Harvard Institute Research Articles

CRISPR/Cas9 ruling expected 

A widely anticipated U.S. court ruling will soon bring to a close another chapter in the fight between the University of California, Berkeley, and Broad Institute of MIT & Harvard over legal rights to the CRISPR/Cas9 gene-editing tool. The troubles began when the U.S. Patent & Trademark Office (USPTO) approved CRISPR/Cas9 patent applications expedited by Broad, even though UC Berkeley submitted its own patent application first. UC Berkeley then petitioned USPTO to hold a proceeding to determine the tool’s original inventor, and USPTO started by deciding if UC Berkeley and Broad claimed to invent the same thing. While Broad’s application specified how to use CRISPR/Cas9 in eukaryotes, like plants and animals, UC Berkeley’s application described using CRISPR/Cas9 only in a test tube and on bacteria. Its broader use in all organisms, including in eukaryotes, was implied, Berkeley’s lawyers argued. But the patent court disagreed and in February 2017 deemed Broad’s

Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19)

More than 1·8 million new cases of HIV-1 infection were diagnosed worldwide in 2016. No licensed prophylactic HIV-1 vaccine exists. A major limitation to date has been the lack of direct comparability between clinical trials and preclinical studies. We aimed to evaluate mosaic adenovirus serotype 26 (Ad26)-based HIV-1 vaccine candidates in parallel studies in humans and rhesus monkeys to define the optimal vaccine regimen to advance into clinical efficacy trials. We conducted a multicentre, randomised, double-blind, placebo-controlled phase 1/2a trial (APPROACH). Participants were recruited from 12 clinics in east Africa, South Africa, Thailand, and the USA. We included healthy, HIV-1-uninfected participants (aged 18-50 years) who were considered at low risk for HIV-1 infection. We randomly assigned participants to one of eight study groups, stratified by region. Participants and investigators were blinded to the treatment allocation throughout the study. We primed participants at weeks 0 and 12 with Ad26.Mos.HIV (5 × 1010 viral particles per 0·5 mL) expressing mosaic HIV-1 envelope (Env)/Gag/Pol antigens and gave boosters at weeks 24 and 48 with Ad26.Mos.HIV or modified vaccinia Ankara (MVA; 108 plaque-forming units per 0·5 mL) vectors with or without high-dose (250 μg) or low-dose (50 μg) aluminium adjuvanted clade C Env gp140 protein. Those in the control group received 0·9% saline. All study interventions were administered intramuscularly. Primary endpoints were safety and tolerability of the vaccine regimens and Env-specific binding antibody responses at week 28. Safety and immunogenicity were also assessed at week 52. All participants who received at least one vaccine dose or placebo were included in the safety analysis; immunogenicity was analysed using the per-protocol population. We also did a parallel study in rhesus monkeys (NHP 13-19) to assess the immunogenicity and protective efficacy of these vaccine regimens against a series of six repetitive, heterologous, intrarectal challenges with a rhesus peripheral blood mononuclear cell-derived challenge stock of simian-human immunodeficiency virus (SHIV-SF162P3). The APPROACH trial is registered with ClinicalTrials.gov, number NCT02315703. Between Feb 24, 2015, and Oct 16, 2015, we randomly assigned 393 participants to receive at least one dose of study vaccine or placebo in the APPROACH trial. All vaccine regimens demonstrated favourable safety and tolerability. The most commonly reported solicited local adverse event was mild-to-moderate pain at the injection site (varying from 69% to 88% between the different active groups vs 49% in the placebo group). Five (1%) of 393 participants reported at least one grade 3 adverse event considered related to the vaccines: abdominal pain and diarrhoea (in the same participant), increased aspartate aminotransferase, postural dizziness, back pain, and malaise. The mosaic Ad26/Ad26 plus high-dose gp140 boost vaccine was the most immunogenic in humans; it elicited Env-specific binding antibody responses (100%) and antibody-dependent cellular phagocytosis responses (80%) at week 52, and T-cell responses at week 50 (83%). We also randomly assigned 72 rhesus monkeys to receive one of five different vaccine regimens or placebo in the NHP 13-19 study. Ad26/Ad26 plus gp140 boost induced similar magnitude, durability, and phenotype of immune responses in rhesus monkeys as compared with humans and afforded 67% protection against acquisition of SHIV-SF162P3 infection (two-sided Fisher's exact test p=0·007). Env-specific ELISA and enzyme-linked immunospot assay responses were the principal immune correlates of protection against SHIV challenge in monkeys. The mosaic Ad26/Ad26 plus gp140 HIV-1 vaccine induced comparable and robust immune responses in humans and rhesus monkeys, and it provided significant protection against repetitive heterologous SHIV challenges in rhesus monkeys. This vaccine concept is currently being evaluated in a phase 2b clinical efficacy study in sub-Saharan Africa (NCT03060629). Janssen Vaccines & Prevention BV, National Institutes of Health, Ragon Institute of MGH, MIT and Harvard, Henry M Jackson Foundation for the Advancement of Military Medicine, US Department of Defense, and International AIDS Vaccine Initiative.

