with the exception of Rspo1 (see Discussion) (Fig. 2H). Accordingly, DPKO cells showed a reduced capacity to form organoids as compared to DPWT cells (Fig. 2I). Together, these results indicated that CPEB2 might be required for the proper differentiation of DP cells.

(A) Representative fluorescence-activated cell sorting (FACS) plots gated on luminal cells depicting luminal subpopulations: ductal differentiated (DD; Sca1+CD49b), ductal progenitors (DPs; Sca1+CD49b+), and alveolar progenitors (APs; Sca1CD49b+). (B) Representative FACS plots for Sca1 gated on luminal cells. FSC-W, forward scatter width. (C) Ratio of the percentage of Sca1high and Sca1low populations in luminal cells (n = 10). Statistics were determined using the Mann-Whitney test, **P < 0.01. (D) Quantification of the percentage of CD49b+ cells gated on luminal cells (n = 17). Statistics were determined using the Mann-Whitney test, *P < 0.05. (E) Quantification of the luminal subpopulations as in (A). Statistics were determined using two-way ANOVA, ***P < 0.001 (n = 17). (F) Preranked GSEA graphical output for the enrichment in DPKO versus DPWT cells of the up-regulated genes in the WT progenitor signature generated by P value (n = 181, see Methods). FDR q 0.0001. FDR, false discovery rate; NES, normalized enrichment score. (G) Expression of luminal progenitor markers in DPWT and DPKO cells. (H) Expression of luminal progenitor markers in APWT and APKO cells. (I) Representative images of organoids from sorted DPWT and DPKO cells and automatic quantification of the number of organoids from sorted DD or DP cells. Scale bars, 100 m. Statistics were determined using two-way ANOVA, **P < 0.01.

Gene set enrichment analysis (GSEA) showed a clear down-regulation in the gene sets related to cell cycle and proliferation (G2M checkpoint and E2F targets) in all four CPEB2 KO epithelial cell populations (fig. S6A). DD cells are highly proliferative (30). Therefore, we next analyzed MEC proliferation in the CPEB2 KO by Ki67 immunostaining (Fig. 3A) and by 5-ethynyl-2-deoxyuridine (EdU) incorporation (Fig. 3B). CPEB2 KO mice displayed reduced MEC proliferation. Note that apoptosis was negligible in adult mammary glands, both in WT and CPEB2 KO animals (fig. S6B).

(A) Representative images and automatic quantification of Ki67+ cells by immunohistochemistry in adult virgin mammary gland in WT and CPEB2 KO (n = 7) mice. Statistics were determined using the Mann-Whitney test, *P < 0.05. Scale bars, 50 m. (B) Representative FACS plots (gated on MECs) and quantification of percentage of EdU incorporation. FSC-A, FSC area. Statistics were determined using two-tailed unpaired Students t test, *P < 0.05. MECs, mammary epithelial cells. (C) Representative images and automatic quantification of ER+ cells by immunohistochemistry in adult virgin mammary gland in WT and CPEB2 KO (n = 5). Statistics were determined using the Mann-Whitney test, *P < 0.05. Scale bars, 25 m. (D) Representative images and automatic quantification of PR+ cells by immunohistochemistry in adult virgin mammary gland in WT and CPEB2 KO (n = 5). Statistics were determined using the Mann-Whitney test, *P < 0.05. Scale bars, 25 m. (E) Preranked GSEA graphical output for the enrichment in Sca1+KO cells (DPKO + DDKO) of the gene set estrogen response early from the Molecular Signatures Database Hallmarks collection (see Methods). FDR q = 0.0139. (F) Heat map representing the log2FC expression of hormone-driven genes in DPKO compared to DPWT. (G) Cpeb2 expression levels normalized by Gapdh in epithelial subpopulations.

Proliferation in the mammary gland is driven by the action of steroid hormones not only for HR+ but also for HR cells (including mammary stem cells) through dominant paracrine effects (4, 31). Thus, we first assessed the levels of ER and PR in constitutive and CK14-driven CPEB2 KO mice. Unexpectedly, ER and PR were up-regulated in the absence of CPEB2, both at mRNA and protein levels (Fig. 3, C and D and fig. S6, C to E). Moreover, the hallmark estrogen response early was significantly increased in KO Sca1+ cells (Fig. 3E), suggesting that the ER transcriptional function was not impaired. Direct ER and PR target genes tended to be up-regulated in the absence of CPEB2 at the transcript levels, while downstream proliferative genes were down-regulated (Fig. 3F). These observations suggest that, although hormone-receptor transcriptional activity is normal, or even increased, the downstream effectors of hormone-driven cell proliferation are defective.

We found that, in the absence of CPEB2, there is a delay in ductal elongation at puberty, as well as reduced ductal branching in adulthood, accompanied by decreased epithelial proliferation and impaired differentiation of HR+ cells. All these phenotypes observed in vivo are concordant with blunted HR signaling (4). Given that CPEB2 was expressed mainly in HR+ cells (Fig. 3G and fig. S7A), we hypothesized that CPEB2 may constitute a previously unidentified posttranscriptional layer of regulation in the ER and PR pathways.

To identify the CPEB2-target mRNAs that could explain the defective response to hormones in MECs, we performed CPEB2 RNA immunoprecipitation (RIP; Fig. 4A). CPEB2 coimmunoprecipitated 169 mRNAs in MECs, which were significantly enriched in the RIP WT compared with the RIP in CPEB2 KO control cells (see Methods, table S1, and fig. S7B). These CPEB2 targets were enriched in canonical CPEs (UUUUA12U), thereby verifying the specificity of the immunoprecipitation (Fig. 4B). Pathway analysis showed that CPEB2-target mRNAs were enriched in breast cancerrelated genes (Fzd2, Jag1, Cdk6, Ccnd1, Sp1, Wnt5a, Kit, Kras, and Lrp6) (Fig. 4C). RIP targets were also overrepresented in the phosphoinositide 3-kinase (PI3K)Akt signaling pathway (Fig. 4C), which has been shown to modulate both genomic and nongenomic activities of the ER and is associated with breast cancer and with endocrine resistance of luminal tumors when mutated (32). The transcription factor 3,5-cyclic adenosine monophosphate OR cyclic adenosine monophosphat responsive element binding protein 1 (CREB1), which is activated downstream PI3K-Akt and regulates estrogen signaling (33, 34), was one of the top three enriched transcripts in the RIP WT (table S1 and fig. S7B). Moreover, individual targets included not only Cpeb2 and Cpeb3 mRNAs (suggesting auto- and cross-feedback CPEB loops) but also regulators of cell fate, morphogenesis, and organogenesis in the Wnt and Notch pathways (1, 35), such as the Wnt surface receptors Fzd2 and Lrp6, and the Notch surface ligand Jag1 (table S1 and fig. S7B). Furthermore, although not statistically significant due to low mRNA expression levels, Rankl (Tnfsf11) was enriched in the CPEB2 RIP, and we also found CyclinD1 (Ccnd1) to be a CPEB2 target (fig. S7B). Rankl and Ccnd1 are the key effectors of the autocrine and paracrine proliferative responses to progesterone, respectively. We validated several of these genes as bona fide CPEB2 target mRNAs by RIPquantitative polymerase chain reaction (qPCR) (Fig. 4D). Given their direct implications on the regulation of hormone-driven proliferation and differentiation in MECs, we further analyzed the regulation of Creb1, Ccnd1, and Rankl. These CPEB2 target mRNAs contained conserved canonical CPEs in their 3UTRs at optimal distances (17) from the polyadenylation sites (fig. S8A). We found that their protein levels were reduced in the absence of CPEB2, without significant variations in their mRNA levels, thereby suggesting translational changes (Fig. 4, E to H and fig. S8B). This CPEB2-mediated regulation of RANKL appeared to be specific for MECs, given that it was not observed in the immune cells of the mammary lymph node (fig. S8C).

