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A Quantitative Tri-fluorescent Yeast Two-hybrid System: From Flow Cytometry to In cellula Affinities

David Cluet
Apr 1, 2020; 19:701-715
Technological Innovation and Resources




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Integrative Metabolic Pathway Analysis Reveals Novel Therapeutic Targets in Osteoarthritis

Beatriz Rocha
Apr 1, 2020; 19:574-588
Research




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Chemical Genetics of AGC-kinases Reveals Shared Targets of Ypk1, Protein Kinase A and Sch9

Michael Plank
Apr 1, 2020; 19:655-671
Research




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Cell Cycle Profiling Reveals Protein Oscillation, Phosphorylation, and Localization Dynamics

Patrick Herr
Apr 1, 2020; 19:608-623
Research




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Proteaphagy in mammalian cells can function independent of ATG5/ATG7

Tatjana Goebel
Apr 16, 2020; 0:RA120.001983v1-mcp.RA120.001983
Research




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Dysregulation of Exosome Cargo by Mutant Tau Expressed in Human-Induced Pluripotent Stem Cell (iPSC) Neurons Revealed by Proteomics Analyses

Sonia Podvin
Apr 15, 2020; 0:RA120.002079v1-mcp.RA120.002079
Research




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Identification of an Unconventional Subpeptidome Bound to the Behcet's Disease-associated HLA-B*51:01 that is Regulated by Endoplasmic Reticulum Aminopeptidase 1 (ERAP1)

Liye Chen
May 1, 2020; 19:871-883
Research




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Human Hepatocyte Nuclear Factor 4-{alpha} Encodes Isoforms with Distinct Transcriptional Functions

Élie Lambert
May 1, 2020; 19:808-827
Research




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Quantitative proteomics of human heart samples collected in vivo reveal the remodeled protein landscape of dilated left atrium without atrial fibrillation

Nora Linscheid
Apr 14, 2020; 0:RA119.001878v1-mcp.RA119.001878
Research




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A cross-linking mass spectrometry approach defines protein interactions in yeast mitochondria

Andreas Linden
Apr 24, 2020; 0:RA120.002028v1-mcp.RA120.002028
Research




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Characterization of signaling pathways associated with pancreatic {beta}-cell adaptive flexibility in compensation of obesity-linked diabetes in db/db mice

Taewook Kang
Apr 7, 2020; 0:RA119.001882v1-mcp.RA119.001882
Research




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Proteome and phosphoproteome analysis of brown adipocytes reveals that RICTOR loss dampens global insulin/AKT signaling

Samuel W Entwisle
Apr 6, 2020; 0:RA120.001946v2-mcp.RA120.001946
Research




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Large-scale Identification of N-linked Intact Glycopeptides in Human Serum using HILIC Enrichment and Spectral Library Search

Qingbo Shu
Apr 1, 2020; 19:672-689
Research




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Selection of features with consistent profiles improves relative protein quantification in mass spectrometry experiments

Tsung-Heng Tsai
Mar 31, 2020; 0:RA119.001792v1-mcp.RA119.001792
Research




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Improving Identification of In-organello Protein-Protein Interactions Using an Affinity-enrichable, Isotopically Coded, and Mass Spectrometry-cleavable Chemical Crosslinker

Karl A. T. Makepeace
Apr 1, 2020; 19:624-639
Research




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A New Type of Learning Community

Setting high standards is expected from all educators. Yet, I think I may have taken this to an extreme in my 2019 spring senior seminar course in algebraic combinatorics. Students walked in to class, got a copy of the syllabus … Continue reading




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Learning During the Pandemic: What we wish our professors and mentors knew

Student Authors: Mayleen Cortez, Brooke Keene-Gomez, Lucy Martinez, Amaury V. Miniño, Jenna Race, Kelemua Tesfaye, and Stephanie. Blog post compiled by Melissa Gutiérrez González, Pamela E. Harris, and Alicia Prieto Langarica. In this blog we center the voices of mathematics students as … Continue reading




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Strengthening Urban Preparedness and Resilience Against Biological Threats in Accra

Invitation Only Research Event

1 March 2019 - 10:30am to 2 March 2019 - 3:00pm

Chatham House, London

Capacity to contain and respond to biological threats varies considerably across the world. Yet such preparedness is vital for prevention, impact-reduction and resilience in the face of biological events, whether they be natural or deliberate outbreaks.

Chatham House is conducting a series of meetings to strengthen urban preparedness for, and resilience against, biological threats in African countries. This meeting will examine the preparedness and prevention mechanisms in Accra, reviewing the comprehensiveness of city-level preparedness.  

This meeting will focus on the formation and implementation of city-level action plans in the context of preparedness for managing biological threats. It will also explore how local authorities are contributing to this effort with their knowledge and expertise.

Attendance at this event is by invitation only.

Nilza Amaral

Project Manager, International Security Programme




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Cybersecurity in the Commonwealth: Building the Foundations of Effective National Responses in the Caribbean

Invitation Only Research Event

8 March 2019 - 9:00am to 5:30pm

Bridgetown, Barbados

Event participants

Joyce Hakmeh, Cyber Research Fellow, International Security Department, Chatham House

This workshop is the second in a series in the 'Implementing the Commonwealth Cybersecurity Agenda' project. The workshop aims to provide a multi-stakeholder pan-Commonwealth platform to discuss how to take the implementation of the 'Commonwealth Cyber Declaration' forward with a focus on the second pillar of the declaration – building the foundations of an effective national cybersecurity response with eight action points. 

As such, the workshop gathers different project implementers under the UK Foreign and Commonwealth Office’s Cyber Programme, in addition to other key relevant stakeholders from the global level, to explore ongoing initiatives which aim to deliver one or more of pillar two’s action points.

The workshop addresses issues from a global perspective and a Commonwealth perspective and will include presentations from selected partners from different Commonwealth countries.

Calum Inverarity

Research Analyst and Coordinator, International Security Department
+44 (0) 207 957 5751




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Transparency and Accountability for Drone Use: European Approaches

Invitation Only Research Event

11 March 2019 - 9:30am to 12 March 2019 - 12:30pm

Chatham House

With increased use of military drones in recent years there have also been many calls for greater transparency and accountability with regards to drone operations.

This would allow for greater public understanding, particularly as the complex nature of military operations today intensifies difficulties in sustaining perceptions of the legitimate use of force.

For example, in Europe, leading states rely on the US for drone platforms and for the infrastructure - such as military communication networks - that enable those operations, while the US also relies on airbases in European states to operate its drone programme.

In addition, with reports that the US is loosening the rules on the use of drones, it is important to understand how European approaches to transparency and accountability may be affected by these developments.

This workshop focuses on how European states can facilitate transparency to ensure accountability for drone use, as well as what the limits might be, considering both the complexity of military operations today and the need for achieving operational goals.

With the US easing restrictions on export controls, the discussion also considers the role of regulation in ensuring accountability and prospects for developing common standards.

Attendance at this event is by invitation only.

Nilza Amaral

Project Manager, International Security Programme




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European Approaches to Remote Warfare

Research Event

15 May 2019 - 9:00am to 6:00pm

Brussels, Belgium

With continuing instability at Europe's borders, along with uncertainty on future US support for NATO, many European countries are increasing their allocations to defence budgets and to collective European strategic defence. In addition, with non-state armed groups creating instability and threatening civilian lives and livelihoods in proximity to the EU’s borders, various operations have been carried out in conflict theatres in the Middle East, North Africa and the Sahel under the auspices of NATO, the UN, the EU or by single EU member states.

Although European military personnel have been deployed in many regions, with countries becoming more reluctant to deploy ‘boots on the ground’, warfare has been increasingly conducted through remote means. This has led to criticism on the limited transparency and accountability mechanisms at work in these operations, while some have questioned the military effectiveness of such tactics or the capacity and willingness of states to ensure that targets are struck accurately and without impact on civilian populations.

Against this background, the EU has started allocating resources to military research and development projects with a focus on unmanned systems and related technologies. Under the auspices of the European Defence Fund such funding is set to increase, while potential bilateral programmes between some states have also been explored. Despite concerns raised by the European Parliament, the development of these policies and technologies has taken place without significant consideration of what the legal, ethical and military-strategic impact of these instruments might be.    

This event will bring together a range of experts, policymakers and civil society organizations to discuss the technology horizon of European defence investments and policy developments around remote warfare. Participants will discuss the implications of the new EU defence fund, legal, ethical, and transparency issues in military research and development and the position of the EU as a global actor. 

This event is being organized in partnership with PAX Netherlands.

THIS EVENT IS NOW FULL AND REGISTRATION HAS CLOSED.

Nilza Amaral

Project Manager, International Security Programme




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How Regulation Could Break the Internet: In Conversation with Andrew Sullivan

Research Event

19 June 2019 - 6:00pm to 7:00pm

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Andrew Sullivan, President and CEO Internet Society
Chair: Emily Taylor, Associate Fellow, International Security Department, Chatham House; Editor, Journal of Cyber Policy

Internet regulation is increasing around the world creating positive obligations on internet providers and exerting negative unintended consequences on the internet infrastructure. In some ways, most of this regulatory activity is justifiable. Governments are concerned about the increased risk that the use of the internet brings to societies. As a response, many governments have been enacting regulations as their main approach to dealing with these concerns. The main challenge is that most of the current regulations are either ill-defined or unworkable.  

On the one hand, several governments have established procedures that seek to analyze the impacts of new regulatory proposals before they were adopted. However, there hasn’t been enough attention aimed at analyzing regulations after they have been adopted and only a few have measures in place to evaluate the impacts of the procedures and practices that govern the regulatory process itself.

On the other hand, much of the regulation creates unintended consequences to the internet itself. It undermines many of its fundamental properties and challenges the integrity and resiliency of its infrastructure.  