Disruption and development: the evolving CRISPR patent and technology landscape.

Pharmaceutical Patent AnalystVol. 7, No. 4 CommentaryDisruption and development: the evolving CRISPR patent and technology landscapeDaniel LimDaniel Lim*Author for correspondence: Tel.: +44 20 3088 3769; E-mail Address: Daniel.lim@allenovery.com Allen & Overy LLP, One Bishops Square, London E1 6AD, UKSearch for more papers by this authorPublished Online:8 Jun 2018https://doi.org/10.4155/ppa-2018-0010AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: Broad InstituteCas9CRISPREPOEuropegene editinggene therapylicensingpatentspriorityrevocationReferences1 The Broad Institute, Inc., Massachusetts Institute of Technology, President and Fellows of Harvard College: EP2771468 (2015).Google Scholar2 Gaudelli NM, Komor AC, Rees HA et al. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature 551, 464–471 (2017).Crossref, Medline, CAS, Google Scholar3 Hu JH, Miller SM, Geurts MH et al. Evolved Cas9 variants with broad PAM compatibility and high DNA specificity. Nature 556, 57–63 (2018).Crossref, Medline, CAS, Google Scholar4 Gootenberg JS, Abudayyeh OO, Kellner MJ et al. Multiplexed and portable nucleic acid detection platform with Cas13, Cas12a, and Csm6. Science doi:10.1126/science.aaq0179 (2018) (Epub ahead of print).Crossref, Google Scholar5 Statement and Background on the CRISPR Patent Process (2018). www.broadinstitute.org/crispr/journalists-statement-and-background-crispr-patent-process.Google Scholar6 The Regents of the University of California, University of Vienna, Emmanuelle Charpentier: EP2800811 (2017).Google Scholar7 The Regents of the University of California, University of Vienna, Emmanuelle Charpentier: EP3241902 (2018).Google Scholar8 Liu XS, Wu H, Krzisch M et al. Rescue of fragile X syndrome neurons by DNA Methylation editing of the FMR1 gene. Cell 172(5), 979–992 (2018).Crossref, Medline, CAS, Google Scholar9 Chen JS, Ma E, Harrington LB et al. CRISPR-Cas12a target binding unleashes indiscriminate single-stranded DNase activity. Science doi:10.1126/science.aar6245 (2018) (Epub ahead of print).Google Scholar10 Jinek M, Chylinski K, Fonfara I et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337(6096), 816–821 (2012).Crossref, Medline, CAS, Google Scholar11 The CRISPR Journal. https://home.liebertpub.com/publications/the-crispr-journal/642.Google Scholar12 Barrangou R, Fremaux C, Deveau H et al. CRISPR provides acquired resistance against viruses in prokaryotes. Science 315(5819), 1709–1712 (2007).Crossref, Medline, CAS, Google Scholar13 Sherkow JS. The CRISPR patent landscape: past, present and future. CRISPR J. 1(1), 5–9 (2018).Crossref, Medline, Google Scholar14 Gene-edited CRISPR mushroom escapes US regulation (2016). www.nature.com/news/gene-edited-crispr-mushroom-escapes-us-regulation-1.19754.Crossref, Google Scholar15 DowDuPont revealed as the surprise leader in global CRISPR patents; study points to potential trouble ahead (2018). www.iam-media.com/blog/detail.aspx?g=4efeae13–7f84–4a30-b414–88a4e6d917ec.Google Scholar16 DuPont Pioneer expands CRISPR-Cas9 patent portfolio with license from Broad Institute of MIT and Harvard (2017). www.pioneer.com/home/site/about/news-media/news-releases/template.CONTENT/guid.EA02CAA5–07DA-AA4D-D17A-E2C6AE20D9FF.Google Scholar17 Sangamo Therapeutics, Inc.: US9873894 (2018); Sangamo Therapeutics, Inc.: US9902974 (2018).Google Scholar18 DuPont Pioneer and Broad Institute join forces to enable democratic CRISPR licensing in agriculture (2017). www.broadinstitute.org/news/dupont-pioneer-and-broad-institute-join-forces-enable-democratic-crispr-licensing-agriculture.Google