(A) Western blot image for CPEB2 and vinculin (as a control) from unbound, input, and immunoprecipitated fractions with anti-CPEB2 antibody in WT and CPEB2 KO MECs. (B) Percentage of genes with (+CPEs, red) or without (CPEs, gray) CPEs in the 3UTR, comparing RIP targets to the mouse transcriptome (all). Statistics were determined using Fishers exact test, ****P < 0.0001. (C) Significantly enriched KEGG pathways (adjusted P < 0.05) in the analyzed RIP targets. cGMP-PKG, cyclic guanosine monophosphate (cGMP)cGMP-dependent Protein Kinase G (PKG). mTOR, mammalian target of rapamycin. (D) RIP-qPCR results showing the RIP values normalized by each input in WT (n = 4) and KO (n = 3) MECs. Gapdh mRNA and RIP in CPEB2 KO MECs are used as negative controls for enrichment in RIP as compared to input. Statistics were determined using the Mann-Whitney test, *P < 0.05. IP, immunoprecipitation. (E) Western blot image for CPEB2, CREB1, and -tubulin (loading control) and normalized quantification of CREB1 protein levels in WT and KO MECs (n = 6). Statistics were determined using the Mann-Whitney test, **P < 0.01. (F) Representative images and manual quantification of RANKL+ cells by immunohistochemistry in adult virgin mammary gland in WT and CPEB2 KO animals (n = 6). Scale bar, 50 m. Statistics were determined using the Mann-Whitney test, **P < 0.01. (G) Western blot image for CPEB2, CyclinD1, and -tubulin (loading control) and normalized quantification of CyclinD1 protein levels in WT and KO MECs (n = 6). Statistics were determined using the Mann-Whitney test, *P < 0.05. (H) mRNA levels of Rankl, Ccnd1, and Creb1 normalized to Gapdh and to WT in MECs (WT, n = 6; KO, n = 4). Statistics were determined using the Mann-Whitney test.

As CPEB2 KO mice displayed defective signaling to estrogen and progesterone, both key in breast cancer development (29, 36, 37), and CPEB2-bound mRNAS were components of breast cancer pathways, we next explored whether CPEB2 participates in breast tumorigenesis. Analysis of the expression of CPEB2 mRNA in patient breast tumor samples using the METABRIC cohort determined an association between CPEB2 and ESR1 levels (Fig. 5A). In agreement with the function of CPEB2 in mammary homeostasis, gene expression profiles that classify breast cancer into various subtypes (38) indicate that ER+ primary breast cancer has a characteristic luminal transcriptional profile. Using both the METABRIC and The Cancer Genome Atlas RNA sequencing (RNA-seq) dataset, we confirmed that CPEB2 levels were decreased in basal-like and Her2 tumors compared to luminal tumors and to morphologically normal surrounding tissue (Fig. 5B and fig. S9A). This observation was extended to human breast cancer cell lines, with several ER+ (luminal-like) cell lines expressing higher levels of CPEB2 mRNA (Fig 5C).

(A) Violin plots for CPEB2 RNA expression depending on ER status; METABRIC cohort (n = 1974). Statistics were determined using the Wald test, P < 10 2.2216. (B) Violin plots for CPEB2 RNA expression in the PAM50 subtypes; METABRIC cohort (n = 1974). Statistics were determined using the Wald test compared to the luminal A subtype: basal-like, P < 10 2.2216; HER2, P < 10 2.2216; and luminal B, P = 0.99003. (C) Quantification of CPEB2 expression levels by RT-qPCR in the indicated breast cancer cell lines. B2M was used as endogenous control. (D) Kaplan-Meier survival curves for patients with luminal A breast cancer [HR (<10 years) = 1.89; P = 0.021; multivariate using tumor size and lymph node as other risk factors n = 550]. (E) Schematic representation of the chemical-induced breast cancer model and kinetics of mammary tumor onset in mice treated with medroxyprogesterone acetate (MPA) and 7,12-dimethylbenz(a)anthracene (DMBA) as indicated. Statistics were determined using the log-rank test, *P < 0.05. (F) Number of macroscopic tumors per animal at time of sacrifice (16 weeks after MPA administration) in WTCK14 (n = 11) and CPEB2 KOCK14 (n = 11) animals. Statistics were determined using the Mann-Whitney test, *P < 0.05. (G) Tumor incidence in WTCK14 (n = 11) and CPEB2 KOCK14 (n = 11) mice. Statistics were determined using chi-square test, *P < 0.05. (H) Western blot image for CPEB2 and vinculin (loading control) in ZR75 cells after KD of CPEB2 using sh_CPEB2 #28 or #78 or in control cells (sh_Control). (I) Relative growth curve of ZR75 cells sh_Control or KD of CPEB2. Cell numbers were quantified relative to day 0 at the indicated time points. Statistics were determined using a two-tailed unpaired Students t test, ***P < 0.001. (J) Surviving fraction of CPEB2 KD ZR75 cells (using sh_CPEB2 #28 and #78) or control ZR75 cells treated with vehicle (0 M), 0.5 M 4-OHT, or 1 M 4-OHT. Number of viable cells was quantified 6 days after 4-OHT treatment. Surviving fraction refers to the fraction of cells present after 4-OHT treatment. Statistics were determined using a two-tailed unpaired Students t test, *P < 0.05 and ***P < 0.001. n.s., not significant. (K) RT-qPCR quantification of MYC expression levels in CPEB2 KD ZR75 cells (sh_CPEB2 #28 or #78) or control ZR75 cells (sh_Control) treated with vehicle (0 M) or 1 M 4-OHT for 48 hours. B2M was used as an endogenous control. Statistics were determined using a two-tailed unpaired Students t test, **P < 0.01 and ***P < 0.001. (L) Quantification of CCND1 expression levels by RT-qPCR in CPEB2 KD ZR75 cells (sh_CPEB2 #28 and #78) or control cells (sh_Control) treated with vehicle (0 M) or 1 M 4-OHT for 48 hours. B2M was used as an endogenous control. Statistics were determined using a two-tailed unpaired Students t test, *P < 0.05, **P < 0.01, and ***P < 0.001.

Next, we explored the association between CPEB2 expression and patient survival at 10 years using the METABRIC public breast cancer primary tumor cohort, for which prognosis annotation was available with sufficient follow-up. We confirmed an interaction between CPEB2 expression and samples classified on the basis of PAM50 molecular subtype (P = 0.0007, continuous model) (39), implying significant differences in prognosis association across biologically diverse tumor subtypes. In luminal A tumors, dependent on ER signaling for growth, high levels of CPEB2 were associated with worse survival compared to samples with the lowest expression [HR (<10 years) = 1.83, P = 0.028, n = 550; Fig. 5D]. No association between CPEB2 expression and tumor size was observed (fig. S9B). Collectively, these findings reveal an association between low CPEB2 expression and survival in patients with luminal ER+ breast cancer.

To experimentally address a potential role of CPEB2 in luminal tumorigenesis, we induced mammary tumor development in WTCK14 and CPEB2 KOCK14 mice, combining the proliferative action of the synthetic progestin medroxyprogesterone acetate (MPA) and the mutagenic agent 7,12-dimethylbenz(a)anthracene (DMBA) (40). Tumor onset was significantly delayed in CPEB2 KOCK14 mice (Fig. 5E), as shown by the higher percentage of tumor-free animals at 20 weeks after MPA treatment, the humane end point determined by the size of WT tumors. Tumor incidence was 63% for WTCK14 animals versus 27% for CPEB2CK14 mice. Moreover, at the end of the experiment, the number of tumors per animal (Fig. 5F) was reduced CPEB2CK14 animals. As previously described (41), these treatments generated hyperplasias, neoplasias, adenomas, adenocarcinomas, and adenosquamous carcinomas. Histopathological analysis of the tumors generated in the CPEB2 KOCK14 and WTCK14 animals revealed no major differences (fig. S9C). Furthermore, we detected lower ER levels in CPEB2 KOCK14 tumors as compared to the WTCK14 ones (fig. S9D), despite the fact that this treatment generates tumors characteristic of the luminal breast cancer subtype with high ER expression (42) (note that determination of significance was limited due to low number of tumors in the CPEB2 KOCK14 mice).

To further explore any functional interactions between ER and CPEB2, we knocked down CPEB2 in ZR75 ER+ luminal human breast cancer cells using two independent short hairpin RNAs (shRNAs; Fig. 5H and fig. S10A). These depletions significantly decreased cell proliferation in vitro but did not increase apoptosis (Fig. 5I and fig. S10B). Next, we treated WT and CPEB2 knockdown (KD) cells with the ER inhibitor 4-hydroxytamoxifen (4-OHT) (Fig. 5J). In contrast to WT ZR75 cells, CPEB2 KD ZR75 cells were insensitive to 4-OHT, thereby indicating that CPEB2 depletion and ER signaling inhibition do not have an additive effect on cell growth and suggesting that CPEB2 and ER act on the same pathway. Consistently, the effects of CPEB2 depletion on MYC and CCND1 expression (genes regulated by ER signaling and mediators of proliferation) were comparable, but not additive, to inhibition of ER signaling by 4-OHT (Fig. 5, K and L). Furthermore, we could also validate the regulation of RANKL by CPEB2 in this breast cancer setting (fig. S10, C and D).

