In a new study, researchers reveal how a key player in cell growth, immunity and the inflammatory response can be transformed into a primary contributor to tumour growth.
Scientists call this Jekyll-and-Hyde molecule NF-kappa B. In healthy cells, it is a powerful ‘first responder,’ a vital part of the body’s immune and inflammatory responses. It spends most of its life in the cell’s cytoplasm, quietly awaiting orders. But when extracellular signals – of a viral or bacterial invasion, for example – set off chemical alarms, the cell unchains this warhorse, allowing it to go into the nucleus where it spurs a flurry of defensive activity, including the transcription of genes that trigger inflammation, promote cell proliferation and undermine cell death.
Researchers have known for years that a hyperactive form of NF-kappa B that gets into the nucleus and stays there is associated with various cancers. But they didn’t know what was keeping it active in the nucleus.
‘Normally in the cell NF-kappa B is in the cytosol, it’s not in the nucleus, and it’s not activated,’ said University of Illinois medical biochemistry professor Lin-Feng Chen, who led the new study. ‘You have to stimulate normal cells to see NF-kappa B in the nucleus. But in cancer cells without any stimulation you can see this nuclear form of NF-kappa B. The cell just won’t die because of this. That is why NF-kappa B is so important in cancer.’
In the new study, Chen’s group found that another molecule known to help regulate gene expression, called BRD4, recognises a specific amino acid on a subunit of the NF-kappa B protein complex after the amino acid has been marked with a specific tag, called an acetyl group. This ‘acetylation’ allows the BRD4 to bind to NF-kappa B, activating it and preventing its degradation in cancer cells.
Previous studies had shown that BRD4’s recognition of the acetylated subunit increased NF-kappa B activation, but this recognition had not been linked to cancer.
BRD4 belongs to a class of molecules that can recognise chemical markers on other proteins and interact with them to spur the marked proteins to perform new tasks. Chemical ‘readers’ such as BRD4 are important players in the field of epigenetics, which focuses on how specific genes are regulated.
‘In epigenetics, there are writers, there are readers and there are erasers,’ Chen said. The writers make modifications to proteins after they are formed, without changing the underlying sequence of the gene that codes for them. These modifications (such as acetylation) signal other molecules (the readers) to engage with the marked proteins in various ways, allowing the proteins to fulfill new roles in the life of the cell. Epigenetic erasers remove the marks when they are no longer of use.
Such protein modifications ‘have been shown to be critically involved in transcription regulation and cancer development,’ the researchers report.
To test whether BRD4 was contributing to the sustained presence of NF-kappa B in the nucleus of cancer cells, Chen and his colleagues exposed lung cancer cells in cell culture and in immune-deficient mice to JQ1, a drug that interferes with BRD4 activity. Exposure to JQ1 blocked the interaction of BRD4 and NF-kappa B, blocked the expression of genes regulated by NF-kappa B, reduced proliferation of lung cancer cells and suppressed the ability of lung cancer cells to induce tumors in immune-deficient mice, the researchers found.
The researchers also discovered that depletion of BRD4 or the treatment of cells with JQ1 induced the degradation of the NF-kappa B subunit recognized by BRD4.
Chen said that BRD4 likely prevents other molecules from recognising the hyperactive NF-kappa B in the nucleus and marking it for degradation.
‘This is an example of how epigenetic regulators and NF-kappa B may one day be targeted for the treatment of cancer,’ he said. University of Illinois at Urbana Champaign

The World Health Organisation (WHO) has urged countries with possible cases of novel coronavirus to share information. The move comes after Saudi Arabia said the development of diagnostic tests had been delayed by patent rights on the NCoV virus by commercial laboratories.
Twenty-two deaths and 44 cases have been reported worldwide since 2012, the WHO says. NCoV is from the same family of viruses as the one that caused Severe Acute Respiratory Syndrome (Sars). An outbreak of Sars in 2003 killed about 770 people. However, NCoV and Sars are distinct from each other, the WHO says.
The virus first emerged in Saudi Arabia, which is where most cases have since arisen. Saudi Deputy Health Minister Ziad Memish raised his concerns at the World Health Assembly in Geneva.