Scholar19 Broad Institute of MIT and Harvard joins discussions to create worldwide CRISPR-Cas9 licensing pool (2017). www.broadinstitute.org/news/broad-institute-mit-and-harvard-joins-discussions-create-worldwide-crispr-cas9-licensing-pool.Google Scholar20 Benson Hill Biosystems receives patent for novel CRISPR technology (2018). https://bensonhillbio.com/benson-hill-biosystems-receives-patent-novel-crispr-technology/.Google Scholar21 Inscripta releases new, unique CRISPR gene-editing enzyme; free to use for all researchers (2017). www.inscripta.com/news/2017/12/13/inscripta-releases-new-unique-crispr-gene-editing-enzyme-free-to-use-for-all-researchers/.Google Scholar22 Editas Medicine extends CRISPR genome editing leadership through licensing of new CRISPR technologies (2016). http://ir.editasmedicine.com/phoenix.zhtml?c=254265&p=irol-newsArticle&ID=2230504.Crossref, Google Scholar23 Monsanto Announces global genome-editing licensing agreement with Broad Institute for newly-characterized CRISPR system (2017). https://monsanto.com/news-releases/monsanto-announces-global-genome-editing-licensing-agreement-with-broad-institute-for-newly-characterized-crispr-system/.Google Scholar24 MADzymes terms & conditions (2018). www.inscripta.com/madzymes/terms/.Google Scholar25 Gene-editing startup Inscripta raises $55.5million (2018). www.reuters.com/article/us-inscripta-fundraising/gene-editing-startup-inscripta-raises-55–5-million-idUSKCN1GC1GP.Google ScholarFiguresReferencesRelatedDetailsCited ByApplication of CRISPR‐Cas9 Technology in Bovine Reproduction3 May 2021CRISPeering: Bioengineering the Host Cells through CRISPRCas9 Genome Editing System as the Next-generation of Cell FactoriesRecent Patents on Biotechnology, Vol. 15, No. 2The trends in CRISPR research: A patent and literature study with a focus on IndiaWorld Patent Information, Vol. 65Patents and the experimental space: social, legal and geographical dimensions of 3D bioprinting25 June 2020 | International Review of Law, Computers & Technology, Vol. 35, No. 1Worldwide CRISPR patent landscape shows strong geographical biases4 June 2019 | Nature Biotechnology, Vol. 37, No. 6 Vol. 7, No. 4 Follow us on social media for the latest updates Metrics Downloaded 211 times History Received 6 April 2018 Accepted 13 April 2018 Published online 8 June 2018 Published in print July 2018 Information© 2018 Newlands PressKeywordsBroad InstituteCas9CRISPREPOEuropegene editinggene therapylicensingpatentspriorityrevocationFinancial & competing interests disclosureThe author is an employee of Allen & Overy LLP. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download

Beam launches for base editing

It’s shaping up to be another year full of cash flowing for CRISPR gene editing. In just the past two months, four companies have launched based on newly discovered or designed versions of CRISPR. Of all those variants, the base editors developed by David R. Liu’s lab at the Broad Institute of MIT & Harvard might be causing the most excitement. They’ve certainly brought in the most money. Just two years ago, Liu debuted his lab’s first base editors, which can make single nucleotide base changes in DNA. Since then, those base editors, along with advanced iterations, have been shared with research labs worldwide more than 3,000 times. They’ve been used to edit DNA of bacteria, fungi, plants, insects, fish, mice, and even human embryos. Amid that whirlwind of development, Liu has been quietly building a company that will try to transform the base editors into treatments for genetic diseases.