Our results indicate that CPEB2 and ESR1 expression in breast cancer are linked and that high CPEB2 levels are associated with poor prognosis in luminal A tumors. Results of MPA/DMBA tumor generation indicated that high CPEB2 expression promotes luminal tumor development, consistent with the hormone dependence of this breast tumor subtype. On the other hand, ER tumors (such as basal like) do not seem to require CPEB2; low levels of CPEB2 result in reduced survival (fig. S9E).

In this work, we unveil a previously unknown layer of posttranscriptional regulation of gene expression orchestrated by CPEB2 in the mammary epithelia hormone responses. Thus, key HR-driven mediators (both cell autonomous and paracrine) of the differentiation and proliferation pathways (such as RANKL, CyclinD1, or CREB1) are encoded by CPEB2-regulated mRNAs. In the absence of CPEB2, the transcriptional activation of these genes fails to be reflected into increased protein levels. Mammary ductal branching and elongation are coordinated by the ovarian steroid hormones estrogen and progesterone, which activate transcriptional programs resulting in epithelial cell differentiation and proliferation. These hormones are sensed by a minority of HR+ cells, which, in turn, signal to adjacent HR cells through paracrine signals that coordinate mammary gland development and remodeling. Although CPEB2 can modulate the expression of more than a hundred genes (table S1) rather than switching on a single gene, the depletion of this RNA binding protein shows phenotypic similarities with the depletion of well-characterized HR-activated genes. CyclinD1 and CREB1 determine the proliferative programs of the estrogen signaling in the mammary gland (34, 43). In turn, RANKL is a key paracrine mediator of progesterone-mediated ductal side branching and MEC proliferation (mediated by NFB and CyclinD1) and differentiation (6, 7, 44, 45). All of these pathways are defective in the absence of CPEB2. In addition to being a CPEB2 target in luminal cells, Ccnd1 is also down-regulated in myoepithelial cells, probably as the result of a paracrine transcriptional effect (fig. S11A). Expression of Rspo1, which was down-regulated in both DPKO and APKO (Fig. 2, G and H), is a RANKL-induced gene (6). Thus, the mammary epithelia defects observed in CPEB2 KO mice could be partly explained by impaired translational activation of Rankl mRNA. However, note that the phenotype of CPEB2 KO mouse model does not phenocopy that of the RANKL KO. RANKL drives mammary alveologenesis (46), which is not defective in CPEB2 KO mice (fig. S11, B and C). Normal alveologenesis in CPEB2 KO mice could be due to a compensatory increase in Cpeb4 mRNA levels, which we observed specifically at the lactating stage but not in adult virgin mammary glands (fig. S11D). Redundancy between CPEB2 and CPEB4 has been reported in other scenarios (47).

In this study, we have focused on the role of CPEB2 in luminal breast cancer as a mediator of ER signaling. Accordingly, CPEB2 is one of the top six genes, together with ESR1, with strongest correlation with ER+ breast cancer prognosis (48). It has been proposed that breast cancer subtypes arise from distinct epithelial differentiation stages and lineages (29). Although the cell-of-origin for luminal tumors has not yet been unambiguously identified, these tumors appear to arise from a population of DPs that not only has clonogenic capacity but also expresses high levels of markers of mature luminal cells, such as ER, PR, GATA3 (GATA binding protein 3), and FOXA1 (Forkhead Box Protein A1) (28, 29, 49, 50). Depletion of CPEB2 generated a differentiation intermediate population with high Sca1/ER levels but low clonogenic capacity and impaired hormonal signaling. Together, our findings reveal a previously unkown posttranscriptional mechanism that regulates mammary gland morphodynamics and influences the outcome of ER+ mammary tumors, which account for 75% of breast cancer cases.

To generate a CPEB2 KO mouse model, the vector (EUCOMM, PRPGS00036-W-3-B04) was electroporated in mouse G4 embryonic stem cells (mixed C57BL/6J and 129/Sv). Positive recombinant embryonic stem cells were identified by Southern blotting, transfected in vitro with the FlpO recombinase to remove the geo-cassette, and microinjected into developing blastocysts. Resulting chimeric mice (Cpeb2 lox/lox) were crossed with C57BL6/J mice, and the mouse colony was maintained in a mixed background (70% C57BL/6J and 30% 129/Sv). To generate CPEB3 KO, mouse ES cells carrying a gene-trap lacZ cassette and a promotor-driven neomycin resistance gene in Cpeb3 intron 3 (clones HEPD0670_2_C02 and HEPD0670_2_G03, EUCOMM) were microinjected into developing blastocysts. Resulting chimeric mice were crossed with 129/Sv C57Bl/6J animals. To obtain a ubiquitous and constitutive depletion, Cpeb2lox/lox mice were crossed with mice expressing DNA recombinase Cre under control of the Sox2 promoter. Excision of exon 4 of Cpeb2 led to a frameshift in the mRNA, generating premature stop codons and resulting in animals that were KO for the CPEB2 protein. For the CPEB3 KO, the Neo cassette and exon 3 were further deleted by crossing Cpeb3loxfrt with transgenic mice expressing Cre under the control of the Sox2 promoter. The mouse colony was maintained in a mixed background (129/Sv C57Bl/6). Epithelial-specific CPEB1 and CPEB2 KO mice were obtained by crossing Cpeb1lox/lox or Cpeb2lox/lox animals with C57BL/6J transgenic mice expressing Cre under control of the Krt14 promoter. Routine genotyping was performed by PCR; primer sequences are listed in table S2.

Agarose gels were incubated under soft agitation with depurination solution (0.25 M HCl, 15 min), denaturation solution (1.5 M NaCl and 0.5 M NaOH, 45 min), and neutralization solution (0.5 M tris and 1.5 M NaCl, 30 min). After overnight transfer, DNA was cross-linked (254 nm, 0.12 J) to a nylon membrane (0.45 mm; Pall Corporation). The membrane was prehybridized with Church buffer for 3 hours at 65C, hybridized with 32P-labeled probes for 12 hours, rinsed with washing buffer (standard saline citrate, 0.1% SDS), and exposed to a phosphorimager screen.

Mice (Mus musculus, C57BL/6J-129/Sv mixed background) were maintained under a standard 12-hour light/12-hour dark cycle at 23C, with free access to food and water. Female littermates between 10 and 12 weeks of age were used, unless otherwise stated. Mice were staged by histological analysis of ovaries or vaginal cytology and were selected for the follicular phase of the oestrous cycle (51, 52). For tumorigenesis experiments, CK14-Creexpressing mice were subcutaneously injected with MPA (Depo-Provera) at 7 weeks of age. They were then given DMBA (1 mg) by gavage weekly during the following 4 weeks (53, 54). Tumors were detected and monitored by manual palpation. Mice were sacrificed when a palpable mass exceeded 1 cm in diameter or at 20 weeks after MPA treatment (time for many WT animals to develop tumors reaching this humane end point). End-point tumors were classified on the basis of previously identified pathological nomenclature (55).

Thoracic and inguinal mammary glands were dissected, and MECs were prepared as previously described (56). In brief, mammary glands were incubated with a collagenase/hyaluronidase solution (STEMCELL Technologies), red blood cells were lysed, and cells were further dissociated with trypsin (Sigma-Aldrich), dispase II (Sigma-Aldrich), and deoxyribonuclease I (Sigma-Aldrich). In general, fluorescence-activated cell sorting (FACS) analysis and sorting were performed in a FACS Aria Fusion sorter (BD Biosciences), and data were analyzed with the BD FACSDiva software. For four-color FACS analysis, a Gallios flow cytometer (Beckman Coulter) was used, and data were analyzed with the FlowJo software. The following antibodies were used: EpCAMphycoerythrin (PE) (130-102-265), CD49fallophycocyamin (APC) (130-100-147), CD45fluorescein isothiocyanate (FITC) (130-102-778), Ter119-FITC (130-102-257), CD31-FITC (130-102-970), CD49b-PE (130-102-778), EpCAM-APC/Cy7 (BioLegend, 118217), and Ly-6A/E (Sca1) PerCP/Cy5.5 (BioLegend, 108123). Antibodies were purchased from Miltenyi Biotec unless otherwise stated. Gating strategies were adjusted as previously described (28). For EdU incorporation experiments, mice received an intraperitoneal injection of EdU (80 mg kg1) and were sacrificed 6 hours later, as previously described (57). After isolation of MECs, samples were processed as indicated in the protocol for Click-iT Plus EdU Flow Cytometry Assay (Invitrogen) using Pacific Blue picolyl azide.

