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Targeting the polyamine pathway—“a means” to overcome chemoresistance in triple-negative breast cancer [Cell Biology]

Triple-negative breast cancer (TNBC) is characterized by its aggressive biology, early metastatic spread, and poor survival outcomes. TNBC lacks expression of the targetable receptors found in other breast cancer subtypes, mandating use of cytotoxic chemotherapy. However, resistance to chemotherapy is a significant problem, encountered in about two-thirds of TNBC patients, and new strategies are needed to mitigate resistance. In this issue of the Journal of Biological Chemistry, Geck et al. report that TNBC cells are highly sensitive to inhibition of the de novo polyamine synthesis pathway and that inhibition of this pathway sensitizes cells to TNBC-relevant chemotherapy, uncovering new opportunities for addressing chemoresistance.




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Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy [Molecular Bases of Disease]

Treatment of patients with triple-negative breast cancer (TNBC) is limited by a lack of effective molecular therapies targeting this disease. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care chemotherapy regimens. Using MDA-MB-468 and SUM-159PT TNBC cells, along with LC-MS/MS and HPLC metabolomics profiling, we found here that exposure of TNBC cells to the cytotoxic chemotherapy drugs cisplatin and doxorubicin alter arginine and polyamine metabolites. This alteration was because of a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). Using gene silencing and inhibitor treatments, we determined that the reduction in ODC was mediated by its negative regulator antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor difluoromethylornithine (DFMO) sensitized TNBC cells to chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines had greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. The alterations in polyamine metabolism in response to chemotherapy, as well as DFMO-induced preferential sensitization of TNBC cells to chemotherapy, reported here suggest that ODC may be a targetable metabolic vulnerability in TNBC.




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South-east Queensland poised to be digital leader: Cisco

30,000 new jobs, $10 billion economy boost could be heading for SEQ.




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'Public servants should get off social media': warning after Islamic State hack

Terrorists and criminals are looking for people to blackmail or seduce into stealing data.




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Australian Federal Police walk away from $145 million Israeli crime-fighting software deal

Police walk away from deal with contractor, conceding numerous issues have put project beyond rescue.




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Human Services' computers keep disabled out of work

Disabled workers are caught in bureaucratic limbo by problematic computer systems.




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Malcolm Turnbull visits Sunshine Coast to view proposal for new undersea communications cable

A plan to make the Sunshine Coast a vital internet gateway is luring Communications Minister Malcolm Turnbull to the area on Friday to view the proposal in person.




is

Public servants warned off internet sex and cheating sites after Ashley Madison hack

Marriage vows are one thing, but the public service Code of Conduct, that's serious.




is

What Uber tells us about disruption

Uber's digital component is only part of it's success and there are other important lessons for any business.




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Cyber security expert issues dire warning over vulnerability of key infrastructure

Data theft and cybercrime is a major source of funding for Islamic State which is likely to have secretly planted insiders "around the world" in positions where critical data could be extracted and exploited, a leading cyber security expert has warned.




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From AFL star to Big Apple start-up, Swift's Joel MacDonald is kicking goals

Two years ago Joel MacDonald was in Melbourne playing in the AFL; now he's kicking goals in New York.




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Australia vulnerable to a cyber-attack disaster

Australian government agencies and organisations are increasingly vulnerable to a major cyber attack yet security has not evolved in more than 20 years, according to an international cybercrime expert.




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Anonymous group hacks Islamic State, tells them to chill out: reports

Terrorists' propaganda appears to be shifting to the Dark Web so that it will be harder to shut down.




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Centrelink apologises for web welfare shutdown

Centrelink clients around Australia are furious over missing payments.




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Centrelink's IT meltdown hits the disability pension

Centrelink's tech woes disrupts Disability Pension medical crackdown.




is

Ricochet uses power of the dark web to help journalists, sources dodge metadata laws

A new internet messaging tool that sidesteps the federal government's metadata collection regime to help journalists protect whistle blowers and assists human rights activists has received a tick of approval from security experts.




is

Why Hollywood animation powerhouses are resisting the cloud

Despite new performance bottlenecks, the digital animation and visual effects industry is very reluctant to move their productions to the cloud, according to Sydney's Animal Logic.




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Apple v FBI: what the fight is about and why you should care

Apple is in the middle of a legal fight with the FBI over creating a 'back door' to unlock a terrorist's iPhone.




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Recruitment drive for cyber security specialists will bring challenges for government

Fear government's cyber security recruitment drive will lead to job cuts.