This event discusses current practices in internet-related regulation and the related challenges. Panellists will discuss how governments can enforce regulations that achieve their intended purpose while at the same time protecting the internet’s core infrastructure and its properties, including its openness, interoperability and global reach.

Calum Inverarity

Research Analyst and Coordinator, International Security Department
+44 (0) 207 957 5751




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Cyber Insurance for Civil Nuclear Facilities: Risks and Opportunities

8 May 2019

This paper sets out a roadmap for how organizations in the civil nuclear sector can explore their options and review their cyber risk exposure.

Éireann Leverett

Senior Risk Researcher, University of Cambridge

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The control room inside the Paks nuclear power plant in Hungary, 10 April 2017. Photo: Getty Images
  • Civil nuclear facilities and organizations hold sensitive information on security clearances, national security, health and safety, nuclear regulatory issues and international inspection obligations. The sensitivity and variety of such data mean that products tailored for insuring the civil nuclear industry have evolved independently and are likely to continue to do so.
  • ‘Air-gaps’ – measures designed to isolate computer systems from the internet – need to be continually maintained for industrial systems. Yet years of evidence indicate that proper maintenance of such protections is often lacking (mainly because very real economic drivers exist that push users towards keeping infrastructure connected). Indeed, even when air-gaps are maintained, security breaches can still occur.
  • Even if a particular organization has staff that are highly trained, ready and capable of handling a technological accident, hacking attack or incidence of insider sabotage, it still has to do business and/or communicate with other organizations that may not have the essentials of cybersecurity in place.
  • Regardless of whether the choice is made to buy external insurance or put aside revenues in preparation for costly incidents, the approach to cyber risk calculation should be the same. Prevention is one part of the equation, but an organization will also need to consider the resources and contingency measures available to it should prevention strategies fail. Can it balance the likelihood of a hacker’s success against the maximum cost to the organization, and put aside enough capital and manpower to get it through a crisis?
  • All civil nuclear facilities should consider the establishment of computer security incident response (CSIR) teams as a relevant concern, if such arrangements are not already in place. The existence of a CSIR team will be a prerequisite for any facility seeking to obtain civil nuclear cyber insurance.
  • Preventing attacks such as those involving phishing and ransomware requires good cyber hygiene practices throughout the workforce. Reducing an organization’s ‘time to recovery’ takes training and dedication. Practising the necessary tasks in crisis simulations greatly reduces the likelihood of friction and the potential for error in a crisis.




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Create a Global Code of Conduct for Outer Space

12 June 2019

Dr Patricia Lewis

Research Director, Conflict, Science & Transformation; Director, International Security Programme
The rules governing human activity in space have been in place for only a few decades, and yet they are already out of date. They need to be built on and extended to reflect the dramatic and rapid changes in the use of space.

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Nighttime view of the strait of Gibraltar. Photo by NASA.

The 1967 Outer Space Treaty (OST) is the mainframe for space law. It recognizes the importance of the use and scientific exploration of outer space for the benefit and in the interests of all countries. It also prohibits national sovereignty in space, including of the Moon and other celestial bodies.

The OST prohibits all weapons of mass destruction in space – in orbit or on other planets and moons – and does not allow the establishment of military infrastructure, manoeuvres or the testing of any type of weapon on planets or moons. As the treaty makes clear, outer space is for peaceful purposes only. Except of course, it is not – nor has it ever been so.

The very first satellite, Sputnik, was a military satellite which kicked off the Cold War space race between the US and the USSR. The militaries of many countries followed suit, and space is now used for military communication, signals intelligence, imaging, targeting, arms control verification and so on.

However, in keeping with international aspirations, space is also being used for all kinds of peaceful purposes such as environmental monitoring, broadcast communications, delivering the internet, weather prediction, navigation, scientific exploration and – very importantly – monitoring the ‘space weather’ (including the activity from the Sun).

There are several other international agreements on space, such as on the rescue of astronauts, the registration of satellites and liability for damage caused by space objects. There is also the Moon Treaty, which governs activities on the Moon and other moons, asteroids and planets.[i]

More recently, states at the UN Committee on the Peaceful Uses of Outer Space (COPUOS) in Vienna have agreed on guidelines to deal with the worrying situation of space debris which is cluttering up orbits and posing a danger to satellites, the space station and astronauts.

The problem the international community now faces is that the use of space is changing dramatically and rapidly. There are more satellites than ever – well over 1,000 – and more owners of satellites – almost every country uses information generated from space. Increasingly, however, those owners are not countries, militaries or international organizations but the commercial sector. Very soon, the owners will even include individuals.

Small ‘mini-satellites’ or ‘cube-sats’ are poised to be deployed in space. These can act independently or in ‘swarms’, and are so small that they piggy-back on the launching of other satellites and so are very cheap to launch. This is changing the cost–benefit equation of satellite ownership and use. Developing countries are increasingly dependent on space for communications, the internet and information on, for example, weather systems, coastal activities and agriculture. 

Another major development is the advent of asteroid mining. Asteroids contain a wide range of metals and minerals – some asteroids are more promising than others, and some are closer to Earth than others. Several companies have been set up and registered around the world to begin the exploitation of asteroids for precious metals (such as platinum) and compounds (such as rare-earth minerals).

Legally, however, this will be a murky venture. The current international treaty regime prohibits the ownership of a celestial body by a country – space is for all. But does international law prohibit the ownership or exploitation of a celestial body by a private company? The law has yet to be tested, but there are space lawyers who think that companies are exempt. Luxembourg and Australia are two countries that have already begun the registration of interest for space-mining companies.

As humanity becomes more dependent on information that is generated in or transmitted through space, the vulnerability to the manipulation of space data is increasing. The demands on the use of communications frequencies (the issue of spectrum availability and rights), managed by the International Telecommunication Union (ITU),[ii] need to be urgently addressed.

There are now constant cyberattacks in space and on the digital information on which our systems rely. For example, position, navigation and timing information such as from GPS or Galileo is not only vital for getting us safely from A to B, but also for fast-moving financial transactions that require accurate timing signals.

Almost all of our electronic systems depend on those timing signals for synchronization and basic functioning. Cyber hacks, digital spoofing and ‘fake’ information are now a real possibility. There is no rules-based order in place that is fit to deal with these types of attacks.

Cyberweapons are only part of the problem. It is assumed that states, if they haven’t already done so, will be positioning ‘defensive’ space weaponry to protect their satellites. The protection may be intended to be against space debris – nets, grabber bars and harpoons, for example, are all being investigated.

All of these ideas, however, could be used as offensive weapons. Once one satellite operator decides to equip its assets with such devices, many others will follow. The weaponization of space is in the horizon.

There are no international rules or agreements to manage these developments. Attempts in Geneva to address the arms race in space have floundered alongside the inability of the Conference on Disarmament to negotiate any instrument since 1996.

Attempts to develop rules of the road and codes of conduct, or even to begin negotiations to prohibit weapons in space, have failed again and again. There are no agreed rules to govern cyber activity. The Tallinn Manuals[iii] that address how international law is applicable to cyberwarfare also address the laws of armed conflict in space, but data spoofing and cyber hacking in space exist in far murkier legal frameworks.

The current system of international space law – which does not even allow for a regular review and consideration of the OST – is struggling to keep up. Space is the inheritance of humankind, yet the current generation of elders – as they have done with so many other parts of our global environment – have let things go and failed to shepherd in the much-needed system of rules to protect space for future generations.

It is not too late, but it will require international cooperation among the major space players: Russia, the US, China, India and Europe – hardly a promising line-up of collaborators in the current political climate.

Filling the governance gaps

Norms of behaviour and rules of the road need to be established for space before it becomes a 21st-century ‘wild west’ of technology and activity. Issues such as cleaning up space debris, the principle of non-interference, and how close satellites can manoeuvre to each other (proximity rules) need to be agreed as a set of international norms for space behaviour.

A cross-regional group of like-minded countries (for example Algeria, Canada, Chile, France, India, Kazakhstan, Malaysia, Nigeria, Sweden, the UAE and the UK) should link up with UN bodies, including the Office for Outer Space Affairs (UNOOSA), COPUOS and ITU, and key private-sector companies to kick-start a new process for a global code of conduct to establish norms and regulate behaviour in space.

The UN could be the host entity for this new approach – or it could be established in the way the Ottawa process for landmines was established, by a group of like-minded states with collective responsibility for, and collective hosting and funding of, the negotiations.

A new approach should also cover cybersecurity in space. The UN processes on space and cyber should intersect more to find ways to create synergies in their endeavours. And the problems ahead as regards spectrum management – particularly given the large number of small satellites and constellations that are to be launched in the near future – need urgent attention in ITU.

What needs to happen

  • The international rules-based order for space – enshrined in particular in the 1967 Outer Space Treaty – has not kept pace with the rapid and dramatic changes in the use of space. New norms of behaviour and rules of the road are needed.
  • These norms and rules need to address a host of contemporary or prospective developments, including asteroid mining, increased numbers of satellite owners, the emergence of ‘mini-satellites’, cyberwarfare, and the potential deployment of ‘defensive’ space weaponry to protect satellites.
  • A cross-regional group of like-minded countries should link up with UN bodies – including UNOOSA, COPUOS and ITU – and key private-sector companies to kick-start a new process for developing a global code of conduct.
  • Problems related to radio spectrum management – given the large number of small satellites and constellations to be launched in the near future – need urgent attention in ITU.

Notes

[i] All of these treaties and other documents can be found at UN Office for Outer Space Affairs (2002), United Nations Treaties and Principles on Outer Space, http://www.unoosa.org/pdf/publications/STSPACE11E.pdf.

[ii] ITU (undated), ‘ITU Radiocommunication Sector’, https://www.itu.int/en/ITU-R/Pages/default.aspx.