A total of 2000 sorted cells were embedded in one drop of basement membrane extracts (Cultrex) and cultured for 15 days in uncoated 24-well glass plates (no. 242-20, zell-kontakt). The culture protocol was adapted from (58); advanced Dulbeccos modified Eagle medium (DMEM)/F12 medium was supplemented with penicillin/streptomycin, GlutaMAX, Hepes (Gibco), hydrocortisone (Lonza Bioscience), B27 (Thermo Fisher Scientific), insulin, N-acetylcysteine, epidermal growth factor, fibroblast growth factor 2 (FGF2; Sigma-Aldrich), FGF10 (PeproTech), heparin (STEMCELL Technologies), Y-27632 (ROCK inhibitor, Tocris), Wnt3a, and R-spondin1 (in-house). ROCK inhibitor was added for the first week, and the medium was refreshed every 3 to 5 days. Full drops were scanned with an Olympus IX81 inverted microscope at 10 magnification (ScanR software). Bright-field Z stacks of each field were projected in a single image, and the full drop was then digitally reconstructed by stitching the different image projections using an ImageJ custom-made macro-developed for this purpose at the Institute of Research in Biomedicine (IRB) Advanced Digital Microscopy Facility.

For mammary gland whole mounts, inguinal mammary glands were placed on a slide and fixed immediately with Carnoys solution overnight. Tissue was then hydrated, stained with carmine alum (Sigma-Aldrich, C1022 and A7167), dehydrated, cleared with xylene, and mounted with Leica CV Mount (14046430011). Images from whole mounts were acquired with an Olympus macroscope (zoom 1.6) and joined with the MosaicJ tool from ImageJ (59). For junction quantification, images were processed using an ImageJ custom-made macro-developed for this purpose and then analyzed using AngioTool (60). For histology and immunohistochemistry, inguinal mammary glands were fixed in 10% neutral-buffered formalin solution and embedded in paraffin. Paraffin-embedded tissue sections (3 m in thickness) were first air-dried and then dried at 60C overnight. Immunohistochemistry was performed using Autostainer Plus (Dako, Agilent). Before immunohistochemistry, sections were dewaxed for Ki67 as part of the antigen retrieval process using the low pH EnVision FLEX Target Retrieval Solutions (Dako) for 20 min at 97C using a PT Link (Dako, Agilent). For caspase 3, samples were dewaxed, and antigen retrieval was performed with citrate buffer (pH 6) for 20 min at 121C with an autoclave. Endogenous peroxidase was quenched by 10-min incubation with peroxidase blocking solution (Dako REAL, S2023). The rabbit polyclonal primary antibodies anti-Ki67 (Abcam, ab15580) and anti-cleaved caspase 3 (Cell Signaling Technology, 9661S) were diluted 1:1000 and 1:300, respectively, with EnVision FLEX Antibody Diluent (Dako, Agilent, K800621) and incubated for 60 and 120 min, respectively, at room temperature. A biotin-free, ready-to-use BrightVision polyhorseradish peroxidase (HRP)anti-rabbit immunoglobulin G (Immunologic, DPVR-110HRP) was used as secondary antibody. Immunohistochemistry for ER (clone 1D5; Dako, M7047), PR (Abcam, ab63605), and RANKL (R&D Systems, AF462) was performed as previously described (61, 62). Antigen-antibody complexes were revealed with 3,30-diaminobenzidine tetrahydrochloride (Dako, K3468). Sections were counterstained with hematoxylin (Dako, S202084) and mounted with toluene-free mounting medium (Dako, CS705) using a Dako CoverStainer. Bright-field images were acquired with a NanoZoomer-2.0 HT C9600 scanner (Hamamatsu). All images were visualized with a gamma correction set at 1.8 in the image control panel of the NDP.view software (Hamamatsu, Photonics, France). Image analysis was performed using TMARKER software (63). For immunofluorescence, Alexa secondary antibodies and 4,6-diamidino-2-phenylindole (DAPI) were used, and images were obtained on an inverted Leica TCS SP5 confocal microscopy.

Beads-homogenized tissue or MECs (EasySep, STEMCELL Technologies) were lysed in ice-cold radioimmunoprecipitation assay (RIPA) lysis buffer (with phosphatase and protease inhibitors) and sonicated for 5 min at high or low intensity, respectively (Standard Bioruptor Diagenode). Cellular debris was pelleted (15,700g, 15 min, 4C), and protein concentration was determined by the DC Protein Assay (Bio-Rad). Equal amounts of proteins were separated by SDSpolyacrylamide gel electrophoresis. After transfer onto nitrocellulose membranes (Sigma-Aldrich, GE10600001), membranes were blocked for 1 hour in 5% milk, and specific proteins were labeled with the corresponding primary antibodies against vinculin (Abcam, ab18058), CPEB3 (Abcam, ab10883), CPEB219, CPEB4 (Abcam, ab83009), CPEB1 (Cell Signaling Technology, no. 13583), CyclinD1 (Santa Cruz Biotechnology, sc-717), CREB1 (Cell Signaling Technology, no. 9197), -tubulin (Sigma-Aldrich, T9026), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH; Life Technologies, AM-4300). Secondary HRP antibodies were also diluted in 5% milk, and proteins were revealed using enhanced chemiluminescence Western blotting detection reagents (GE Healthcare).

Human breast carcinoma cell lines MDA-MB-231, BT549, MDA-MB-435, MDA-MB-468, SKBR3, BT474, T47D, MCF7, and ZR75 were obtained from the American Type Culture CollectionLGC Standards Ltd. Partnership. All cell lines were cultured in DMEM d-glucose medium (Gibco) supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin, except BT459 cells, which were cultured in supplemented RPMI medium (Gibco). All cells were cultured at 37C and in a 5% CO2 humidified atmosphere. For lentiviral infection, human embryonic kidney293 T cells were transfected with pLKO lentiviral vectors and plasmids encoding lentiviral particles using standard methods. pLKO sh_CPEB2 plasmids were obtained from Sigma-Aldrich MISSION shRNA library (clones TRCN0000149728 and TRCN0000149778). Recipient cells were transduced with the viral medium and selected with puromycin (2 g ml1) for 72 hours.

In vitro cell proliferation was assessed using the CyQUANT Cell Proliferation Kit following the manufacturers instructions. For 4-OHT sensitivity experiments, 4-OHT or vehicle (ethanol) was added to the cell culture at the indicated concentrations 24 hours after plating. Cell numbers were quantified after 6 days using BIO-TEK FL600 fluorescence microplate reader at 485 to 530 nm.

To detect early apoptosis (APC labeled), cultured cells were trypsinized and processed following the Annexin V Apoptosis Detection Kit (Thermo Fisher Scientific). DAPI solution was also added to the cell suspension to detect the total number of dead cells. A Gallios cytometer (Beckman Coulter) was used for the analysis.

Total RNA was extracted by TRIzol reagent (Invitrogen). RNA (1 g) was reverse-transcribed with oligo(dT) and random primers using SuperScript IV (Thermo Fisher Scientific) or RevertAid (Thermo Fisher Scientific), following the manufacturers recommendations. Real-time qPCR (RT-qPCR) was performed in a LightCycler 480 (Roche) using PowerUp SYBR Green Master Mix (Roche). Primer sequences are listed in table S2. RNA quantifications were normalized to GAPDH as endogenous control. For human breast carcinoma cell lines, RNA extraction (PureLink RNA Mini Kit, Thermo Fisher Scientific), reverse transcription (High-Capacity cDNA Reverse Transcription Kit, Applied Biosystems), and real-time PCR (TaqMan Universal Master Mix, Applied Biosystems) were performed and analyzed as previously described (64). The TaqMan probes (Applied Biosystems) used were Hs0139673_m1 (CPEB2), Hs00153408_m1 (MYC), Hs00765553_m1 (CCND1), and Mm00437762_m1 (B2M). For microarrays, samples in duplicates from sorted cells from WT and CPEB2 KO animals were processed at IRB Barcelonas Functional Genomics Core Facility following standard procedures. Affymetrix MG-430 PM strip data for DPs, DD, APs, and myoepithelial cell population samples in WT and CPEB2 KO in biological duplicates were processed with Bioconductor (65) using robust multiarray average (RMA) background correction, quantile normalization, and RMA summarization to obtain probeset expression estimates (66). Centroid locations from the principal component for the different combinations between cell populations and genotypes, as well as the resultant Euclidean distances between centroids, were computed. Dispersion within groups (the average Euclidean distance between samples and their corresponding population/genotype centroid) was also measured. Limma 3.22.7 (67) was then used to identify differentially expressed genes between CPEB2 KO and WT in all four cell populations, with P < 0.01 and |FC| > 2. Lists of up- and down-regulated genes between DPWT and DDWT were generated by selecting candidate genes with the highest and lowest FC percentiles and P < 0.01 (1% most up- and down-regulated genes, n = 181 and n = 101, respectively). Alternatively, after selecting with the highest and lowest FC percentiles, we also filtered these using a FDR threshold of 0.1. This resulted in a more stringent list of 24 up-regulated and no down-regulated genes in WT DP versus WT NCL. Enrichment for these gene lists, as well as for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Broad Institute hallmark gene set categories in whole-genome gene lists ranked by mean log2FC between cell populations and genotypes, was assessed with the GSEA preranked algorithm (68). M. musculus GO and KEGG gene set collections were generated using the org.Mm.eg.db Bioconductor package (October 2014). Homo sapiens Hallmark gene set was downloaded from the Molecular Signatures Database and translated to M. musculus using Ensembl human-mouse homology information (August 2016).