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Malcolm Turnbull promises $50 million reboot for troubled myGov

Takeover of troubled portal by Digital Transformation Office confirmed




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Government agencies name cybercrime as their top fraud risk: PwC

The 'typical' corrupt bureaucrat is a male, university-educated middle manager, aged 41 to 50.




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Centrelink apologises for new privacy breach

Rookie email error shares hundred of email addresses – twice.




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Is the Australian government agile and innovative? Not to those in the start-ups world

Public service departments "too nervous" to innovate, say start-ups.




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Brisbane City Council IT contract faces potential $60 million blow-out

A $122 million Brisbane City Council IT contract will be renegotiated after a systems replacement program was delayed by 18 months, with a potential cost blow-out of up to $60 million.




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Centrelink debt debacle shows government is unprepared for digital revolution

The public service needs to embrace partnerships if it's to harvest big data's massive yields.




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ACT scientist teaches computers to police the border

A Canberra-based scientist is teaching computers to pick up suspicious activity at the border.




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Medicare details available on dark web is just tip of data breach iceberg

The next wave of government reform will have to focus on data management.




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Brisbane City Council terminates $122 million IT contract

Brisbane CIty Council has terminated a $122 million IT contract that had been plagued with cost blow outs and lengthy delays.




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Robot to greet visitors to Queensland government office

Visitors to two Queensland government offices in 1 William Street will be greeted by a robot, as part of a new trial.




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Cyber security threat: Is Australia's power grid safe from hackers?

Cyber attacks have labelled the number one threat to power and utility companies worldwide, a new EY report has found.




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ACT human rights commission 'concerned' about new app for ACT police

Canberrans' privacy rights could be threatened by the new app.




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Privacy Commissioner’s small budget to make policing new data breach laws difficult, experts say

New laws that mandate companies notify individuals about data breaches add to Privacy Commissioner's already-stacked caseload, but do not come with new funding.




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The New Macroeconomics of Populism

17 June 2019

David Lubin

Associate Fellow, Global Economy and Finance Programme
The nationalist urge to keep the world off your back extends to foreign finance.

2019-06-17-AMLO.jpg

Mexican president Andrés Manuel López Obrador throws out the first pitch at a baseball game in March. Photo: Getty Images.

It is nearly 30 years since Rudiger Dornbusch and Sebastian Edwards published a seminal book, The Macroeconomics of Populism. Their conclusion back then was that the economic policies of populist leaders were quintessentially irresponsible. These governments, blinded by an aim to address perceived social injustices, specialised in profligacy, unbothered by budget constraints or whether they might run out of foreign exchange.

Because of this disregard for basic economic logic, their policy experiments inevitably ended badly, with some combination of inflation, capital flight, recession and default. Salvador Allende’s Chile in the 1970s, or Alan García’s Peru in the 1980s, capture this story perfectly.

These days, the macroeconomics of populism looks different. Of course there are populist leaders out there whose policies follow, more or less, the playbook of the 1970s and 1980s. Donald Trump may prove to be one of those, with a late-cycle fiscal expansion that seemed to have no basis in economic reasoning; Recep Tayyip Erdogan, by some accounts, may be another.

But a much more interesting phenomenon is the apparent surge in populist leaders whose economic policies are remarkably disciplined.

Take Mexico’s president, Andrés Manuel López Obrador. When it comes to fiscal policy, it is odd indeed that this fiery critic of neoliberalism seems fully committed to austerity. His budget for 2019 targets a surplus before interest payments of 1 per cent of GDP, and on current plans he intends to increase that surplus next year to 1.3 per cent of GDP. He has upheld the autonomy of the central bank and, so far at least, his overall macroeconomic framework is anything but revolutionary.

Hungary’s prime minister Viktor Orban offers another example of conservative populism. Under his watch, budget deficits have been considerably lower than they had been previously, helping to push the stock of public debt down from 74 per cent of GDP in 2010, the year Orban took over, to 68 per cent last year.

This emphasis on the virtues of fiscal prudence is also visible in Poland, where Jaroslaw Kaczynski’s PiS has managed public finances with sufficient discipline in the past few years to push the debt/GDP ratio below 50 per cent last year, the first time this has happened since 2009.

The obvious question is: what has changed in the decades since Dornbusch and Edwards went into print?

One answer is that today’s populists tend to strive for national self-reliance, which encourages them to avoid building up any dependence on foreign capital. And since that goal is achieved by keeping a tight rein on macro policy, fiscal indiscipline is avoided in order to limit vulnerability to foreign influences.