‘We are still struggling with diagnostics and the reason is that the virus was patented by scientists and is not allowed to be used for investigations by other scientists,’ he said. ‘I think strongly that the delay in the development of … diagnostic procedures is related to the patenting of the virus.’
WHO chief Margaret Chan expressed dismay at the information.
‘Why would your scientists send specimens out to other laboratories on [sic] a bilateral manner and allow other people to take intellectual property rights on a new disease?’ she asked.
‘Any new disease is full of uncertainty.’
She is urging the WHO’s 194 member states to only share ‘viruses and specimens with WHO collaborating centres… not in a bilateral manner.’
She added: ‘I will follow it up. I will look at the legal implications together with the Kingdom of Saudi Arabia. No IP (intellectual property) should stand in the way of you, the countries of the world, to protect your people.’ BBC

Using a novel method of analysing genetic variations in families, researchers at Johns Hopkins have found that individually harmless genetic variations affecting related biochemical processes may team up to increase the risk of schizophrenia. They say their findings bring some clarity to the murky relationship between genetics and schizophrenia, and may lead to a genetic test that can predict which medications will be effective for individual patients.
‘It’s long been clear that schizophrenia runs in families, but schizophrenia as a simple inherited disease didn’t make sense from an evolutionary point of view because people with the disease tend to have fewer children and the disease-causing genetic variants shouldn’t survive,’ says Dimitri Avramopoulos, M.D., Ph.D., an associate professor of psychiatry in the McKusick-Nathans Institute of Genetic Medicine. Moreover, he says, studies searching for schizophrenia-linked gene variants have found only weak connections to a few genes — nothing that would explain the persistent prevalence of the disease, which affects about 1 percent of the population.
Most geneticists believe that the culprit in so-called complex genetic diseases such as schizophrenia is not just one genetic variant, but more than one acting in concert. It’s also likely that individual cases of the disease are caused by different combinations of variants, Avramopoulos says. He and fellow researchers took this hypothesis a step further, theorising that while our bodies can usually compensate for one faulty gene that affects a particular system, more than one hit to the same system is likely to tip people toward disease.
The research team devised a technique for analysing gene-sequencing data that explores whether variants cluster in a subset of cases in a non-random way. After finding support for their hypothesis in previously obtained data on 123 families with at least two schizophrenia-affected members, they decided to sequence genes connected through a biochemical chain reaction that has been linked to the disease in 48 inpatients. Known as the neuregulin signalling pathway, that chain reaction relays signals within the nervous system.
As they had predicted, the researchers found that some of the families had multiple neuregulin signalling-related variants while others had none, a distribution that was highly unlikely to result from chance. Moreover, the schizophrenia patients with neuregulin signalling variants experienced more hallucinations but less impairment than the other schizophrenia patients in the study.
‘These results support the idea that there’s no single genetic recipe for schizophrenia, but that a build-up of mutations in a pathway related to the disease — like neuregulin signalling — can be the culprit,’ Avramopoulos says. ‘The results are also evidence for the current theory that schizophrenia isn’t a single disease at all, but a suite of related disorders.’ Those patients in the study who did not have neuregulin signalling-related variants likely carried variants in a different pathway instead, he notes.
While the results of the study were surprisingly clear-cut given the small number of families in the study, Avramopoulos cautions that larger studies are needed to confirm the results before drawing any firm conclusions. He also plans to study the exact roles of the schizophrenia-linked variants the team identified. Finally, the encouraging results mean it would be worthwhile to apply the new analytic method to other common diseases, such as diabetes and heart disease, which also appear to have complex genetic roots. John Hopkins University School of Medicine

Paper is known for its ability to absorb liquids, making it ideal for products such as paper towels. But by modifying the underlying network of cellulose fibres, etching off surface ‘fluff’ and applying a thin chemical coating, researchers have created a new type of paper that repels a wide variety of liquids – including water and oil.
The paper takes advantage of the so-called ‘lotus effect’ – used by leaves of the lotus plant – to repel liquids through the creation of surface patterns at two different size scales and the application of a chemical coating. The material, developed at the Georgia Institute of Technology, uses nanometer- and micron-scale structures, plus a surface fluorocarbon, to turn old-fashioned paper into an advanced material.