Rajat Gupta: A Scientist in Doctor's Clothing.

Rajat Gupta is a postdoctoral research fellow in the laboratory of Sekar Kathiresan at the Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard in Boston. He studies the genetics of coronary artery disease, examining the biological mechanisms by which certain genetic variants confer risk.1–4 Gupta also teaches medical students at Harvard Medical School and is a practicing cardiologist at the Massachusetts General Hospital in Boston. Becoming a doctor had been Gupta’s dream since childhood, he told Circulation Research in a recent phone conversation. He grew up in a small town in central Michigan called Okemos, which Gupta fondly describes as a block of ice, and spent his spare time either ice-skating or escaping the cold in the local library. He would plow through books ravenously, memorizing facts and figures, teaching himself human anatomy and imagining that one day he would serve the people of his local community as their physician. But then, around the time that Gupta was heading off to university to study medicine, his childhood plan started to shift. He read an inspiring magazine article about a physician who was also a scientist and realized that there was an alternative way to tackle health problems and disease. Figure. Rajat Gupta As soon as I arrived at the University of Michigan as an undergraduate studying biochemistry, I started to look for research opportunities. I e-mailed as many laboratories as I could find, asking if they would be willing to take someone with zero experience. As a result, I started working nights and weekends in the rheumatology laboratory of David Fox. I worked alongside a great postdoctoral fellow from Japan, Yoshi Morita, essentially as his technician, and he taught …

Monsanto jumps on base editing

Monsanto is getting a head start in accessing a new gene-editing tool called DNA base editing that it hopes will help it improve major row crops. The agriculture giant says it will invest $100 million in a plant genome start-up called Pairwise. The firm was founded by gene-editing heavy hitters David Liu and Feng Zhang of Broad Institute of MIT & Harvard and J. Keith Joung of Massachusetts General Hospital and Harvard Medical School. Base editing is a type of gene editing that uses guide RNA and a form of the CRISPR/Cas9 enzyme to change adenine-thymine base pairs to guanine-cytosine pairs. In contrast, older CRISPR/Cas9 tools cut the double-stranded DNA at a particular point, and natural repair mechanisms put it back together, generally stopping the function of a gene. In human health, the instability of cytosine can create genetic mutations that lead to inherited diseases. Gene editing can turn back

Broad and Rockefeller settle CRISPR dispute

The CRISPR patent dispute between the University of California, Berkeley, and Broad Institute of MIT & Harvard continues unabated, but a separate dispute between Broad and Rockefeller University has concluded. Rockefeller researcher Luciano Marraffini was an author on a foundational 2013 Science paper describing CRISPR gene editing along with Feng Zhang of Broad. Both scientists’ names were included on patents for using CRISPR in prokaryotes, but eukaryotic patents did not include Marraffini. Under a settlement between Broad and Rockefeller, the patents will remain unchanged.

Johns Hopkins research gets venture backing

Deerfield Management, a life sciences investment management firm, and Johns Hopkins University have formed a collaboration called Bluefield Innovations to support therapeutic research and discovery at the university. Funded by Deerfield, the venture will offer up to $65 million over five years for early-stage research with additional funding for projects with strong commercial potential. Therapies developed at Bluefield will be licensed to third parties or launched as start-up ventures. Companies spun off from Bluefield may receive funding from Deerfield. The unusual deal is the second recently for Deerfield. Just last month it formed a similar collaboration worth $50 million with Broad Institute of MIT & Harvard. Dave Greenwald, director of business development at Johns Hopkins Technology Ventures, says the new partnership is unique but advantageous for both parties. “We are constantly looking at ways to commercialize research coming out of Johns Hopkins, and Deerfield is looking to access innovation earlier