Perhaps this is because the 'them', or the perceived enemy, for many of today’s populists tends to be outside the country rather than inside. Broadly speaking, it is the forces of globalisation — and global capital in particular — that are the problem for these leaders, and self-reliance is the only way to keep those forces at arm’s length. This helps to explain why, for example, Orban has been so keen to repay debt to Hungary’s external creditors. He has relied instead on selling bonds to Hungarian households to finance his deficits, even though the interest rates on those bonds are much higher than he would pay to foreign creditors. It also helps explain why the PiS in Poland has presided over a decline in foreign holdings of its domestic bonds. Foreign investors owned 40 per cent of Poland’s domestic government debt back in 2015, but only 26 per cent now.

In other words, among many of today’s populists there is a blurring of the distinction between populism and nationalism. And the nationalistic urge to keep the rest of the world off your back seems to dominate the populist urge to spend money. The perfect example of that instinct is Vladimir Putin: not necessarily a populist, but his administration has been emphatic about the need to keep public spending low and to build solid financial buffers. National self-reliance is an economic obsession for the Russian government, and provides a model for other countries who wish to insulate themselves from international finance.

One of the reasons why the macroeconomics of populism have changed in this way is the historical legacy of economic disaster. If you are a populist leader in a country where financial crisis is part of living memory — as it is in Mexico, Hungary and Russia, say — you might do well to err on the side of conservatism for fear of repeating the mistakes of your predecessors.

But another reason why populism looks different for countries like Poland, Hungary, Mexico and Russia has to do with mere luck. Hungary and Poland, in particular, enjoy the luck of geography: having been absorbed into the EU, they have received financial transfers from Brussels averaging some 3-4 per cent of GDP in the past few years, so that populism in these countries has been solidly underpinned by the terms of their EU membership. López Obrador is enjoying the inheritance of his predecessor’s sound macro policy, together with a buoyant US economy and low US interest rates. Russia has had the good fortune of oil exports to rely on.

The thing about luck is that it can run out. So maybe it’s not quite time yet to bury the old macroeconomics of populism. But for the time being, it seems true to say that many of today’s populists have an unexpectedly robust sense of economic discipline.

This article was originally published in the Financial Times.




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Financial Markets: Lessons Learned Since the Financial Crisis and What the Future Holds

Invitation Only Research Event

2 September 2019 - 5:15pm to 6:30pm

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

Event participants

Professor Robert Shiller, Sterling Professor of Economics, Yale University
Chair: Marianne Schneider-Petsinger, Research Fellow, US and the Americas Programme Chatham House

The 2007-08 financial crisis wreaked havoc on the lives of millions of people across the globe, and upended the faith of many in the prevailing economic system, with many countries still recovering a decade on.

Drawing on extensive research in his new book, Narrative Economics: How Stories Go Viral and Drive Major Economic Events, Professor Shiller will draw on a rich array of historical examples and data and outline a new way to think about economic change, and the narratives that shape it, to provide answers to questions such as whether lessons have been learned since the last financial crisis, are the same dislocations likely to occur again and what toolkits, if any, are there for anticipating the next financial crisis or recession?

Attendance at this event is by invitation only.

Event attributes

Chatham House Rule

Department/project

US and Americas Programme




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Brexit identities and British public opinion on China

6 November 2019 , Volume 95, Number 6

Wilfred M. Chow, Enze Han and Xiaojun Li

Many studies have explored the importance of public opinion in British foreign policy decision-making, especially when it comes to the UK's relations with the United States and the European Union. Despite its importance, there is a dearth of research on public opinion about British foreign policy towards other major players in the international system, such as emerging powers like China. We have addressed this knowledge gap by conducting a public opinion survey in the UK after the Brexit referendum. Our research findings indicate that the British public at large finds China's rise disconcerting, but is also pragmatic in its understanding of how the ensuing bilateral relations should be managed. More importantly, our results show that views on China are clearly split between the two opposing Brexit identities. Those who subscribe strongly to the Leave identity, measured by their aversion to the EU and antipathy towards immigration, are also more likely to hold negative perceptions of Chinese global leadership and be more suspicious of China as a military threat. In contrast, those who espouse a Remain identity—that is, believe that Britain would be better served within the EU and with more immigrants—are more likely to prefer closer engagement with China and to have a more positive outlook overall on China's place within the global community.