[iii] The NATO Cooperative Cyber Defence Centre of Excellence (CCDCOE), ‘Tallinn Manual 2.0’, https://ccdcoe.org/research/tallinn-manual/.

This essay was produced for the 2019 edition of Chatham House Expert Perspectives – our annual survey of risks and opportunities in global affairs – in which our researchers identify areas where the current sets of rules, institutions and mechanisms for peaceful international cooperation are falling short, and present ideas for reform and modernization.




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Cybersecurity by Design in Civil Nuclear Power Plants

24 July 2019

Cyberattacks are increasingly challenging critical national infrastructure. This paper considers the security by design approach for civil nuclear power plants and analyses areas of risk and opportunities for the nuclear industry.

Dr Beyza Unal

Senior Research Fellow, International Security Programme

Roger Brunt

Managing Director, Grosmont Howe Ltd

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An employee climbs into the cooling tower of the third and fourth unit at Mochovce nuclear power plant in Slovakia on 2 July 2019. Photo: Getty Images

Summary

  • The application of ‘security by design’ in nuclear new builds could provide operators with the opportunity to establish a robust and resilient security architecture at the beginning of a nuclear power plant’s life cycle. This will enhance the protection of the plant and reduce the need for costly security improvements during its operating life.
  • Security by design cannot fully protect a nuclear power plant from rapidly evolving cyberattacks, which expose previously unsuspected or unknown vulnerabilities.
  • Careful design of security systems and architecture can – and should – achieve levels of protection that exceed current norms and expectations. However, the sourcing of components from a global supply chain means that the integrity of even the most skilfully designed security regime cannot be guaranteed without exhaustive checks of its components.
  • Security by design may well include a requirement for a technical support organization to conduct quality assurance of cyber defences and practices, and this regime should be endorsed by a facility’s executive board and continued at regular intervals after the new build facility has been commissioned.
  • Given the years it takes to design, plan and build a new nuclear power plant, it is important to recognize that from the point of ‘design freeze’ onwards, the operator will be building in vulnerabilities, as technology continues to evolve rapidly while construction fails to keep pace with it. Security by design cannot be a panacea, but it is an important factor in the establishment of a robust nuclear security – and cybersecurity – culture.




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Cyber Governance in the Commonwealth: Towards Stability and Responsible State Behaviour in Cyberspace

Invitation Only Research Event

7 October 2019 - 10:30am to 5:30pm

Addis Ababa, Ethiopia

This roundtable is part of a series under the project, 'Implementing the Commonwealth Cybersecurity Agenda', funded by the UK Foreign and Commonwealth Office (FCO). The roundtable aims to provide a multi-stakeholder, pan-Commonwealth platform to discuss how to implement the Commonwealth Cyber Declaration with a focus on its third pillar 'To promote stability in cyberspace through international cooperation'.

In particular, the roundtable focuses on points 3 and 4 of the third pillar which revolve around the commitment to promote frameworks for stability in cyberspace including the applicability of international law, agreed voluntary norms of responsible state behaviour and the development and implementation of confidence-building measures consistent with the 2015 report of the UNGGE. 

The workshop also focuses on the commitment to advance discussions on how existing international law, including the Charter of the United Nations and applicable international humanitarian law, applies in cyberspace.

The roundtable addresses the issue of global cyber governance from a Commonwealth perspective and will also include a discussion around the way forward, the needed capacity of the different Commonwealth countries and the cooperation between its members for better cyber governance.

Participants include UNGGE members from Commonwealth countries in addition to representatives to the UN Open-Ended Working Group from African countries as well as members from academia, civil society and industry.

Calum Inverarity

Research Analyst and Coordinator, International Security Department
+44 (0) 207 957 5751




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Examining Measures to Mitigate Cyber Vulnerabilities of Space-based Strategic Assets

Invitation Only Research Event

30 October 2019 - 9:30am to 4:00pm

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Beyza Unal, Senior Research Fellow, International Security Department, Chatham House
Patricia Lewis, Research Director, International Security Department, Chatham House

Strategic systems that depend on space-based assets, such as command, control and communication, early warning systems, weapons systems and weapons platforms, are essential for conducting successful NATO operations and missions. Given the increasing dependency on such systems, the alliance and key member states would therefore benefit from an in-depth analysis of possible mitigation and resilience measures.

This workshop is part of the International Security Department’s (ISD) project on space security and the vulnerability of strategic assets to cyberattacks, which includes a recently published report. This project aims to create resilience in NATO and key NATO member states, building the capacity of key policymakers and stakeholders to respond with effective policies and procedures. This workshop will focus on measures to mitigate the cyber vulnerabilities of NATO’s space-dependent strategic assets. Moreover, participants will discuss the type of resilience measures and mechanisms required.

Attendance at this event is by invitation only. 

Calum Inverarity

Research Analyst and Coordinator, International Security Department
+44 (0) 207 957 5751




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Smart Peace

With the number of violent conflicts increasing, there is a worldwide need to respond more effectively. Dialogue and mediation are proven to be effective in preventing and resolving conflicts, which are often complex, political and frequently-changing.

But there is more to be done to understand how these approaches can adapt – responding quickly to changing politics and overcoming obstacles that block progress.

Smart Peace is a global initiative led by Conciliation Resources, which combines the varied expertise of different consortium partners to address the challenges of building peace – focusing on the Central African Republic, Nigeria and Myanmar.

This work combines peacebuilding techniques, conflict analysis, rigorous evaluation and behavioural insights. The resulting lessons will help communities, international organisations and governments to implement peace strategies with greater confidence.

This project is funded with UK aid from the UK government.

Smart Peace Partners

Department contact

Nilza Amaral

Project Manager, International Security Programme




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Trump’s Threat to Target Iran’s Cultural Heritage Is Illegal and Wrong

7 January 2020

Héloïse Goodley

Army Chief of General Staff Research Fellow (2018–19), International Security
Targeting cultural property is rightly prohibited under the 1954 Hague Convention.

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Donald Trump at Mar-a-Lago in December. Photo: Getty Images

As tensions escalate in the Middle East, US President Donald Trump has threatened to strike targets in Iran should they seek to retaliate over the killing of Qassem Soleimani. According to the president’s tweet, these sites includes those that are ‘important to Iran and Iranian culture’.

Defense Secretary Mark Esper was quick on Monday to rule out any such action and acknowledged that the US would ‘follow the laws of armed conflict’. But Trump has not since commented further on the matter.

Any move to target Iranian cultural heritage could constitute a breach of the international laws protecting cultural property. Attacks on cultural sites are deemed unlawful under two United Nations conventions; the 1954 Hague Convention for the Protection of Cultural Property during Armed Conflict, and the 1972 UNESCO World Heritage Convention for the Protection of the World Cultural and Natural Heritage.

These have established deliberate attacks on cultural heritage (when not militarily necessary) as a war crime under the Rome Statute of the International Criminal Court in recognition of the irreparable damage that the loss of cultural heritage can have locally, regionally and globally.

These conventions were established in the aftermath of the Second World War, in reaction to the legacy of the massive destruction of cultural property that took place, including the intense bombing of cities, and systematic plunder of artworks across Europe. The conventions recognize that damage to the cultural property of any people means ‘damage to the cultural heritage of all mankind’. The intention of these is to establish a new norm whereby protecting culture and history – that includes cultural and historical property – is as important as safeguarding people.

Such historical sites are important not simply as a matter of buildings and statues, but rather for their symbolic significance in a people’s history and identity. Destroying cultural artefacts is a direct attack on the identity of the population that values them, erasing their memories and historical legacy. Following the heavy bombing of Dresden during the Second World War, one resident summed up the psychological impact of such destruction in observing that ‘you expect people to die, but you don’t expect the buildings to die’.

Targeting sites of cultural significance isn’t just an act of intimidation during conflict. It can also have a lasting effect far beyond the cessation of violence, hampering post-conflict reconciliation and reconstruction, where ruins or the absence of previously significant cultural monuments act as a lasting physical reminder of hostilities.

For example, during the Bosnian War in the 1990s, the Old Bridge in Mostar represented a symbol of centuries of shared cultural heritage and peaceful co-existence between the Serbian and Croat communities. The bridge’s destruction in 1993 at the height of the civil war and the temporary cable bridge which took its place acted as a lasting reminder of the bitter hostilities, prompting its reconstruction a decade later as a mark of the reunification of the ethnically divided town.

More recently, the destruction of cultural property has been a feature of terrorist organizations, such as the Taliban’s demolition of the 1,700-year-old Buddhas of Bamiyan in 2001, eliciting international condemnation. Similarly, in Iraq in 2014 following ISIS’s seizure of the city of Mosul, the terrorist group set about systematically destroying a number of cultural sites, including the Great Mosque of al-Nuri with its leaning minaret, which had stood since 1172. And in Syria, the ancient city of Palmyra was destroyed by ISIS in 2015, who attacked its archaeological sites with bulldozers and explosives.

Such violations go beyond destruction: they include the looting of archaeological sites and trafficking of cultural objects, which are used to finance terrorist activities, which are also prohibited under the 1954 Hague Convention.

As a war crime, the destruction of cultural property has been successfully prosecuted in the International Criminal Court, which sentenced Ahmad Al-Faqi Al-Mahdi to nine years in jail in 2016 for his part in the destruction of the Timbuktu mausoleums in Mali. Mahdi led members of Al-Qaeda in the Islamic Maghreb to destroy mausoleums and monuments of cultural and religious importance in Timbuktu, irreversibly erasing what the chief prosecutor described as ‘the embodiment of Malian history captured in tangible form from an era long gone’.

Targeting cultural property is prohibited under customary international humanitarian law, not only by the Hague Convention. But the Convention sets out detailed regulations for protection of such property, and it has taken some states a lot of time to provide for these.