MECs (EasySep, STEMCELL Technologies) were isolated from WT and CPEB2 KO animals (with two animals pooled per duplicate). Pellets were washed twice with cold Hanks balanced salt solution, lysed with RIPA buffer [50 mM tris-HCl (pH 8), 150 mM NaCl, 1 mM MgCl2, 1% NP-40, 1 mM EDTA, 0.1% SDS, protease inhibitor cocktail, and ribonuclease inhibitors] and sonicated for 5 min at low intensity with Standard Bioruptor Diagenode. After centrifugation (10 min, 4C), supernatants were collected, precleared, and immunoprecipitated (4 hours, 4C) with 10 g of anti-CPEB2 antibody (69) bound to 50 l of Dynabeads Protein G (Invitrogen). Beads were washed and split for either protein or RNA extraction. For RNA isolation, beads were resuspended in 100 l of proteinase K buffer with 70 g of proteinase K (Roche) and incubated for 30 min at 42C and 30 min at 65C. RNA was extracted following standard phenol/chloroform protocol. Samples were processed at IRB Barcelonas Functional Genomics Facility following standard procedures: Illumina Hi-Seq 2000 50base pair single-end RIP-sequencing (RIP-seq) data for WT and CPEB2 KO in biological duplicates, as well as their respective input samples of MECs, were checked for general sequencing quality control and adapter contamination using the FastQC software version 0.11, and no relevant problems were found. Afterward, reads were aligned against the M. musculus University of California, Santa Cruz mm10 ribosomal RNA (rRNA) genome using Bowtie1 0.12.9 (70) with two mismatches and default options to identify and remove reads coming from potential rRNA contamination from downstream analysis. Curated (non-rRNA) reads were then aligned against the M. musculus mm10 reference genome using Bowtie2 2.2.2 (71), allowing for one mismatch and reporting the best alignment site per read. All samples reported >15 million aligned reads. Potential amplification artefacts (duplicated reads) were detected and removed with the sambamba software version 0.5.1 using default options. Binary tiled data file tracks for visual inspection in the Integrative Genomics Viewer (IGV) software were generated using igvtools version 2. Read counts at 3UTR level (longest 3UTR per gene, mm10 genome Ensembl, March 2017) were computed using the featureCounts function from the Rsubread package version 1.24.2 with options minMQS = 1. Then, an interaction analysis of WT and CPEB2 KO RIP samples and their respective input controls (RIPWT/InputWT versus RIPKO/InputKO) was performed with DESeq2 (72). Target 3UTRs were selected using an interaction FC threshold of >1.5 and interaction Benjamini-Hochberg adjusted P < 0.1 (see table S1, high-confidence RIP target genes, n = 169). GO enrichment for selected targets was performed using the online Enrichr (73, 74) tool.

For animal experiments, data were expressed as means SEM, and statistics were analyzed with the GraphPad Prism software. Experiments were performed following a randomized block design. Littermates kept in the same cage since weaning were used whenever possible. The experiment was blinded before experimental analysis. For human breast carcinoma cell lines, P values were generated using the Students t test (unpaired, two tailed); P < 0.05 was considered significant. Error bars were calculated as SE in all the statistical analysis shown. Number of independent experiments is indicated in the figure legends.

Transcriptomic and clinical data from the METABRIC breast cancer dataset (75, 76) were downloaded from the cBioPortal for Cancer Genomics database (77). Association of gene expression with molecular features (PAM50 subtype and ER status) was evaluated using a linear model, while a Cox model was fitted to assess association with overall survival. Statistical significance was assessed using the corresponding F tests of log-likelihood ratio tests. A Wald test was used for pairwise comparisons when necessary. In all cases, the cohort of origin of the sample was included as a covariate in the models.

For survival analyses, sample groups of low, medium, and high expression levels were defined using the tertiles of the intensity distribution after correction by cohort effects, as estimated by a linear model in which PAM50 subtypes were included as covariates. Association of gene expression with early relapse was modeled using a step function for a prespecified cutoff of a 10-year follow-up. Hazard ratios and their corresponding 95% confidence intervals were computed as a measure of association. For visualization purposes, Kaplan-Meier curves were estimated for groups of tumors that showed low, medium, or high expression. The threshold for statistical significance was set at 5%. All analyses were conducted with R (78).

Follow this link:
The RNA binding protein CPEB2 regulates hormone sensing in mammary gland development and luminal breast cancer - Science Advances

Higher risk of infection, changes to treatment makes COVID-19 a double threat for cancer patients – theday.com

The coronavirus pandemic has caused significant changes and delays to treatment plans for many people battling cancer, who are more susceptible to the virus due to weakened immune systems, nationwide statistics show.

A survey conducted by The American Cancer Society Cancer Action Network in late March and early April found that half of more than 1,000 patients and survivors surveyed had seen their treatment interrupted in some way. Many are working with health care providers to alter their treatment plans skipping treatments, delaying therapies and surgeries, changing dosages and switching to virtual visits to lower their risk of exposure to the virus.

Thesurvey asked respondents about their experience accessing health care as a result of the pandemic, including the availability of appointments and services, and concerns about being able to safely get their treatments in the future. It found that27% of patients in active treatment said they have had their treatment delayed. Of those, 13% saidthey haveno clear timeline for whentreatment will resume.

Additionally, many cancer patients also have had their support systems ripped away, as they practice social isolation and see annual support events such as Relay for Life in southeastern Connecticut canceled.

Balancing risks

Approximately 20,300 people in Connecticut will be diagnosed with cancer in 2020 and 6,390 will die from the disease, according to Bryte Johnson, Connecticut Government Relations Director for American Cancer.

Andy Salner, medical director for the Hartford HealthCare Cancer Institute at Hartford Hospital, said cancer patients often have weakened immune systems, so may more easily contract the virus than someone without cancer. They alsomay developa more severe case ofthe COVID-19, the disease caused by the virus,and have a harder time fighting it.

Some cancers themselves, like multiple melanomas and most types of Leukemia, impact the immune system directly by altering blood cells. People with cancer might also be poorly nourished because cancer itself can make it hard to digest food, cancer cells can use up nutrients and cancer treatments like radiation therapy and chemotherapy can cause nausea and lack of appetite, according to the Cancer Action Network.

Radiation therapy, immunotherapy and chemotherapy also can lead to short-term immune system damage, and bone marrow or stem cell transplants that use high-dose treatments to kill cancer also may harm immune system cells for weeks to months, according to the American Cancer Society. Chemotherapy is the most common cause of a weakened immune system, because it causes a decrease in white blood cells, meaning a person's body won't be able to fight off infections as effectively.

At the Hartford Healthcare Cancer Institute in Waterford, oncologists Michael Kane and Sapna Khubchandani complete thousands of patient visits each year, and are helping patients design new treatment plansto battle and monitor their cancer while reducing their risk of exposure to the coronavirus.

For one local woman, a COVID-19 diagnosis meant missing her final session of chemotherapy, Khubchandani said. She did not identify the patient for privacy reasons.

Khubchandani said she didnt think missing one session so late in the treatment plan would have too much of an impact on the patient, but it wasnt ideal. An elective surgery related to the woman's cancer treatment, meant to take place after she completed chemotherapy, was delayed due to the virus, Khubchandani said.

COVID-19 has caused doctors to delay many suchnonemergency surgeries related to cancer treatment, including breast biopsies, lumpectomies or colonoscopies. Khubchandani, Kane and Salner all said they have had to make changes to surgery plans, either for patient safety or due to a lack of beds in intensive care units that are overwhelmed with patients battling the virus.

Doctors have been exploring alternatives, such as putting patients on hormonal treatment as they await surgery, so that were still treating the cancer while we wait, which will buy them time, Khubchandani said.

From some of his patients, Kane has made adjustments to medication dosages or administration intervals, to limit visits. Its all about individualizing treatment for each patients scenario, he said.