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The great Chinese surprise: the rupture with the United States is real and is happening

4 March 2020 , Volume 96, Number 2

Xiangfeng Yang

Ample evidence exists that China was caught off guard by the Trump administration's onslaught of punishing acts—the trade war being a prime, but far from the only, example. This article, in addition to contextualizing their earlier optimism about the relations with the United States under President Trump, examines why Chinese leaders and analysts were surprised by the turn of events. It argues that three main factors contributed to the lapse of judgment. First, Chinese officials and analysts grossly misunderstood Donald Trump the individual. By overemphasizing his pragmatism while downplaying his unpredictability, they ended up underprepared for the policies he unleashed. Second, some ingrained Chinese beliefs, manifested in the analogies of the pendulum swing and the ‘bickering couple’, as well as the narrative of the ‘ballast’, lulled officials and scholars into undue optimism about the stability of the broader relationship. Third, analytical and methodological problems as well as political considerations prevented them from fully grasping the strategic shift against China in the US.




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Chinese Overseas Direct Investment and the Economic Crisis: Reaching Out

1 January 2009 , Number 5

Decisions taken today will determine the course of events for a generation. Nowhere is this truer than over the question of China’s investment abroad. This issue lies at the heart of what part the country will play in the global finance and trade system, and how it will work with the rest of the world in laying the foundations for longer term growth and stability after the current crisis is over.

Professor Kerry Brown

Associate Fellow, Asia-Pacific Programme

Peter Wood

Independent China strategist based in Hong Kong

HaierFlickr.jpg

Chinese companies establish a presence abroad.




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Blaming China Is a Dangerous Distraction

15 April 2020

Jim O'Neill

Chair, Chatham House
Chinese officials' initial effort to cover up the coronavirus outbreak was appallingly misguided. But anyone still focusing on China's failings instead of working toward a solution is essentially making the same mistake.

2020-04-15-China-coronavirus-health

Medical staff on their rounds at a quarantine zone in Wuhan, China. Photo by STR/AFP via Getty Images.

As the COVID-19 crisis roars on, so have debates about China’s role in it. Based on what is known, it is clear that some Chinese officials made a major error in late December and early January, when they tried to prevent disclosures of the coronavirus outbreak in Wuhan, even silencing healthcare workers who tried to sound the alarm.

China’s leaders will have to live with these mistakes, even if they succeed in resolving the crisis and adopting adequate measures to prevent a future outbreak. What is less clear is why other countries think it is in their interest to keep referring to China’s initial errors, rather than working toward solutions.

For many governments, naming and shaming China appears to be a ploy to divert attention from their own lack of preparedness. Equally concerning is the growing criticism of the World Health Organization (WHO), not least by Donald Trump who has attacked the organization - and threatens to withdraw US funding - for supposedly failing to hold the Chinese government to account.

Unhelpful and dangerous

At a time when the top global priority should be to organize a comprehensive coordinated response to the dual health and economic crises unleashed by the coronavirus, this blame game is not just unhelpful but dangerous.

Globally and at the country level, we all desperately need to do everything possible to accelerate the development of a safe and effective vaccine, while in the meantime stepping up collective efforts to deploy the diagnostic and therapeutic tools necessary to keep the health crisis under control.

Given there is no other global health organization with the capacity to confront the pandemic, the WHO will remain at the center of the response, whether certain political leaders like it or not.

Having dealt with the WHO to a modest degree during my time as chairman of the UK’s independent Review on Antimicrobial Resistance (AMR), I can say that it is similar to most large, bureaucratic international organizations.

Like the International Monetary Fund (IMF), the World Bank, and the United Nations, it is not especially dynamic or inclined to think outside the box. But rather than sniping at these organizations from the sidelines, we should be working to improve them.

In the current crisis, we all should be doing everything we can to help both the WHO and the IMF to play an effective, leading role in the global response. As I have argued before, the IMF should expand the scope of its annual Article IV assessments to include national public-health systems, given that these are critical determinants in a country’s ability to prevent or at least manage a crisis like the one we are now experiencing.

I have even raised this idea with IMF officials themselves, only to be told that such reporting falls outside their remit because they lack the relevant expertise. That answer was not good enough then, and it definitely isn’t good enough now.

If the IMF lacks the expertise to assess public health systems, it should acquire it. As the COVID-19 crisis makes abundantly clear, there is no useful distinction to be made between health and finance. The two policy domains are deeply interconnected, and should be treated as such.

In thinking about an international response to today’s health and economic emergency, the obvious analogy is the 2008 global financial crisis which started with an unsustainable US housing bubble, fed by foreign savings owing to the lack of domestic savings in the United States.

When the bubble finally burst, many other countries sustained more harm than the US did, just as the COVID-19 pandemic has hit some countries much harder than it hit China.

And yet not many countries around the world sought to single out the US for presiding over a massively destructive housing bubble, even though the scars from that previous crisis are still visible. On the contrary, many welcomed the US economy’s return to sustained growth in recent years, because a strong US economy benefits the rest of the world.