Although the UK was an original signatory to the 1954 Hague Convention, it did not ratify it until 2017, introducing into law the Cultural Property (Armed Conflicts) Act 2017, and setting up the Cultural Protection Fund to safeguard heritage of international importance threatened by conflict in countries across the Middle East and North Africa.

Ostensibly, the UK’s delay in ratifying the convention lay in concerns over the definition of key terms and adequate criminal sanctions, which were addressed in the Second Protocol in 1999. However, changing social attitudes towards the plunder of antiquities, and an alarming increase in the use of cultural destruction as a weapon of war by extremist groups to eliminate cultures that do not align with their own ideology, eventually compelled the UK to act.

In the US, it is notoriously difficult to get the necessary majority for the approval of any treaty in the Senate; for the Hague Convention, approval was achieved in 2008, following which the US ratified the Convention in 2009.

Destroying the buildings and monuments which form the common heritage of humanity is to wipe out the physical record of who we are. People are people within a place, and they draw meaning about who they are from their surroundings. Religious buildings, historical sites, works of art, monuments and historic artefacts all tell the story of who we are and how we got here. We have a responsibility to protect them.




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Building LGBTIQ+ Inclusivity in the Armed Forces, 20 Years After the Ban Was Lifted

16 January 2020

Will Davies

Army Chief of General Staff Research Fellow, International Security Programme
Change was slow to come but progress has since been swift. Not only can a continuing focus on inclusivity benefit service people and the organization, it is also an essential element of a values-based foreign policy.

2020-01-16-Westminster.jpg

Crew members from HMS Westminster march through Admiralty Arch as they exercise their freedom of the city in August 2019 in London. Photo: Getty Images.

The new UK government will conduct a review of foreign, security and defence policy in 2020. If the UK decides to use values as a framework for foreign policy this needs to be reflected in its armed forces. One area where this is essential is continuing to deepen inclusivity for LGBTIQ+ personnel, building on the progress made since the ban on their service was lifted in 2000.

I witnessed the ban first-hand as a young officer in the British Army in 1998. As the duty officer I visited soldiers being held in the regimental detention cells to check all was well. One day a corporal, who I knew, was there awaiting discharge from the army having been convicted of being gay. On the one hand, here was service law in action, which was officially protecting the army’s operational effectiveness and an authority not to be questioned at my level. On the other, here was an excellent soldier in a state of turmoil and public humiliation. How extreme this seems now.

On 12 January 2000 Tony Blair’s Labour government announced an immediate lifting of the ban for lesbian, gay and bisexual personnel (LGB) and introduced a new code of conduct for personal relationships. (LGB is the term used by the armed forces to describe those personnel who had been banned prior to 2000.) This followed a landmark ruling in a case taken to the European Court of Human Rights in 1999 by four LGB ex-service personnel – supported by Stonewall – who had been dismissed from service for their sexuality.

Up to that point the Ministry of Defence's long-held position had been that LGB personnel had a negative impact on the morale and cohesion of a unit and damaged operational effectiveness. Service personnel were automatically dismissed if it was discovered they were LGB, even though homosexuality had been decriminalized in the UK by 1967.

Proof that the armed forces had been lagging behind the rest of society was confirmed by the positive response to the change among service personnel, despite a handful of vocal political and military leaders who foresaw negative impacts. The noteworthy service of LGBTIQ+ people in Iraq and Afghanistan only served to debunk any residual myths.

Twenty years on, considerable progress has been made and my memories from 1998 now seem alien. This is a story to celebrate – however in the quest for greater inclusivity there is always room for improvement.

Defence Minister Johnny Mercer last week apologized following recent calls from campaign group Liberty for a fuller apology. In December 2019, the Ministry of Defence announced it was putting in place a scheme to return medals stripped from veterans upon their discharge.

The armed forces today have a range of inclusivity measures to improve workplace culture including assessments of workplace climate and diversity networks supported by champions drawn from senior leadership.

But assessing the actual lived experience for LGBTIQ+ people is challenging due to its subjectivity. This has not been helped by low participation in the 2015 initiative to encourage people to declare confidentially their sexual orientation, designed to facilitate more focused and relevant policies. As of 1 October 2019, only 20.3 per cent of regular service people had declared a sexual orientation.

A measure of positive progress is the annual Stonewall Workplace Equality Index, the definitive benchmarking tool for employers to measure their progress on LGBTIQ+ inclusion in the workplace; 2015 marked the first year in which all three services were placed in the top 100 employers in the UK and in 2019 the Royal Navy, British Army and Royal Air Force were placed 15th=, 51st= and 68th respectively.

Nevertheless, LGBTIQ+ service people and those in other protected groups still face challenges. The 2019 Ministry of Defence review of inappropriate behaviour in the armed forces, the Wigston Report, concluded there is an unacceptable level of sexual harassment, bullying and discrimination. It found that 26-36% of LGBTIQ+ service people have experienced negative comments or conduct at work because of their sexual orientation.

The Secretary of State for Defence accepted the report’s 36 recommendations on culture, incident reporting, training and a more effective complaints system. Pivotal to successful implementation will be a coherent strategy driven by fully engaged leaders.

Society is also expecting ever higher standards, particularly in public bodies. The armed forces emphasise their values and standards, including ‘respect for others’, as defining organisational characteristics; individuals are expected to live by them. Only in a genuinely inclusive environment can an individual thrive and operate confidently within a team.

The armed forces also recognize as a priority the need to connect to and reflect society more closely in order to attract and retain talent from across all of society. The armed forces’ active participation in UK Pride is helping to break down barriers in this area.

In a post-Brexit world, the UK’s values, support for human rights and reputation for fairness are distinctive strengths that can have an impact on the world stage and offer a framework for future policy. The armed forces must continue to push and promote greater inclusivity in support. When operating overseas with less liberal regimes, this will be sensitive and require careful handling; however it will be an overt manifestation of a broader policy and a way to communicate strong and consistent values over time.

The armed forces were damagingly behind the times 20 years ago. But good progress has been made since. Inclusion initiatives must continue to be pushed to bring benefits to the individual and the organization as well as demonstrate a values-based foreign policy.




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The Commonwealth Cyber Declaration: Achievements and Way Forward

Invitation Only Research Event

4 February 2020 - 9:15am to 5:30pm

Chatham House, London

In April 2018, the Commonwealth Heads of Government Meeting (CHOGM), held in London, saw the creation and the adoption of the Commonwealth Cyber Declaration. The declaration outlines the framework for a concerted effort to advance cybersecurity practices to promote a safe and prosperous cyberspace for Commonwealth citizens, businesses and societies. 

The conference will aim to provide an overview on the progress made on cybersecurity in the Commonwealth since the declaration was announced in 2018. In addition, it will examine future challenges and potential solutions going forward.

This conference is part of the International Security Programme's project on Implementing the Commonwealth Cybersecurity Agenda and will convene a range of senior Commonwealth representatives as well as a selection of civil society and industry stakeholders. This project aims to develop a pan-Commonwealth platform to take the Commonwealth Cyber Declaration forward by means of a holistic, inclusive and representative approach.

Please see below meeting summaries from previous events on Cybersecurity in the Commonwealth:  

Attendance at this event is by invitation only. 

Esther Naylor

Research Assistant, International Security Programme
+44 (0)20 7314 3628




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The Smart Peace Initiative: An Integrated and Adaptive Approach to Building Peace

Invitation Only Research Event

12 May 2020 - 10:00am to 11:30am
Add to Calendar

Smart Peace brings together global expertise in conflict analysis and research, peacebuilding and mediation programming, and behavioural science and evaluation. Together, Smart Peace partners are developing integrated and adaptive peace initiatives, working with local partners to prevent and resolve complex and intractable conflicts in Central African Republic, Myanmar and northern Nigeria.
 
This roundtable is an opportunity for Smart Peace partners to share the Smart Peace concept, approach and objectives, and experiences of the first phases of programme implementation. Roundtable discussions among participants from policy, practice and research communities will inform future priorities and planning for Smart Peace learning, advocacy and communication.
 
Smart Peace partners include Conciliation Resources, Behavioural Insights Team, The Centre for Humanitarian Dialogue, Chatham House, ETH Zurich, International Crisis Group and The Asia Foundation.

Nilza Amaral

Project Manager, International Security Programme




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Cyber Security and Nuclear Weapons

This project aims to improve resilience in NATO’s nuclear weapons systems against cyber threats.

Cyber security is a vital part of the national and international strategic infrastructure and weapons systems. The increasing cyber capabilities of countries such as China, Russia and North Korea put the North Atlantic Treaty Organization’s (NATO’s) nuclear systems - capabilities that include nuclear command, control and communication, weapons systems and early warning systems - in danger.

There is an urgent need to study and address cyber challenges to nuclear assets within NATO and in key NATO countries. Greater awareness of the potential threats and vulnerabilities is key to improving preparedness and mitigating the risks of a cyber-attack on NATO nuclear weapons systems.

Chatham House produces research responding to the need for information on enhancing cybersecurity for command, control and communications. This project constitutes the beginning of the second phase of the Cyber Security of Nuclear Weapons Systems: Threats, Vulnerabilities and Consequences, a report published in January 2018 in partnership with the Stanley Foundation.

The project responds to the need both for more public information on cyber risks in NATO’s nuclear mission, and to provide policy-driven research to shape and inform nuclear policy within NATO member states and the Nuclear Planning Group.

This project is supported by the Ploughshares Fund and the Stanley Foundation.




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Nuclear Weapons: Innovative Approaches for the Complex International Security Environment

This programme of work addresses the conundrum of nuclear weapons as a wicked problem in a complex adaptive system.