Worrying about the unknown

For one of Kane's patients, Richard van Etten ofHadlyme, protecting the 89-year-old from COVID-19 meant forgoing the transfusion he normally receives every three weeks.

Van Etten has been battling cancer since 2018, first in his bladder, then a cancerous module in his left lung, then in his lymph nodes.

Hecompleted chemotherapy and recently started a new drug called Keytruda, administered via infusions through a port for the cancer in his bladder and lymph nodes.

He recently learned that the cancer in his lymph nodes is gone, but his care team decided to continue his transfusions in case there were any residual cancer cells left, he said. But whenthe coronavirusbecame a concern, they decided to stop.

The virus hit and I was very hesitant about continuing my infusions, which were taking place in Waterford, he said. I talked with Dr. Kane and we decided to forgo them for now.

Since the start of the pandemic, he has been to the treatment center only once, to have his port cleaned. He said he is being very careful and is barely leaving his home, where he lives with his wife and daughter.

Van Etten said that he is absolutely anxious about contracting COVID-19, mostly due to his age. He said he feels confident about his decision to delay his treatment to limit his exposure to the virus but is worried about what might be happening inside his body.

Knowing that I was either in remission or close to it when I stopped, that it was at least temporarily under control, makes me feel OK with missing my infusions, he said. But that doesnt mean that in the back of my mind I dont wonder if it might be coming back.

Heis anxiously awaiting his next in-person visit, a PET scan scheduled for June 1, thats going to tell me whether any of the cancer has come back or not, he said.

Margie Elkins is a breast cancer survivor and active volunteer for the American Cancer Society and several other cancer organizations in southeastern Connecticut. While she is missing regular checkups and experiencing some delays in her own follow-up care, she said, One of the things that really worries me is not only the people who are experiencing delays in treatment but the people who have yet to be diagnosed, because the longer you wait in some cases, the larger the cancer becomes."

For thosewhose treatment hasbeen delayed, Its like their life is on hold because they dont know if their cancer is getting worse or getting better, she said.

Salner said delaying treatments certainly poses a risk. I think the worry would be that the cancer cells could potentially grow during that time (that treatments are delayed), that the treatment might be less effective if its delayed too far, he said.

Among survey respondents whose care had been canceled, delayed or changed by the pandemic, the most commonly impacted services were imaging procedures to monitor growth of cancer, supportive services such as therapy and in-person provider visits.

Salner said that decisions to delay chemotherapies and radiation, or reversing the order of treatments to prevent weakening of the immune system during the pandemic, were being made regularly and in partnership with patients and their families.

We want to balance making sure that we deliver the best cancer therapy possible but also place the patient at the lowest risk for getting what could be a life-threatening infection, he said.

In Waterford, Kane and Khubchandani have started screening patients for COVID-19 before starting them on chemotherapy or immunotherapy to ensure they are strong and healthy enough for the treatment. If a patient does have the virus, the doctors are delaying chemotherapy or immunotherapy in almost all cases. The ultimate decision though, is primarily left up to the patient. If they want to receive treatment, they likely will be able to, doctors agree.

Kane and Khubchandani also are implementing general precautions for people entering their offices: taking patients temperature, calling patients the day before to screen for COVID-19 symptoms and opting for virtual visits when possible. At the Waterford treatment center, theyve reduced the number of chairs in the waiting room and are scheduling laboratory services further apart. All doctors and patients are wearing masks at all times.

The extra precautions seem to be helping, Salner said. The Hartford Healthcare group has not seen a large influx of cancer patients testing positive for COVID-19.

Finding support

Some survivors are concerned about the emotional impact of COVID-19 on people currently battling cancer, worrying that they may feel overwhelmed and alone, both in their diagnosis and by social distancing.

Elkins said that she felt isolated when she was first diagnosed with stage1 breast cancer years ago, and can only imagine how that feeling is being compounded by the isolation of quarantine.

Greg Schlough, event chairman for the American Cancer Society Relay for Life of Southeastern CT, said that in his experience, cancer is a disease that causes people to really rally around you. The survivor saidthose with cancer tend to rely on their family and friends for support, like he did after being diagnosed with stage 3 melanoma on his 40th birthday in September 2000.

At the beginning, you get that doom and gloom feeling but when people start to come around and you start to see other people who have survived, you are able to say Hey, Im going to beat this thing. You know that you have people backing up and cheering you on, he said.

Right now, folks fighting cancer, especially a new diagnosis, may be struggling to find that support as they practice social distancing from their family and friends.

Schlough, in remission for 20 years, said that if he was a cancer patient right now, he would be afraid to go outside, and cant imagine how new patients are feeling.

For patients who are struggling with feelings of isolation or fear, events like the annual relay provide an opportunity to connect with others who are fighting the same fight, or who are examples of strength and survival. This years relay, which was set to be held on July 14 in Norwich, has been postponed indefinitely.

The annual fundraiser normally raises an average of $80,000 to $120,000 a year for the American Cancer Society, helping the society fund resources and support services to help people with cancer.

Schlough said organizers are hoping to reschedule the event for the end of summer, but it wouldfunction in accordance with social distancing guidelines and everyone will be required to wear masks. People currently in treatment, he said, may have to miss out or participate virtually.

Wed rather see them there next year smiling than this year with the risk of getting sick, he said.

Schloughsuggests patients or survivors who are emotionally strugglingor needhelp understanding treatment options shouldreach out to friends and family for over-the-phone support or call the American Cancer Societys hotline, 1 (800) 227-2345.

t.hartz@theday.com

See the rest here:
Higher risk of infection, changes to treatment makes COVID-19 a double threat for cancer patients - theday.com

The Latest Technological Innovations in Orthopedic Surgery 2020 Technology – IMC Grupo

Technology across the world is improving and innovatingwith time. Over the years, man-managed labor has almost finished from themarket and more and more technological and scientific gadgets are taking placemaking human labor more effective, efficient, and precise.

Medical science has also taken a lot of advantage fromthis scientific advancement therefore, we can say that doctors are making fulluse of science and technology and the world of medicine has evolved quiterapidly.

Orthopedic hospitalshave also seena remarkable transformation over time and the days when a regular orthopedicclinic only comprised of a few tools and a bad. The launch of innovativetechnologies, biologics, and hybrid items into the orthopedic industry isincreasingly growing.

Any of these emerging inventions gain regulatory approvalby showing significant equivalence to the US System of the Food and DrugAdministration (FDA) 510(k).

Surgeons play a key role in the implementation ofemerging technology to patients and will play a leading role in supportinghealthy, efficient, adequate, and cost-effective treatment, particularly forsurgical procedures. Surgeons will track and record the health results andadverse effects of their patients utilizing modern technologies and ensure thatthe new technology works as expected.

Ortho-biologics utilizes the regenerative ability ofcells in the human body. Ortho-biologics are created from compounds naturallypresent in the body which are used to facilitate the recovery of fracturedbones which injured joints, ligaments, and tendons.

These involve bone graft, growth factors, stem cells,platelet-infused plasma, autologous blood, and autologous controlled serum. Themesenchymal stem cells (MSCs) contained in the bone marrow has been shown to besuccessful in the production of the appropriate tissues.

Result in Orthopedic Procedures

Recent advances in this area, including growth factor andstem cell therapies, may contribute to faster recovery. One breakthrough isdrug-free bone grafts, which may be used to cure conditions such as orthopedicsurgery. Clinical trials have demonstrated that growth factors can improve thehealing cycle.

Stem cells will continually self-regenerate and transforminto either form of cell, providing an unmatched source of regenerativemedicine technology. Definitions of musculoskeletal procedures utilizing stemcells are listed below.

Biotechnology firms began utilizing orthopedic stemcells. For starters, BioTime works on stem cell therapies for age-relateddegenerative diseases, IntelliCell BioSciences on adipose-derived stem cellsfor orthopedic conditions, and Bio-Tissues on Ortho-biological treatments forcartilage defects.

Orthopedic procedures using robots are less intrusive anddeliver reproducible accuracy, resulting in shorter hospital stays and quickerrecovery times. The Swiss clinic, La Source, recorded a decline in averagehospitalization from 10 to 6 days with the usage of surgical robots.Nevertheless, this technology is also costly to develop, so solid,evidence-based trials are required to prove that robotic technology contributesto improved outcomes.

The Da Vinci Surgical Method became the first U.S. Food andDrug Administration (FDA)-an authorized robotic surgery program in 2000. Morebusinesses are investing in this technology to enhance navigation duringservice or to receive 3-D scans that aid in the design of custom joints.