So, rather than applying a double standard and fixating on China’s undoubtedly large errors, we would do better to consider what China can teach us. Specifically, we should be focused on better understanding the technologies and diagnostic techniques that China used to keep its - apparent - death toll so low compared to other countries, and to restart parts of its economy within weeks of the height of the outbreak.

And for our own sakes, we also should be considering what policies China could adopt to put itself back on a path toward 6% annual growth, because the Chinese economy inevitably will play a significant role in the global recovery.

If China’s post-pandemic growth model makes good on its leaders’ efforts in recent years to boost domestic consumption and imports from the rest of the world, we will all be better off.

This article was originally published in Project Syndicate




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Webinar: European Democracy in the Last 100 Years: Economic Crises and Political Upheaval

Members Event Webinar

6 May 2020 - 1:00pm to 2:00pm

Event participants

Pepijn Bergsen, Research Fellow, Europe Programme, Chatham House

Dr Sheri Berman, Professor of Political Science, Barnard College

Chair: Hans Kundnani, Senior Research Fellow, Europe Programme, Chatham House

 

In the last 100 years, global economic crises from the Great Depression of the 1930s to the 2008 financial crash have contributed to significant political changes in Europe, often leading to a rise in popularity for extremist parties and politics. As Europe contends with a perceived crisis of democracy - now compounded by the varied responses to the coronavirus outbreak - how should we understand the relationship between externally-driven economic crises, political upheaval and democracy?

The panellists will consider the parallels between the political responses to some of the greatest economic crises Europe has experienced in the last century. Given that economic crises often transcend borders, why does political disruption vary between democracies? What can history tell us about the potential political impact of the unfolding COVID-19-related economic crisis? And will the unprecedented financial interventions by governments across Europe fundamentally change the expectations citizens have of the role government should play in their lives?

This event is based on a recent article in The World Today by Hans Kundnani and Pepijn Bergsen who are both researchers in Chatham House's Europe Programme. 'Crawling from the Wreckage' is the first in a series of articles that look at key themes in European political discourse from the last century. You can read the article here

This event is open to Chatham House Members. Not a member? Find out more.




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Parenteral lipids shape gut bile acid pools and microbiota profiles in the prevention of cholestasis in preterm pigs

Lee Call
Apr 29, 2020; 0:jlr.RA120000652v1-jlr.RA120000652
Research Articles




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Sphingolipids distribution at mitochondria-associated membranes (MAM) upon induction of apoptosis.

Vincent Mignard
Apr 29, 2020; 0:jlr.RA120000628v1-jlr.RA120000628
Research Articles




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Metabolic regulation of the lysosomal cofactor bis(monoacylglycero)phosphate in mice

Gernot F. Grabner
Apr 29, 2020; 0:jlr.RA119000516v1-jlr.RA119000516
Research Articles




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Lithium ion adduction enables UPLC-MS/MS-based analysis of multi-class 3-hydroxyl group-containing keto-steroids

Qiuyi Wang
Apr 1, 2020; 61:570-579
Methods




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Phosphatidylinositol Metabolism, Phospholipases, Lipidomics, and Cancer:In Memoriam of Michael J. O. Wakelam (1955-2020)

Edward A Dennis
Apr 28, 2020; 0:jlr.T120000868v1-jlr.T120000868
Tribute




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HDL inhibits endoplasmic reticulum stress-induced apoptosis of pancreatic {beta}-cells in vitro by activation of Smoothened

Mustafa Yalcinkaya
Apr 1, 2020; 61:492-504
Research Articles




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A simple method for sphingolipid analysis of tissues embedded in optimal cutting temperature compound

Timothy D Rohrbach
Apr 27, 2020; 0:jlr.D120000809v1-jlr.D120000809
Methods




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Of mice and men: murine bile acids explain species differences in the regulation of bile acid and cholesterol metabolism

Sara Straniero
Apr 1, 2020; 61:480-491
Research Articles




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Hexacosenoyl-CoA is the most abundant very long-chain acyl-CoA in ATP binding cassette transporter D1-deficient cells

Kotaro Hama
Apr 1, 2020; 61:523-536
Patient-Oriented and Epidemiological Research




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Schnyder corneal dystrophy-associated UBIAD1 is defective in MK-4 synthesis and resists autophagy-mediated degradation

Dong-Jae Jun
May 1, 2020; 61:746-757
Research Articles




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Circulating oxidized LDL increased in patients with acute myocardial infarction is accompanied by heavily modified HDL.

Naoko Sawada
Apr 14, 2020; 0:jlr.RA119000312v1-jlr.RA119000312
Research Articles