Understanding the complexity and the wickedness of the situation allows analysts and strategic planners to approach these complex and intractable issues in new and transformative ways – with a better chance of coping or succeeding and reducing the divisions between experts.

Using complexity theory, a complex adaptive system representing the international system and its interaction with the environment can be represented through an interactive visualization tool that will aid thought processes and policy decision-making. 

Until recently, analysts did not have the tools to be able to create models that could represent the complexity of the international system and the role that nuclear weapons play. Now that these tools are available, analysts should use them to enable decision-makers to gain insights into the range of possible outcomes from a set of possible actions.

This programme builds on work by Chatham House on cyber security and artificial intelligence (AI) in the nuclear/strategic realms.

In order to approach nuclear weapons as wicked problems in a complex adaptive system from different and sometimes competing perspectives, the programme of work involves the wider community of specialists who do not agree on what constitutes the problems of nuclear weapons nor on what are the desired solutions.

Different theories of deterrence, restraint and disarmament are tested. The initiative is international and inclusive, paying attention to gender, age and other aspects of diversity, and the network of MacArthur Grantees are given the opportunity to participate in the research, including in the writing of research papers, so that the complexity modelling can be tested against a wide range of approaches and hypotheses.

In addition, a Senior Reference Group will work alongside the programme, challenging its outcome and findings, and evaluating and guiding the direction of the research.

This project is supported by the MacArthur Foundation.




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Perspectives on Nuclear Deterrence in the 21st Century

20 April 2020

Nuclear deterrence theory, with its roots in the Cold War era, may not account for all eventualities in the 21st century. Researchers at Chatham House have worked with eight experts to produce this collection of essays examining four contested themes in contemporary policymaking on deterrence.

Dr Beyza Unal

Senior Research Fellow, International Security Programme

Yasmin Afina

Research Assistant, International Security Programme

Dr Patricia Lewis

Research Director, Conflict, Science & Transformation; Director, International Security Programme

Dr John Borrie

Associate Fellow, International Security Programme

Dr Jamie Shea

Associate Fellow, International Security Programme

Peter Watkins

Associate Fellow, International Security Programme

Dr Maria Rost Rublee

Associate Professor of International Relations, Monash University

Cristina Varriale

Research Fellow in Proliferation and Nuclear Policy, RUSI

Dr Tanya Ogilvie-White

Adjunct Senior Fellow, Griffith Asia Institute, Griffith University

Dr Andrew Futter

Associate Professor of International Politics, University of Leicester

Christine Parthemore

Chief Executive Officer, Council on Strategic Risks (CSR)

2020-04-20-NuclearDeterrence.jpeg

Royal Navy Vanguard Class submarine HMS Vigilant returning to HMNB Clyde after extended deployment. The four Vanguard-class submarines form the UK's strategic nuclear deterrent force. Photo: Ministry of Defence.

Summary

  • This collection of essays explores, from the perspectives of eight experts, four areas of deterrence theory and policymaking: the underlying assumptions that shape deterrence practice; the enduring value of extended deterrence; the impact of emerging technologies; and the ‘blurring’ of the lines between conventional and nuclear weapons.
  • Nuclear deterrence theory, with its roots in the Cold War era, may not account for all eventualities in security and defence in the 21st century, given the larger number of nuclear actors in a less binary geopolitical context. It is clear that a number of present factors challenge the overall credibility of ‘classical’ nuclear deterrence, meaning that in-depth analysis is now needed.
  • Uncertainty as to the appetite to maintain the current nuclear weapons policy architecture looms large in discussions and concerns on global and regional security. The demise of the Intermediate-Range Nuclear Forces Treaty, doubts over the potential extension of the New Strategic Arms Reduction Treaty, heightened regional tensions in Northeast and South Asia, together with the current and likely future risks and challenges arising from global technological competition, making it all the more urgent to examine long-held assumptions in the real-world context.
  • Extended deterrence practices differ from region to region, depending on the domestic and regional landscape. Increased focus on diplomatic capabilities to reduce risks and improve the long-term outlook at regional level, including by spearheading new regional arms-control initiatives, may be a viable way forward. Addressing the bigger picture – notably including, on the Korean peninsula, Pyongyang’s own threat perception – and the links between conventional and nuclear missile issues will need to remain prominent if long-term and concrete changes are to take hold.
  • Most states have long held nuclear weapons to be ‘exceptional’: their use would represent a dramatic escalation of a conflict that must never be attained. Latterly, however, some officials and scholars have made the case that the impact of the use of a low-yield nuclear weapon would not be entirely distinct from that of a large-scale conventional attack. This blurring of lines between conventional and nuclear deterrence strips nuclear weapons of their exceptional nature, in a context in which states are faced with diverse, complex and concurrent threats from multiple potential adversaries that are able to synchronize non-military and military options, up to and including nuclear forces. The use of nuclear weapons risks becoming a ‘new normal’, potentially reducing the threshold for use – to cyberattacks, for example. This has direct implications for discussions around strategic stability. 
  • While emerging technologies may offer tremendous opportunities in the modernization of nuclear weapons, they also present major risks and destabilizing challenges. Artificial intelligence, automation, and other developments in the cyber sphere affect dynamics on both the demand and supply sides of the nuclear deterrence equation. States and alliance such as NATO must adapt their deterrence thinking in light of these technological developments, and define their primary purpose and priorities in this shifting security context. Resilience planning, adaptation to the evolving security environment, threat anticipation, and consistent crisis management and incident response – as well as thinking about the mitigation measures necessary to prevent conflict escalation should deterrence fail – will all be critical in upholding nuclear deterrence as both policy and practice.




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Nuclear Tensions Must Not Be Sidelined During Coronavirus

1 May 2020

Ana Alecsandru

Research Assistant, International Security Programme
Although the pandemic means the Nuclear Non-Proliferation Treaty (NPT) Review Conference (RevCon) is postponed, the delay could be an opportunity to better the health of the NPT regime.

2020-05-01-Iran-Peace-Nuclear

Painted stairs in Tehran, Iran symbolizing hope. Photo by Fatemeh Bahrami/Anadolu Agency/Getty Images.

Despite face-to-face diplomatic meetings being increasingly rare during the current disruption, COVID-19 will ultimately force a redefinition of national security and defence spending priorities, and this could provide the possibility of an improved political climate at RevCon when it happens in 2021.

With US presidential elections due in November and a gradual engagement growing between the EU and Iran, there could be a new context for more cooperation between states by 2021. Two key areas of focus over the coming months will be the arms control talks between the United States and Russia, and Iran’s compliance with the 2015 Joint Comprehensive Plan of Action (JCPOA), also known as the Iran Nuclear Deal.

It is too early to discern the medium- and longer-term consequences of COVID-19 for defence ministries, but a greater focus on societal resilience and reinvigorating economic productivity will likely undercut the rationale for expensive nuclear modernization.

Therefore, extending the current New START (Strategic Arms Reduction Treaty) would be the best, most practical option to give both Russia and the United States time to explore more ambitious multilateral arms control measures, while allowing their current focus to remain on the pandemic and economic relief.

Continuing distrust

But with the current treaty — which limits nuclear warheads, missiles, bombers, and launchers — due to expire in February 2021, the continuing distrust between the United States and Russia makes this extension hard to achieve, and a follow-on treaty even less likely.

Prospects for future bilateral negotiations are hindered by President Donald Trump’s vision for a trilateral arms control initiative involving both China and Russia. But China opposes this on the grounds that its nuclear arsenal is far smaller than that of the two others.

While there appears to be agreement that the nuclear arsenals of China, France, and the UK (the NPT nuclear-weapons states) and those of the states outside the treaty (India, Pakistan, North Korea, and Israel) will all have to be taken into account going forward, a practical mechanism for doing so proves elusive.

If Joe Biden wins the US presidency he seems likely to pursue an extension of the New START treaty and could also prevent a withdrawal from the Open Skies treaty, the latest arms control agreement targeted by the Trump administration.

Under a Biden administration, the United States would also probably re-join the JCPOA, provided Tehran returned to strict compliance with the deal. Biden could even use the team that negotiated the Iran deal to advance the goal of denuclearization of the Korean peninsula.

For an NPT regime already confronted by a series of longstanding divergences, it is essential that Iran remains a signatory especially as tensions between Iran and the United States have escalated recently — due to the Qassim Suleimani assassination and the recent claim by Iran’s Revolutionary Guard Corps to have successfully placed the country’s first military satellite into orbit.

This announcement raised red flags among experts about whether Iran is developing intercontinental ballistic missiles due to the dual-use nature of space technology. The satellite launch — deeply troubling for Iran’s neighbours and the EU countries — may strengthen the US argument that it is a cover for the development of ballistic missiles capable of delivering nuclear weapons.

However, as with many other countries, Iran is struggling with a severe coronavirus crisis and will be pouring its scientific expertise and funds into that rather than other efforts — including the nuclear programme.

Those European countries supporting the trading mechanism INSTEX (Instrument in Support of Trade Exchanges) for sending humanitarian goods into Iran could use this crisis to encourage Iran to remain in compliance with the JCPOA and its NPT obligations.

France, Germany and the UK (the E3) have already successfully concluded the first transaction, which was to facilitate the export of medical goods from Europe to Iran. But the recent Iranian escalatory steps will most certainly place a strain on the preservation of this arrangement.

COVID-19 might have delayed Iran’s next breach of the 2015 nuclear agreement but Tehran will inevitably seek to strengthen its hand before any potential negotiations with the United States after the presidential elections.

As frosty US-Iranian relations — exacerbated by the coronavirus pandemic — prevent diplomatic negotiations, this constructive engagement between the E3 and Iran might prove instrumental in reviving the JCPOA and ensuring Iran stays committed to both nuclear non-proliferation and disarmament.