Organizations that are interested, in robotics areinclined towards the following technological masterpieces:

Several modern surgical techniques are enhancing theresults. These involve motion-preservation methods, minimally intrusive surgery,tissue-guided surgery, and cement-free joint repair.

Motion recovery strategies require partial or completedisk removal and the usage of active stability systems and interspinous spacersthat do not impair versatility.

Minimally intrusive procedures involve the use ofendoscopes, tubular retractors, and computer-aided guidance devices, allowingan incision of just 2 cm instead of 12 cm in conventional therapies. Minimallyinvasive treatments are gaining popularity in joint and hip replacement and spinalsurgery.

Smart devices provide built-in sensors to offer real-timetracking and post-operative evaluation details to surgeons for better patientsafety across the clinical process. Such implants have the ability to minimizeperiprosthetic infection, which is an increasing orthopedic issue.Sensor-enabled innovations also presented health care professionals with arange of innovative, cost-effective goods.

Companies working in this field include:

3-D orthopedic printing is gaining traction in themanufacture of personalized braces, surgical equipment, and orthotics from arange of materials. 3-D printing technology cuts operating times, saves energy,increases the long-term reliability of the implant, and enhances the healtheffects of surgical procedures. 3-D printing technologies of orthopedics areinclusive of:

Companies investing in 3-D Orthopedic Printing

Medical science has taken a huge turn with the introduction of technology. The orthopedic industry has also transformed to a huge extent making sure that the specialists and surgeons are able to treat and operate on their patients without any hassle. Almost all the orthopedic hospitals are equipped with high-end gadgets and tools to assist the doctor.

Even though the technology has evolved greatly since thefield of medicine was invented, it is important to understand that this is justa beginning and there are many more things to come in the future.

See the rest here:
The Latest Technological Innovations in Orthopedic Surgery 2020 Technology - IMC Grupo

Nancy Davidson describes plans for reopening the Seattle Cancer Care Alliance as COVID-19 wave recedes – The Cancer Letter

publication date: May. 15, 2020

Nancy E. Davidson, MD

President and executive director, Seattle Cancer Care Alliance

Senior vice president, director and member, Clinical Research Division, Fred Hutchinson Cancer Research Center

Raisbeck Endowed Chair for Collaborative Research, Fred Hutch

Professor and head of medical oncology, University of Washington

This story is part of The Cancer Letters ongoing coverage of COVID-19s impact on oncology. A full list of our coverage, as well as the latest meeting cancellations, is availablehere.

Nancy Davidson is now in the eleventh week of managing the COVID-19 pandemicthe longest stretch experienced by any health executive in the U.S.

And now, like her peers throughout the country, Davidson, president and executive director of the Seattle Cancer Care Alliance, is in the midst of ramping up plans for a comeback of cancer services.

The Cancer Letter asked Davidson to discuss these plans and share her thoughts on the way cancer care will evolve both at SCCA and nationwide.

This conversation is part of an informal series of stories, interviews, and commentaries that track cancer institutions as they seek to reopen, reorganize, and reinvent in the wake of the COVID-19 pandemic:

Health systems and academic cancer centers are cutting expenses to make up for operational shortfalls resulting from the pandemiclaying off employees, furloughing staff, and cutting salaries and benefits (The Cancer Letter, May 8, 2020).

Community oncology practices are experiencing a significant decrease in patient volume, as weekly visits dropped by nearly 40%, while cancellations and no-shows have nearly doubled (The Cancer Letter, May 1, 2020).

Washington was the first state to record what at the time was believed to be the first COVID-19 caseon Jan. 15, in a traveler from Wuhan, China.

Washington was also the first to register what appeared to be the first COVID-19 death, and SCCA as well as Fred Hutchinson Cancer Center, a component of the alliance, were the first major cancer institutions to take decisive action and shut down non-essential operations (The Cancer Letter, March 13, 2020).

At this writing, the state of Washington has 18,964 confirmed cases and 991 COVID-related deaths. The disease peaked weeks ago, and the spread has slowed. On May 15, for example, 101 new cases and 5 deaths were reported in the state. Washington ranks 18th in the number of cases.

Now, SCCA is among the first to make plans to reopen its operations.

We are bringing our stem cell transplant and our CAR T programs back online in a very thoughtful way, and theres a lot of pent-up demand for that. We had over a hundred transplant patients whove been waiting in the queue, for example. And so, were beginning to recall them and bring them in, Davidson said to The Cancer Letter.

We looked at things like imaging, close to a thousand mammograms that didnt take place because screening mammograms were paused during this time of maximum separation. And so, were also beginning to think about how we can thoughtfully recall those patients. Some patients who had more elective therapies also put it off for a while.

And so, we have a pretty good idea of what the numbers are. I mean, youre right. We are actively reaching out to patients and letting them know that the system was always safe. But were now at a position where we think that they can safely come for their in-person care.

And I think thatll be an important thing going forward, especially in cancer. You and I know that cancer didnt take a pause during the COVID pandemic, and it isnt taking a pause in the near future. We really need to be in a position where we can try to optimize our care going forward. We do know that some of our patients are worried. Theyre concerned about the possibility that they would somehow increase their exposure by coming in to their visits. And so, we have very, very robust testing in place in Washington. Thats also helped us.

Davidson spoke with Paul Goldberg, editor and publisher of The Cancer Letter.

Paul Goldberg:

You have more experience with more phases of COVID-19 than anyone else in the U.S. So, going back to the beginning, to what feels like a decade ago, you moved very, very fast and set up prioritization, and closed things down. What was it like to be on the inside of those decisions?

Nancy Davidson:

Paul, youre right that were in the 10th week of our pandemic response at the Seattle Cancer Care Alliance. As you point out, we are the first of the United States NCI-designated comprehensive cancer centers to experience this in a meaningful way. And at the time, I think that we knew that we were entering into uncharted territory, but territory that we were well equipped to deal with.

As you point out, were in a state that has had a very robust response.

We work at an institution that has a lot of people who are already involved in research in viruses. Fred Hutch houses one of the big coordinating centers for the HIV vaccine efforts, so that we felt that we were in a good position to do this, but we were kind of learning on the job.

Oncologists, though, are very good at dynamic situations, and tackling risk; right? Thats what we do for a living.

PG:

Well, you have also seen more impact on your institution and research, both clinical and basic. How would you summarize this impact?

ND:

We have seen much more impact than all of us would like on our cancer research.

Obviously, our COVID research is flourishing right now, but on the cancer side, we made the decision institutionally, across Fred Hutch and Seattle Cancer Care Alliance, to really slow down our basic laboratory research in accordance with the state guidelines and with our own modeling about what we should do to try to flatten the curve.

And we also made the decision to really limit access to some of our clinical trials, particularly the phase I clinical trials, where we felt that the real goal of a phase I trial is toxicity rather than improving patient wellbeing. And we also closed some of our phase III clinical trials, because we felt that a standard treatment option was available for those patients.

But Paul, weve continued our phase II clinical trials all during this time, for patients where we thought that clinical trial participation would be important for their wellbeing, and we certainly have continued care on trial for everybody who was already on trial. The new accrual was limited more to folks who were going on to the phase II trials.

And were now doing the reverse.

Were at a point where were able now to think about how to wind up after the wind-down. And so, right now, we are, in a very thoughtful and deliberate fashion, opening about 10% new trials and 10% of our closed trials over the next week or so.

Well look carefully at the impact of that, and then we hope to continue that ramp up in a stepwise fashion. And weve tried to prioritize those for trials that are in patients best interests, trials that really reflect some of our primary research interests as an institution, and those where we think that we can try to optimize the safety of the participants and our staff.

PG:

Do you think anything has been irrevocably lost, in terms of data?

ND:

I think that in some of our clinical trials, we werent able to collect every single piece of data that mightve been mandated by the clinical trial.

Certainly, we were able to collect all the data that would be vital for patient safety. And we may not be able to get all of those things, but I suspect that for the clinical trials that have remained in operation and those that will be restarting, that well be able to gather the information that we need to address the primary aims of the clinical trial.

PG:

Ive heard it said that with randomization, problems affect both sides of the trial. So, with randomized trials, you might actually be in okay shape.

ND:

I think so. Many of the randomized trials are very large trials; right? And one would hope that what were going to see is a short period of a pause, and then, youre right, the trial will resume in its full form, and that we will not have any compromise of the primary outcome of the trial.

PG:

What about clinical care? Has that been set back?

ND:

No, I dont think so. I do think that oncologists are pretty good at dealing with adversity, as are our patients. So, we have remained operational the entire time. Weve actually used this as an opportunity to accelerate some of the initiatives that we probably should have done before.