CRISPR can now edit RNA

As CRISPR gene editing marches closer to the clinic, several researchers have been tinkering to unleash the DNA editor on another nucleic acid: RNA, the intermediary messenger between DNA and proteins. A team led by Feng Zhang of Broad Institute of MIT & Harvard now reports the first CRISPR complex engineered to edit individual bases of RNA (Science 2017, DOI: 10.1126/science.aaq0180). “This is quite exciting, and I am talking about a competitor here, so I shouldn’t be excited,” says Mitchell R. O’Connell, who studies CRISPR RNA targeting at the University of Rochester Medical Center. RNA editors will be valuable instruments for controlling gene expression in the lab, O’Connell says. And as a potential therapy, RNA editing “could be a safer alternative to gene editing” because changes to DNA are permanent, but edits to RNA are temporary since cells make new RNA all the time, he adds. The new study comes

Broad and Deerfield form lucrative pact

In a unique partnership, the health care venture firm Deerfield Management will invest more than $50 million in drug discovery projects at Broad Institute of MIT & Harvard. During the five-year pact, Deerfield will support academic research—initially five to 10 projects—and have an option to create companies based on promising programs. While a number of research institutions have hooked up with drug companies that want to gain early access to academic discoveries, Broad’s pact with an investment firm is unusual.

Obsessive compulsive disorder genes

Four genes have been identified that are linked to obsessive compulsive disorder (OCD). The genes all play a role in the same brain circuit and may help explain why people are more likely to have OCD if they have a relative with the condition. People with OCD have intrusive thoughts and feel driven to repeat rituals to relieve their anxiety. To investigate if OCD has a genetic basis, Hyun Ji Noh at the Broad Institute of MIT and Harvard and her colleagues compared more than 600 genes across 592 people with OCD, and 560 people who don't have it.

Monsanto gains a CRISPR platform

Monsanto has signed a deal to use the CRISPR/Cas9 gene-editing platform of Seoul, South Korea-based ToolGen to develop products for agriculture. Gene-editing tools can add, delete, or change genes in plants much more quickly than traditional plant breeding and biotechnology methods can, Monsanto says. Monsanto is working to catch up with DuPont Pioneer, the first agricultural company to access CRISPR tools. Early this year Monsanto signed a nonexclusive deal for CRISPR/Cpf1 technology from the Broad Institute of MIT & Harvard.

Florence Wagner

The field of psychiatric drug discovery needs a jump start. Not everyone responds to the available therapies, and those who do often have to deal with unmanageable side effects. Moreover, current drugs are all based on old biology: For example, the last time a truly novel drug for schizophrenia or bipolar disorder made it to market, Florence (Flo) Wagner hadn’t even been born. She thinks it’s time for a reboot. So Wagner is wielding her medicinal chemistry skills to show that drug targets previously deemed too risky can be tackled. At the Stanley Center for Psychiatric Research at the Broad Institute of MIT & Harvard, where she is director of medicinal chemistry, Wagner and her colleagues take innovative approaches to go after some psychiatric targets that have stumped pharma. “Industry wouldn’t have touched a couple of the projects we’ve worked on,” says Edward Scolnick, chief scientist at the Stanley Center

Broad jump-starts CRISPR patent pool

Seeking to simplify the increasingly complex patent landscape for the gene-editing technique CRISPR/Cas9, Broad Institute of MIT & Harvard has applied to place its patents into a new pool that would provide nonexclusive licenses for commercial users. However, so far the University of California, Berkeley, the other big patent owner, has not signaled that it will participate in the pool. Indeed, Broad and UC Berkeley have been engaged in a high-stakes patent fight since late last year. And Berkeley is waiting for a ruling on its CRISPR/Cas9 patent application by the U.S. Patent & Trademark Office. For biotechnology companies seeking to use the gene-editing tool, a patent pool could be a one-stop shop providing access to multiple patents under one license. Instead of granting exclusive rights, the pool would give licenses to all companies and apply the same pricing scheme. But according to Jorge L. Contreras of the University of