While countries focus their efforts on tackling the coronavirus pandemic, it is understandable resources may be limited for other global challenges, such as the increasing risk of nuclear weapons use across several regions.

But the potential ramifications of the COVID-19 crisis for the NPT regime are profound. Ongoing tensions between the nuclear-armed states must not be ignored while the world’s focus is elsewhere, and the nuclear community should continue to work together to progress nuclear non-proliferation and disarmament, building bridges of cooperation and trust that can long outlast the pandemic.




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Webinar: How is the MENA Region Dealing with the COVID-19 Outbreak?

Research Event

2 April 2020 - 12:30pm to 1:30pm

Event participants

Omar Dewachi, Associate Professor of Medical Anthropology, Department of Anthropology, Rutgers University
Tin Hinane El Kadi, Associate Fellow, MENA Programme, Chatham House
Moderator: Sanam Vakil, Deputy Head & Senior Research Fellow, MENA Programme, Chatham House

At this webinar, part of the Chatham House MENA Programme Online Event Series, experts will explore how the coronavirus pandemic is impacting the economy, state-society relations and healthcare throughout the Middle East and North Africa. How are governments handling this crisis and what measures have they put in place to stop the spread of the virus? Why are some governments withholding information about the number of cases? What has the response from the public been so far? How is this affecting the region and how does it compare to the global picture?

The event will be held on the record.

Reni Zhelyazkova

Programme Coordinator, Middle East and North Africa Programme
+44 (0)20 7314 3624




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Webinar: Reimagining the Role of State and Non-State Actors in (Re)building National Health Systems in the Arab World

Research Event

22 April 2020 - 1:00pm to 2:00pm

Event participants

Fadi El-Jardali, Professor of Health Policy and Systems, American University of Beirut
Moderator: Nadim Houry, Executive Director, Arab Reform Initiative

As new cases of COVID-19 continue to surge, countries around the world struggle to mitigate the public health and economic effects of the virus. It is becoming increasingly clear that an effective pandemic response requires a whole-of-government, whole-of-society approach. In the Arab world, where health systems are already strained by armed conflicts and displaced populations, a whole-of-society response to the pandemic is particularly critical as countries have become increasingly dependent on non-state actors, notably the private sector, for healthcare provision and any response that includes the state alone may not be sufficient to address the pandemic.

In a recent article, Fadi El-Jardali, argued that while the pandemic will have grave health and economic consequences for years to come, it brings with it a valuable opportunity to re-envision the role of state and non-state actors in strengthening health systems. The article addressed the need for increased collaboration between state and non-state actors, and the rethinking of existing cooperation models to provide quality healthcare services for all.  

In this webinar, part of the Chatham House project on the future of the state in the Middle East and North Africa, Dr El-Jardali will discuss how state and non-state actors can collaborate more effectively to address the shortcomings of national health care systems amidst the pandemic and beyond. The article’s author will share insights on the different capacities available in Arab societies that governments can draw upon to ensure that Universal Health Coverage, equity considerations and social justice are at the core of health systems.

You can express your interest in attending by following this link. You will receive a Zoom confirmation email should your registration be successful. Alternatively, you can watch the event live on the MENA Programme Facebook page.

 

Reni Zhelyazkova

Programme Coordinator, Middle East and North Africa Programme
+44 (0)20 7314 3624




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Breaking the Cycle of Violence: Transitional Justice for the Victims of ISIS in Syria

28 April 2020

This paper aims to assist the region’s local authorities, and their key foreign backers, in understanding how transitional justice can provide alternative avenues for holding local ISIS members to account while contributing to the healing of communities.

Haid Haid

Senior Consulting Fellow, Middle East and North Africa Programme

2020-04-28-Syria-prison.jpg

A fighter with the Syrian Democratic Forces monitors prisoners accused of being affiliated with ISIS, at a prison in the northeastern Syrian city of Hassakeh on 25 October 2019. Photo: Getty Images.

Summary

  • Following the territorial defeat of Islamic State of Iraq and Syria (ISIS) in northeastern Syria, the Kurdish-led autonomous administration in the region is now grappling with the task of quickly dealing with thousands of the group’s detained members while bringing justice to their victims. To that end, local authorities are focusing on the use of counterterrorism laws and courts to charge captured ISIS members and determine their guilt accordingly.
  • The piecemeal approach to justice is deeply flawed, and raises particular concerns about due process. No precise instruments exist to determine the personal responsibility of ISIS individuals for specific crimes, or for their role in war crimes committed by the group. In any event, the scale of the crimes and the number of victims – as well as severe shortages of resources and workers – make dispensation of justice extremely difficult through the traditional legal system.
  • Not all detained ISIS members receive prison sentences. Individuals who did not hold senior roles in the group’s apparatus and are not accused of ‘major’ crimes (in practice, largely defined as fighting for ISIS and murder) are being released under limited reconciliation deals with tribal leaders. But the involvement of local community leaders in those efforts is not enough to ensure positive results. Many victims are upset at seeing ISIS members walk free without even admitting their guilt publicly or apologizing for the pain they caused.
  • To overcome the limitations of the current, counterterrorism-focused framework, a ‘transitional justice’ approach could provide judicial and non-judicial instruments to establish accountability for ISIS crimes and reduce community resistance to the reintegration of group members. A combination of non-judicial mechanisms such as truth commissions, missing persons’ committees, and reparations and victim-healing programmes could play a vital role in providing ISIS victims with a sense of justice while contributing to peacebuilding and stability.
  • Ignoring the urgency of developing a long-term plan to serve justice and contribute to community healing will almost certainly allow ISIS to continue to prevent the recovery and development of northeastern Syria. This, in turn, risks undermining the stability of the country and the region at large.




ea

Nuclear Tensions Must Not Be Sidelined During Coronavirus

1 May 2020

Ana Alecsandru

Research Assistant, International Security Programme
Although the pandemic means the Nuclear Non-Proliferation Treaty (NPT) Review Conference (RevCon) is postponed, the delay could be an opportunity to better the health of the NPT regime.

2020-05-01-Iran-Peace-Nuclear

Painted stairs in Tehran, Iran symbolizing hope. Photo by Fatemeh Bahrami/Anadolu Agency/Getty Images.

Despite face-to-face diplomatic meetings being increasingly rare during the current disruption, COVID-19 will ultimately force a redefinition of national security and defence spending priorities, and this could provide the possibility of an improved political climate at RevCon when it happens in 2021.

With US presidential elections due in November and a gradual engagement growing between the EU and Iran, there could be a new context for more cooperation between states by 2021. Two key areas of focus over the coming months will be the arms control talks between the United States and Russia, and Iran’s compliance with the 2015 Joint Comprehensive Plan of Action (JCPOA), also known as the Iran Nuclear Deal.

It is too early to discern the medium- and longer-term consequences of COVID-19 for defence ministries, but a greater focus on societal resilience and reinvigorating economic productivity will likely undercut the rationale for expensive nuclear modernization.

Therefore, extending the current New START (Strategic Arms Reduction Treaty) would be the best, most practical option to give both Russia and the United States time to explore more ambitious multilateral arms control measures, while allowing their current focus to remain on the pandemic and economic relief.

Continuing distrust

But with the current treaty — which limits nuclear warheads, missiles, bombers, and launchers — due to expire in February 2021, the continuing distrust between the United States and Russia makes this extension hard to achieve, and a follow-on treaty even less likely.

Prospects for future bilateral negotiations are hindered by President Donald Trump’s vision for a trilateral arms control initiative involving both China and Russia. But China opposes this on the grounds that its nuclear arsenal is far smaller than that of the two others.

While there appears to be agreement that the nuclear arsenals of China, France, and the UK (the NPT nuclear-weapons states) and those of the states outside the treaty (India, Pakistan, North Korea, and Israel) will all have to be taken into account going forward, a practical mechanism for doing so proves elusive.

If Joe Biden wins the US presidency he seems likely to pursue an extension of the New START treaty and could also prevent a withdrawal from the Open Skies treaty, the latest arms control agreement targeted by the Trump administration.

Under a Biden administration, the United States would also probably re-join the JCPOA, provided Tehran returned to strict compliance with the deal. Biden could even use the team that negotiated the Iran deal to advance the goal of denuclearization of the Korean peninsula.

For an NPT regime already confronted by a series of longstanding divergences, it is essential that Iran remains a signatory especially as tensions between Iran and the United States have escalated recently — due to the Qassim Suleimani assassination and the recent claim by Iran’s Revolutionary Guard Corps to have successfully placed the country’s first military satellite into orbit.

This announcement raised red flags among experts about whether Iran is developing intercontinental ballistic missiles due to the dual-use nature of space technology. The satellite launch — deeply troubling for Iran’s neighbours and the EU countries — may strengthen the US argument that it is a cover for the development of ballistic missiles capable of delivering nuclear weapons.

However, as with many other countries, Iran is struggling with a severe coronavirus crisis and will be pouring its scientific expertise and funds into that rather than other efforts — including the nuclear programme.

Those European countries supporting the trading mechanism INSTEX (Instrument in Support of Trade Exchanges) for sending humanitarian goods into Iran could use this crisis to encourage Iran to remain in compliance with the JCPOA and its NPT obligations.

France, Germany and the UK (the E3) have already successfully concluded the first transaction, which was to facilitate the export of medical goods from Europe to Iran. But the recent Iranian escalatory steps will most certainly place a strain on the preservation of this arrangement.

COVID-19 might have delayed Iran’s next breach of the 2015 nuclear agreement but Tehran will inevitably seek to strengthen its hand before any potential negotiations with the United States after the presidential elections.

As frosty US-Iranian relations — exacerbated by the coronavirus pandemic — prevent diplomatic negotiations, this constructive engagement between the E3 and Iran might prove instrumental in reviving the JCPOA and ensuring Iran stays committed to both nuclear non-proliferation and disarmament.