All of us have become very adept at telehealth now, and we are hoping that well be able to right-size how we would use that going forward. And, of course, were hoping that the reimbursement strategies nationally will make that a viable alternative for some patients where its appropriate.

We continued all of our infusion therapies, by and large. The one place where we made some pretty strategic decisions was to slow access to our cell-based therapy trials and treatments, our CAR T trials and our stem cell transplant trials.

As members of a healthcare ecosystem, we needed to be in line with the priorities of the state of Washington and the Puget Sound region at the time, to make sure that we freed up inpatient beds and critical care resources for what we thought would be the surge of COVID-19 patients.

And so, that meant that those transplant and CAR T patients were the patients who were the most likely to require those things, and we made the decision to slow their entry into our system. Were now restarting that, too, Paul. As of last week, were reentering some of the most needy patients who require those particular kinds of interventions, because we feel that we have the hospital capacity to care for them should they become ill.

PG:

Have you had to do triage on COVID? On, say, ventilators?

ND:

Thankfully, we have not. I think, again, the state of Washington has been very forward-thinking on this. In our state, early on there were a lot of workplaces that put people to work from home. The Fred Hutch and the SCCA did this early on; the governor has been very diligent in the state of Washington.

And so, I think we were in happy circumstances where, thankfully, our critical care capacity was higher than our needs. And so there was never a time that Im aware of where in the University of Washington system we had to triage the use of ventilators.

PG:

What role have disparities played in this crisis?

ND:

Well, gosh, I think thats an area where were all trying to sort it through; right?

Our region has a large homeless population. Thats certainly a major form of disparity. And so, I think that within the region, were trying to work collectively with our government facilities and with our partner organizations to make sure that our homeless population has access to the kind of care that they need across the boardthings that are related to prevention or treatment in COVID, as well as underlying social and health problems that they might have.

Ours is a state that has a large Native American population, and so, were trying to make sure that we work pretty actively with our tribes, where appropriate, to make sure that theyre getting the appropriate health care.

And you may know that also in our region the Yakima Valley, which is in the middle of the state, is the home of our larger Hispanic population. That region has been particularly hard hit, and I think that might have to do with the nature of the workforce and the kinds of jobs.

These are folks who often work in situations where its hard to distance in the workplace, and they work in vital industries, and so, this is a population thats also been especially hard hit. So, were trying very hard to make sure that we understand these individuals who are at particular risk, and we do everything we can to try to mitigate that risk within those individuals.

PG:

How soon do you think you might have some data?

ND:

I dont have a good answer for you on that one right now. I think that everybody is pedaling as fast as they can, Paul, to try to get data generally. And then, also, for specific populations.

For example, populations of patients with cancer.

AACR had a session where they tried to review what we know about cancer as a risk factor for COVID, and it looks to me like we dont have a clear understanding of that as a field, either. So, there are a lot of places where we have knowledge that we really have to gain over relatively short period of time.

PG:

What about financial impact? Have you had to have furloughs or any other forms of belt-tightening?

ND:

We think our workforce is incredibly important. Thats obviously one of our most important resources, and so, wed like very much to retain our workforce as best as we can going forward. Weve been fortunate that many people were in a situation where they could work from home.

And so, many of our workforce members who dont have to be physically in the office or who are not directly patient-facing are working from home and theyre working extremely hard.

I think it will be interesting to see how it goes over time. What the healthcare workforce looks like generally is something that were all going to need to be thinking about as we go into the months and the years aheadwhat weve learned from this, and what we can use to try to optimize the delivery of healthcare going forward generally, and also the delivery of cancer care specifically.

PG:

People talk about a rebound in demand for carepatients showing up saying, Take care of us. You should probably be starting to see it about now, I would think. Is it happening?

ND:

We are hoping that were going to see that shortly, and, actually, were trying to begin to promote that, if you will.

First, I told you about the fact that we are bringing our stem cell transplant and our CAR T programs back online in a very thoughtful way, and theres a lot of pent-up demand for that. We had over a hundred transplant patients whove been waiting in the queue, for example. And so, were beginning to recall them and bring them in.

We looked at things like imaging, close to a thousand mammograms that didnt take place because screening mammograms were paused during this time of maximum separation. And so, were also beginning to think about how we can thoughtfully recall those patients. Some patients who had more elective therapies also put it off for a while. And so, we have a pretty good idea of what the numbers are. I mean, youre right. We are actively reaching out to patients and letting them know that the system was always safe. But were now at a position where we think that they can safely come for their in-person care.

And I think thatll be an important thing going forward, especially in cancer. You and I know that cancer didnt take a pause during the COVID pandemic, and it isnt taking a pause in the near future. We really need to be in a position where we can try to optimize our care going forward. We do know that some of our patients are worried. Theyre concerned about the possibility that they would somehow increase their exposure by coming in to their visits. And so, we have very, very robust testing in place in Washington. Thats also helped us.

Go here to see the original:
Nancy Davidson describes plans for reopening the Seattle Cancer Care Alliance as COVID-19 wave recedes - The Cancer Letter

The first breakthrough coronavirus antibody drug might finally be here – BGR

The moment we find COVID-19 treatments that are truly effective, well see the novel coronavirus with different eyes. Yes, the virus is highly transmissible and can lead to severe illness and death. But effective drugs that can block its ability to infect cells and meds that can reduce respiratory distress and inflammation will turn the new disease into an infection that well learn to live with.

Several experts warned this week that the novel coronavirus is here to stay, and we may never get rid of it even when the vaccines arrive. But an increasing number of reports detail various therapies that can be used to improve the odds of recovery. Some of them rely on drugs that were developed to treat other conditions. Others use stem cells. And then there are plasma transfusions from patients who survived COVID-19.

Researchers are also working on a new type of drug thats related to plasma therapy, antibody-based meds that can offer the same kind of protection as a plasma transfusion. Now, we have learned that one of the antibodies capable of blocking the SARS-CoV-2 virus from binding to cells has proven to be 100% effective in labs.

The novel coronavirus binds to human cells via a spike protein that can link up to ACE2 receptors. Then the virus enters the cell where it wreaks havoc. The cell deciphers the viruss genetic information to create more and more copies of the virus. The cell dies in the process, and the new replicas are released into the body where they are free to infect other cells and continue to replicate.

The immune system detects pathogens and can fight them very efficiently. Many people will get COVID-19 and never know it because theyll never even present any symptoms. That means the immune system cleared the virus before it could cause complications, and the resulting antibodies will be able to deal with the illness in the future, providing immunity against COVID-19 for an unknown period of time. Thats why plasma treatments work. Doctors use the antibodies from donors to treat other patients with weaker immune systems. But demand for plasma far exceeds supply, and thats why monoclonal antibody drugs would work better.

Sorrento is one of several companies working on this breakthrough type of drug. The pharmaceutical company has found what it describes as a potent anti-SARS-CoV-2 antibody that can completely prevent the virus from linking to ACE2 cells in lab tests. The antibody is called STI-1499, and Sorrento says its been able to deliver 100% inhibition of the virus in healthy cells after four days of incubation.

Sorrento has screened billions of antibodies in its proprietary G-MAB fully human antibody library and identified hundreds of candidates that can bind to the S1 subunit of the SARS-CoV-2 spike protein. A dozen of them have been able to block the interaction between S1 and ACE2.

STI-1499 stood out for its ability to completely block SARS-CoV-2 infection of healthy cells in the experiments. The company says that the virus was neutralized even in low antibody doses. This antibody will likely be the first antibody to be used in the COVI-SHIELD antibody cocktail that will include a combination of antibodies meant to deal with potential mutations of the coronavirus. STI-1499 is also expected to be used as a standalone therapy in a COVI-GUARD drug, assuming it receives regulatory approval.

Sorrento will request priority evaluation and accelerated review. Clinical trials will have to prove the antibody works just as well in patients as it does in lab conditions.

Assuming STI-1499 is effective and safe, Sorrento says itll be able to produce up to 200,000 doses per month, and the company plans to make 1 million of them while its waiting for FDA approval. Manufacturing capacity could be increased through partnerships to meet demand. If all goes well, STI-1499 might be among the first brand new drugs developed specifically to treat COVID-19.

Doctors analyzing lung CT scan. Image Source: STEPHANIE LECOCQ/EPA-EFE/Shutterstock

Chris Smith started writing about gadgets as a hobby, and before he knew it he was sharing his views on tech stuff with readers around the world. Whenever he's not writing about gadgets he miserably fails to stay away from them, although he desperately tries. But that's not necessarily a bad thing.

Originally posted here:
The first breakthrough coronavirus antibody drug might finally be here - BGR