2017 ISCB Innovator Award: Aviv Regev.

2017 marks the second year of the International Society for Computational Biology (ISCB) Innovator Award, which recognizes an ISCB scientist who is within two decades of having completed his or her graduate degree and has consistently made outstanding contributions to the field. The 2017 winner is Dr. Aviv Regev, Professor of Biology at the Massachusetts Institute of Technology (MIT), a Core Member and Chair of the Faculty of the Broad Institute of MIT and Harvard, and an HHMI Investigator. Regev will receive her award and deliver a keynote address during International Conference on Intelligent Systems for Molecular Biology/European Conference on Computational Biology (ISMB/ECCB) 2017 in Prague, Czech Republic (July 21 - 25, 2017).

Cell scientist to watch – Mitchell Guttman

ABSTRACT Mitchell received a bachelor's degree in molecular and computational biology and a master's degree in computational biology and bioinformatics from the University of Pennsylvania. He then joined the laboratory of Eric Lander at the Broad Institute of MIT and Harvard and was awarded his PhD in 2012. The same year he was named in the Forbes ‘30 under 30: science and healthcare’ list of rising stars and received an NIH early independence award. Mitchell subsequently moved to the California Institute of Technology as an Assistant Professor to establish his own laboratory. He has received numerous awards, including being named a Robertson Investigator of the New York Stem Cell Foundation, an Investigator at the Heritage Medical Research Institute and a Pew-Stewart scholar for cancer research in 2015. Having identified and characterised a new class of functional large non-coding RNA (lncRNA) genes, his laboratory aims to understand the mechanisms by which lncRNAs act to control cellular functions through regulation of proteins, binding to genomic DNA targets and contributing to nuclear organisation.

Genomic sequencing of treatment-resistant metastatic breast cancer reveals key alterations.

M ultiple genomic and molecular alterations not present in primary tumor samples were discovered through genomic sequencing of estrogen receptor (ER)-positive metastatic breast cancer that had become resistant to therapies. These alterations could help determine the choice of next therapy, clinical trial eligibility, and novel drug targets. The research was presented at the San Antonio Breast Cancer Symposium, which was held December 6–10, 2016. Nikhil Wagle, MD, deputy director of the Joint Center for Cancer Precision Medicine, a collaborative initiative among Dana-Farber Cancer Institute (DFCI), Brigham and Women's Hospital, Boston Children's Hospital, and the Broad Institute of MIT and Harvard; Ofir Cohen, PhD, a postdoctoral researcher at the Broad Institute of MIT and DFCI; and colleagues analyzed treatment-resistant, metastatic samples from 130 patients with breast cancer who were treated at DFCI. They analyzed pretreatment samples of the primary tumors from 34 of these patients. Using massively parallel (also known as “next-generation”) sequencing, the researchers sequenced the whole exome (the genes encoding all of the proteins in the cancer cell) and transcriptome (all the genetic messages in the cell that direct expression of the proteins) of the breast cancer samples. They discovered that the genomic landscape of drug-resistant, ERpositive metastatic breast cancer significantly differs from that of primary ER-positive breast cancer. At the same time, they identified multiple clinically relevant genomic and molecular alterations in the metastatic biopsies, including frequent alterations in the genes ESR1, ERBB2, PIK3CA, PTENT, RB1, and AKT1, among others. In addition, transcriptomic sequencing revealed several likely types of resistance. As more samples from patients have been sequenced, researchers have been able to distinguish between events found both in the primary and metastatic samples and events found only in the metastatic samples. Such results may highlight events that predispose patients to metastasis, lending weight to the belief that the comprehensive characterization of primary tumors may help to predict cancer outcomes. The relevant results from the study have been returned to the clinicians and patients, who are using them to aid in clinical decision making, Dr. Wagle notes. The ultimate plan is to integrate the functional and clinical findings into a “resistance atlas” for patients with ER-positive metastatic breast cancer, which should help with treatment decisions and the development of new combination treatments for the disease, he adds.