While countries focus their efforts on tackling the coronavirus pandemic, it is understandable resources may be limited for other global challenges, such as the increasing risk of nuclear weapons use across several regions.

But the potential ramifications of the COVID-19 crisis for the NPT regime are profound. Ongoing tensions between the nuclear-armed states must not be ignored while the world’s focus is elsewhere, and the nuclear community should continue to work together to progress nuclear non-proliferation and disarmament, building bridges of cooperation and trust that can long outlast the pandemic.




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Webinar: Breaking the Cycle of Violence: Transitional Justice for the Victims of ISIS in Syria

Research Event

12 May 2020 - 2:00pm to 3:00pm
Add to Calendar

Haid Haid, Senior Consulting Fellow, Middle East and North Africa Programme, Chatham House
Sara Kayyali, Syria Researcher, Middle East and North Africa Division, Human Rights Watch
Moderator: Lina Khatib, Director, Middle East and North Africa Programme, Chatham House

You can register your interest here. Alternatively, you can watch the webinar live on the MENA Programme Facebook page.

Following the territorial defeat of Islamic State of Iraq and Syria (ISIS) in northeastern Syria, the Kurdish-led autonomous administration in the region is now grappling with the task of quickly dealing with thousands of the group’s detained members while bringing justice to their victims. To that end, local authorities are focusing on the use of counterterrorism laws and courts to charge captured ISIS members and determine their guilt accordingly.

In a recent research paper, author Haid Haid argues that this approach to justice is deeply flawed as it raises concerns about due process and lacks the precise instruments to determine the personal responsibility of ISIS individuals for specific crimes, or for their role in war crimes committed by the group. The paper proposes that a ‘transitional justice’ approach could provide judicial and non-judicial instruments to establish accountability for ISIS crimes and reduce community resistance to the reintegration of group members.

In this webinar, part of the MENA Programme’s Online Event Series, speakers will examine the benefits of such an approach to justice for overcoming the limitations of the current, counterterrorism-focused framework. Panelists will discuss the alternative mechanisms local authorities and their key foreign backers can use to hold local ISIS members to account while contributing to the healing of communities.
 
The event will be held on the record.

Reni Zhelyazkova

Programme Coordinator, Middle East and North Africa Programme
+44 (0)20 7314 3624




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Evidence Against an Important Role of Plasma Insulin and Glucagon Concentrations in the Increase in EGP Caused by SGLT2 Inhibitors

Sodium–glucose cotransport 2 inhibitors (SGLT2i) lower plasma glucose but stimulate endogenous glucose production (EGP). The current study examined the effect of dapagliflozin on EGP while clamping plasma glucose, insulin, and glucagon concentrations at their fasting level. Thirty-eight patients with type 2 diabetes received an 8-h measurement of EGP ([3-3H]-glucose) on three occasions. After a 3-h tracer equilibration, subjects received 1) dapagliflozin 10 mg (n = 26) or placebo (n = 12); 2) repeat EGP measurement with the plasma glucose concentration clamped at the fasting level; and 3) repeat EGP measurement with inhibition of insulin and glucagon secretion with somatostatin infusion and replacement of basal plasma insulin and glucagon concentrations. In study 1, the change in EGP (baseline to last hour of EGP measurement) in subjects receiving dapagliflozin was 22% greater (+0.66 ± 0.11 mg/kg/min, P < 0.05) than in subjects receiving placebo, and it was associated with a significant increase in plasma glucagon and a decrease in the plasma insulin concentration compared with placebo. Under glucose clamp conditions (study 2), the change in plasma insulin and glucagon concentrations was comparable in subjects receiving dapagliflozin and placebo, yet the difference in EGP between dapagliflozin and placebo persisted (+0.71 ± 0.13 mg/kg/min, P < 0.01). Under pancreatic clamp conditions (study 3), dapagliflozin produced an initial large decrease in EGP (8% below placebo), followed by a progressive increase in EGP that was 10.6% greater than placebo during the last hour. Collectively, these results indicate that 1) the changes in plasma insulin and glucagon concentration after SGLT2i administration are secondary to the decrease in plasma glucose concentration, and 2) the dapagliflozin-induced increase in EGP cannot be explained by the increase in plasma glucagon or decrease in plasma insulin or glucose concentrations.




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The National Oncology PET Registry (NOPR): A monumental effort by a few leaders




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3-year freedom from progression following 68GaPSMA PET CT triaged management in men with biochemical recurrence post radical prostatectomy. Results of a prospective multi-center trial.

Background: 68Ga PSMA PET CT (PSMA) is increasingly used in men with biochemical recurrence (BCR) post radical prostatectomy (RP), but its longer term prognostic / predictive potential in these men is unknown. The aim of this study was to evaluate the predictive value of PSMA PET for 3 year freedom from progression (FFP) in men with BCR post RP undergoing salvage radiotherapy (sRT). Methods: This prospective multi-center study enrolled 260 men between 2015 and 2017. Eligible patients were referred for PSMA with rising PSA following RP. Management following PSMA was recorded but not mandated. PSMA protocols were standardised across sites and reported prospectively. Clinical, pathological and surgical information, sRT, timing and duration of androgen deprivation (ADT), 3 year PSA results and clinical events were documented. FFP was defined as a PSA rise ≤ 0.2ng/mL above nadir post sRT, with no additional treatment. Results: The median PSA was 0.26ng/mL (IQR 0.15 - 0.59) and follow-up 38 months (IQR 31-43). PSMA was negative in 34.6% (90/260), confined to prostate fossa 21.5% (56/260), pelvic nodes 26.2% (68/260), and distant disease 17.7% (46/260). 71.5% (186/260) received sRT, 38.2% (71/186) to the fossa only, 49.4% (92/186) fossa + pelvic nodes and 12.4% (23/186) nodes alone/SBRT. PSMA was highly predictive of FFP at 3 years following sRT. Overall, FFP was achieved in 64.5% (120/186) of those who received sRT, 81% (81/100) with negative/fossa confined vs. 45% (39/86) for extra fossa disease (p<0.0001). On logistic regression PSMA was more independently predictive of FFP than established clinical predictors, including PSA, T-stage, surgical margin status or Gleason score (P < 0.002). 32% of men with a negative PSMA PET did not receive treatment. Of these, 66% (19/29) progressed, with a mean rise in PSA of 1.59ng/mL over the 3 years. Conclusion: PSMA PET result is highly predictive of FFP at 3 years in men undergoing sRT for BCR following RP. In particular, men with negative PSMA PET or disease identified as still confined to the prostate fossa demonstrate high FFP, despite receiving less extensive radiotherapy and lower rates of additional ADT than those with extra fossa disease.




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Head-to-head comparison of 68Ga-DOTA-JR11 and 68Ga-DOTATATE PET/CT in patients with metastatic, well-differentiated neuroendocrine tumors: a prospective study

Purpose: 68Ga-DOTA-JR11 is an antagonist for somatostatin receptor used in neuroendocrine imaging. The purpose of this study is to compare 68Ga-DOTA-JR11 and 68Ga-DOTATATE PET/CT in patients with metastatic, well-differentiated neuroendocrine tumors. Methods: Patients with histologically-proven, metastatic and/or unresectable, well-differentiated neuroendocrine tumors were prospectively recruited in this study. They received an intravenous injection of 68Ga-DOTATATE (4.0 ± 1.3 mCi) on the first day and 68Ga-DOTA-JR11 (4.0 ± 1.4 mCi) on the second day. Whole-body PET/CT scans were performed at 40 to 60 minutes after injection on the same scanner. Physiologic uptake of normal organs, lesion numbers, and lesion uptake were compared. Results: Twenty-nine patients were prospectively enrolled in the study. The SUVmax of the spleen, renal cortex, adrenal glands, pituitary glands, stomach wall, normal liver parenchyma, small intestine, pancreas, and bone marrow were significantly lower on 68Ga-DOTA-JR11 than on 68Ga-DOTATATE PET/CT (P<0.001). 68Ga-DOTA-JR11 detected significantly more liver lesions (539 vs. 356, P = 0.002), but fewer bone lesions (156 vs. 374, P = 0.031, Figure 3) than 68Ga-DOTATATE. The tumor-to-background ratio of liver lesions was significantly higher on 68Ga-DOTA-JR11 (7.6 ± 5.1 vs. 3.4 ± 2.0, P<0.001). 68Ga-DOTA-JR11 and 68Ga-DOTATATE PET/CT showed comparable results for primary tumors and lymph node metastases based on either patient-based or lesion-based comparison. Conclusion: 68Ga-DOTA-JR11 performs better in the detection ability and TBR of liver metastases. However, 68Ga-DOTATATE outperforms 68Ga-DOTA-JR11 in the detection of bone metastases. The differential affinity of different metastatic sites provides key information for patient selection in imaging and peptide receptor radionuclide therapy.




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Can fluorescence-guided surgery help identify all lesions in unknown locations or is the integrated use of a roadmap created by preoperative imaging mandatory? A blinded study in prostate cancer patients.

Rationale: Lymphatic tracers can help visualize the lymphatic drainage patterns and sentinel nodes of individual prostate cancer patients. To determine the role of nuclear medicine, in particular the positional guidance of a SPECT/CT-based 3D imaging roadmap, in this process we studied to which extend fluorescence-guidance underestimated the number of target lesions. Methods: SPECT/CT imaging was performed after intraprostatic tracer administration of either ICG-99mTc-nanocolloid (hybrid tracer group) or 99mTc-nanocolloid to create a roadmap that depicted all sentinel nodes (SNs). Patients who received 99mTc-nanocolloid were injected with "free" ICG immediately prior to surgery ("free" ICG group). Before unblinding, fluorescence-guidance was used for intraoperative SN identification. This was followed by extended pelvic lymph node dissection (ePLND). Following unblinding of the SPECT/CT images, the number of missed SN’s were recorded and their resection was pursued when the anatomy allowed. Results: Preoperative SPECT/CT revealed no differences in the SN identification rate between ICG-99mTc-nanocolloid and 99mTc-nanocolloid. However, fluorescence-guidance only allowed intraoperative removal of all SNs in 40% of patients in the hybrid tracer group and in 20% of patients in the "free" ICG group. Overall, 75.9% of the intraoperatively resected SNs in the hybrid tracer group and 51.8% of the SNs in the "free" ICG group were removed solely under fluorescence-guidance. During ePLND 22 additional SNs were resected (7 in the hybrid tracer group and 15 in the "free" ICG group). After unblinding 18 remaining SNs were identified (6 in the hybrid group and 12 in the "free" ICG group). In the "free" ICG group, ex vivo evaluation of the excised specimens revealed that 14 SNs removed under ePLND or after unblinding contained radioactivity but no fluorescence. Conclusion: The preoperative imaging roadmap provided by SPECT/CT enhanced the detection of prostate SNs in more ectopic locations in 17 of the 25 patients and the hybrid tracer ICG-99mTc-nanocolloid was shown to outperform "free" ICG. Overall, fluorescence-guided pelvic nodal surgery underestimated the number of SNs in 60-80% of patients.




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Tau PET imaging with 18F-PI-2620 in patients with Alzheimer's disease and healthy controls: a first-in-human study

18F-PI-2620 is a positron emission tomography (PET) tracer with high binding affinity for aggregated tau, a key pathologic feature of Alzheimer’s disease (AD) and other neurodegenerative disorders. Preclinically, 18F-PI-2620 binds to both, 3R and 4R tau isoforms. The purpose of this first-in-human study was to evaluate the ability of 18F-PI-2620 to detect tau pathology in AD patients using PET imaging, as well as to assess its safety and tolerability of this new tau PET tracer. Methods: Participants with clinical diagnosis of probable AD and healthy controls (HC) underwent dynamic 18F-PI-2620 PET imaging for 180 min. 18F-PI-2620 binding was assessed visually and quantitatively using Distribution Volume Ratios (DVR) estimated from non-invasive tracer kinetics and standardized uptake value ratios (SUVR) measured at different time points post-injection (p.i.) with the cerebellar cortex as the reference region. Time-activity curves and SUVR were assessed in AD and HC, as well as DVR and SUVR correlations and effect size (Cohen’s d) over time. Results: 18F-PI-2620 showed peak brain uptake around 5 min p.i. and fast wash-out in non-target regions. In AD subjects, focal asymmetric uptake was evident in temporal and parietal lobes, precuneus, and posterior cingulate cortex. DVR and SUVR in these regions were significantly higher in AD compared to HC. Very low background signal was observed in HC. 18F-PI-2620 administration was safe and well tolerated. SUVR time activity curves in most regions and subjects achieved a secular equilibrium after 40 min p.i.. A strong correlation (R2 > 0.93) was found between non-invasive DVR and SUVR for all imaging windows starting >30 min p.i.. Similar effect sizes between AD and HC groups were obtained across the different imaging windows. 18F-PI-2620 uptake in neocortical regions was significantly correlated with the degree of cognitive impairment. Conclusion: Initial clinical data obtained in AD and HC demonstrate the high image quality with excellent signal-to-noise of 18F-PI-2620 PET for imaging tau deposition in AD subjects. Non-invasive quantification using DVR and SUVR for 30 min imaging windows between 30-90 min p.i., e.g. 45-75 min, provides robust and significant discrimination between AD and HC subjects. 18F-PI-2620 uptake in expected regions is highly correlated to neurocognitive performance.




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Combined Visual and Semi-quantitative Evaluation Improves Outcome Prediction by Early Mid-treatment 18F-fluoro-deoxi-glucose Positron Emission Tomography in Diffuse Large B-cell Lymphoma.

The purpose of this study was to assess the predictive and prognostic value of interim FDG PET (iPET) in evaluating early response to immuno-chemotherapy after two cycles (PET-2) in diffuse large B-cell lymphoma (DLBCL) by applying two different methods of interpretation: the Deauville visual five-point scale (5-PS) and a change in standardised uptake value by semi-quantitative evaluation. Methods: 145 patients with newly diagnosed DLBCL underwent pre-treatment PET (PET-0) and PET-2 assessment. PET-2 was classified according to both the visual 5-PS and percentage SUV changes (SUV). Receiver operating characteristic (ROC) analysis was performed to compare the accuracy of the two methods for predicting progression-free survival (PFS). Survival estimates, based on each method separately and combined, were calculated for iPET-positive (iPET+) and iPET-negative (iPET–) groups and compared. Results: Both with visual and SUV-based evaluations significant differences were found between the PFS of iPET– and iPET+ patient groups (p<0.001). Visually the best negative (NPV) and positive predictive value (PPV) occurred when iPET was defined as positive if Deauville score 4-5 (89% and 59%, respectively). Using the 66% SUV cut-off value, reported previously, NPV and PPV were 80 and 76%, respectively. SUV at 48.9% cut-off point, reported for the first time here, produced 100% specificity along with the highest sensitivity (24%). Visual and semi-quantitative SUV<48.9% assessment of each PET-2 gave the same PET-2 classification (positive or negative) in 70% (102/145) of all patients. This combined classification delivered NPV and PPV of 89% and 100% respectively, and all iPET+ patients failed to achieve or remain in remission. Conclusion: In this large consistently treated and assessed series of DLBCL, iPET had good prognostic value interpreted either visually or semi-quantitatively. We determined that the most effective SUV cut-off was at 48.9%, and that when combined with visual 5-PS assessment, a positive PET-2 was highly predictive of treatment failure.




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Initial studies with [11C]vorozole positron emission tomography detect over-expression of intra-tumoral aromatase in breast cancer

Introduction: Aromatase inhibitors are the mainstay of hormonal therapy in estrogen receptor positive, postmenopausal breast cancer, although response rate is just over 50%. The goal of the present study was to validate and optimize positron emission tomography (PET) with 11C-vorozole for measuring aromatase expression in postmenopausal breast cancer. Methods: Ten newly diagnosed, postmenopausal women with biopsy confirmed breast cancer were administered 11C-vorozole intravenously and PET emission data collected between 40 – 90 minutes post-injection. Tracer injection and scanning were repeated 2 hours after ingestion of 2.5mg letrozole p.o. Mean and maximal standard uptake values and ratios to non-tumor tissue (SUVs, SUVRs) were calculated for tumor and non-tumor regions at baseline and after letrozole. Biopsy specimens from the same tumors were stained for aromatase using immunohistochemistry and evaluated for stain intensity and the percentage of immune-positive cells. Results: Seven of the 10 women (70%) demonstrated increased focal uptake of tracer (SUVR>1.1) coinciding with the mammographic location of the lesion. The other 3 women (30%) did not show increased uptake in the tumor (SUVR <1.0). All of the cases with SUVR above 1.1 had SUVs above 2.4 and there was no overlap in SUV between the two groups, with mean SUV in tumors overexpressing aromatase (SUVR>1.1) ranging from 2.47 to 13.6, while tumors not overexpressing aromatase (SUVR<1) ranged from 0.8 to 1.8. Pretreatment with letrozole reduced tracer uptake in the majority of subjects; although the %blocking varied across and within tumors. Tumors with high SUV in vivo also showed high staining intensity on IHC. Conclusion: PET with 11C-vorozole is a useful technique for measuring aromatase expression in individual breast lesions, enabling a non-invasive quantitative measurement of baseline and post-treatment aromatase availability in primary tumors and metastatic lesions.




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SUV25 and {micro}PERCIST: Precision Imaging of Response to Therapy in Co-Clinical FDG-PET Imaging of Triple Negative Breast Cancer (TNBC) Patient-Derived Tumor Xenografts (PDX)

Numerous recent works highlight the limited utility of established tumor cell lines in recapitulating the heterogeneity of tumors in patients. More realistic preclinical cancer models are thought to be provided by transplantable, patient-derived tumor xenografts (PDX). Inter- and intra-tumor heterogeneity of PDX, however, present several challenges in developing optimal quantitative pipelines to assess response to therapy. The objective of this work was to develop and optimize image metrics of FDG-PET to assess response to combination docetaxel/carboplatin therapy in a co-clinical trial involving triple negative breast cancer (TNBC) PDX. We characterize the reproducibility of SUV metrics to assess response to therapy and optimize a preclinical PERCIST (µPERCIST) paradigm to complement clinical standards. Considerations in this effort included variability in tumor growth rate and tumor size; solid tumor vs. tumor heterogeneity and necrotic phenotype; and optimal selection of tumor slice versus whole tumor. A test-retest protocol was implemented to optimize the reproducibility of FDG-PET SUV thresholds, SUVpeak metrics, and µPERCIST parameters. In assessing response to therapy, FDG-PET imaging was performed at baseline and +4 days following therapy. The reproducibility, accuracy, variability, and performance of imaging metrics to assess response to therapy were determined. We defined an index—"Quantitative Response Assessment Score (QRAS)"—to integrate parameters of prediction and precision, and thus aid in selecting optimal image metrics of response to therapy. Our data suggests that a threshold value of 25% (SUV25) of SUVmax was highly reproducible (<9% variability). Concordance and reproducibility of µPERCIST were maximized at α=0.7 and β=2.8 and exhibited high correlation to SUV25 measures of tumor uptake. QRAS scores favor SUV25 followed by SUVP14 as optimal metrics of response to therapy. Additional studies are warranted to fully characterize the utility of SUV25 and µPERCIST SUVP14 as image metrics of response to therapy across a wide range of therapeutic regiments and PDX models.