Abstract MS2-1: MS2-1 Targeting the ATR checkpoint in cancer therapy

Abstract Rémi Buisson1, Michael S. Lawrence2, Cyril H. Benes1 & Lee Zou1,3 1. Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, MA. 2. Broad Institute of Harvard and MIT, Cambridge, MA. 3. Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA. Recent cancer genomics studies have revealed that the mutation signatures of APOBEC3A/B are commonly detected in several cancer types, such as bladder, breast, head and neck cancers, lung adenocarcinoma, and lung squamous cell carcinoma. APOBEC3A/B are members of the APOBEC family of cytosine deaminases. While APOBEC3 proteins are important for the innate immunity against viral infection, they are not expressed in normal tissues. When APOBEC3A/B are aberrantly expressed in cancer cells, they become potent “mutators”, which may promote genomic instability and contribute to tumor evolution. Interestingly, recent studies have suggested that APOBEC3A/B may act during DNA replication. However, whether the APOBEC3A/B activity in cancer cells induces DNA replication stress, and whether this activity creates a vulnerability in cancer cells that can be exploited therapeutically, remains unknown. In this study, we show that APOBEC3A imposes a unique type of mutator-driven DNA replication stress, and that the ATR kinase plays a crucial role in antagonizing this stress. APOBEC3A expression activates ATR during DNA replication through UNG2-generated abasic sites. Surprisingly, ATR inhibition in APOBEC3A-expressing cells results in a drastic surge of abasic sites at replication forks, revealing an ATR-mediated feedback loop countering the action of APOBEC3A during replication. Mechanistically, ATR inhibition unleashes APOBEC3A-driven ssDNA accumulation at replication forks, which propagates the substrate of APOBEC3A and ultimately drives cells into replication catastrophe. In a panel of cancer cell lines, ATR inhibitor selectively induces replication catastrophe in those harboring high APOBEC3A/B activity, showing that the APOBEC3A/B activity in cancer cells confers susceptibility to ATR inhibition. Together, these results suggest that the unique APOBEC-driven replication stress in cancer cells may offer a new opportunity for ATR-targeted therapy. Citation Format: Zou L. MS2-1 Targeting the ATR checkpoint in cancer therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr MS2-1.

Higher education social media marketing: 12 content types universities post on Facebook

The purpose of this study is to explore and categorise how universities in the USA and Thailand use Facebook as a platform to engage their audiences. Although many higher education institutions (HEIs) currently use social media to communicate, research on how they use the platform is lacking. In this paper, the author studied the Facebook posts of three universities from the USA (Massachusetts Institute of Technology, Harvard, and Stanford) and three universities from Thailand (Mahidol, Chulalongkorn, and Thammasat). A total of 1394 Facebook posts by the six universities in 2014 were analysed using content analysis. This study established 12 post types: research, faculty, curriculum, campus, students, alumni, industry, events, products, image and reputation, announcements, and others. The most common post type by USA universities is research, whereas the most common post types by Thai universities are events and announcements. From the findings, the author suggests that HEIs have to be both proactive and strategic on social media. Furthermore, to publish great content on Facebook, universities have to visualise and tell stories well.

Higher education social media marketing: 12 content types universities post on Facebook

The purpose of this study is to explore and categorise how universities in the USA and Thailand use Facebook as a platform to engage their audiences. Although many higher education institutions (HEIs) currently use social media to communicate, research on how they use the platform is lacking. In this paper, the author studied the Facebook posts of three universities from the USA (Massachusetts Institute of Technology, Harvard, and Stanford) and three universities from Thailand (Mahidol, Chulalongkorn, and Thammasat). A total of 1394 Facebook posts by the six universities in 2014 were analysed using content analysis. This study established 12 post types: research, faculty, curriculum, campus, students, alumni, industry, events, products, image and reputation, announcements, and others. The most common post type by USA universities is research, whereas the most common post types by Thai universities are events and announcements. From the findings, the author suggests that HEIs have to be both proactive and strategic on social media. Furthermore, to publish great content on Facebook, universities have to visualise and tell stories well.