The modified paper could be used as the foundation for a new generation of inexpensive biomedical diagnostics in which liquid samples would flow along patterns printed on the paper using special hydrophobic ink and an ordinary desktop printer. This paper could also provide an improved packaging material that would be less expensive than other oil- and water-repelling materials, while being both recyclable and sustainable.
‘Paper is a very heterogeneous material composed of fibres with different sizes, different lengths and a non-circular cross-section,’ said Dennis Hess, a professor in the Georgia Tech School of Chemical and Biomolecular Engineering. ‘We believe this is the first time that a superamphiphobic surface – one that repels all fluids – has been created on a flexible, traditional and heterogeneous material like paper.’
The new paper, which is both superhydrophobic (water-repelling) and super oleophobic (oil-repelling), can be made from standard softwood and hardwood fibres using a modified paper process. In addition to Hess, the research team included Lester Li, a graduate research assistant, and Victor Breedveld, an associate professor in the School of Chemical and Biomolecular Engineering
Producing the new paper begins with breaking up cellulose fibres into smaller structures using a mechanical grinding process. As in traditional paper processing, the fibres are then pressed in the presence of water – but then the water is removed and additional processing is done with the chemical butanol. Use of butanol inhibits the hydrogen bonding that normally takes place between cellulose fibres, allowing better control of their spacing.
‘The desirable properties we are seeking are mainly controlled by the geometry of the fibres,’ Hess explained.
The second step involves using an oxygen plasma etching process – a technique commonly used in the microelectronics industry – to remove the layer of amorphous ‘fluffy’ cellulose surface material, exposing the crystalline cellulose nanofibrils. The process thereby uncovers smaller cellulose structures and provides a second level of ‘roughness’ with the proper geometry needed to repel liquids.
Finally, a thin coating of a fluoropolymer is applied over the network of cellulose fibers. In testing, the paper was able to repel water, motor oil, ethylene glycol and n-hexadecane solvent.
The researchers have printed patterns onto their paper using a hydrophobic ink and a desktop printer. Droplets applied to the pattern remain on the ink pattern, repelled by the adjacent superamphiphobic surface.
That capability could facilitate development of inexpensive biomedical diagnostic tests in which a droplet containing antigens could be rolled along a printed surface where it would encounter diagnostic chemicals. If appropriate reagents are used, the specific colour or colour intensity of the patterns could indicate the presence of a disease. Because the droplets adhere tightly to the printed lines or dots, the samples can be sent to a laboratory for additional testing.
‘We have shown that we can do the operations necessary for a microfluidic device,’ Hess said. ‘We can move the droplet along a pattern, split the droplet and transfer the droplet from one piece of paper to another. We can do all of these operations on a two-dimensional surface.’
For Hess, Li and Breedveld, creating a superhydrophobic suface was relatively straightforward because water has a high surface tension. For oils, which have a low surface tension, the key to creating the repellent surface is to create re-entrant – or undercut – angles between the droplets and the surface.
Previous examples of superamphiphobic surfaces have been made on rigid surfaces through lithographic techniques. Such processes tend to produce fragile surfaces that are prone to damage, Hess said.
The principal challenge has been to create high-performance in a material that is anything but geometrically regular and consistent.
‘Working with heterogeneous materials is fascinating, but it’s very difficult not just to control them, because there is no inherent consistent structure, but also to change the processing conditions so you can get something that, on average, is what you need,’ he said. ‘It’s been a real learning experience for us.’
The new paper has so far been made in samples about four inches on a side, but Hess sees no reason why the process couldn’t be scaled up. Though long-term testing of the new paper hasn’t been done, Hess is encouraged by what he’s seen so far. Georgia Institute of Technology

A multi-institutional team of researchers have pinpointed the genetic traits of the cells that give rise to gliomas – the most common form of malignant brain cancer. The findings provide scientists with rich new potential set of targets to treat the disease.
‘This study identifies a core set of genes and pathways that are dysregulated during both the early and late stages of tumour progression,’ said University of Rochester Medical Center (URMC) neurologist Steven Goldman, M.D., Ph.D., the senior author of the study and co-director of the Center for Translational Neuromedicine. ‘By virtue of their marked difference from normal cells, these genes appear to comprise a promising set of targets for therapeutic intervention.’
As its name implies, gliomas arise from a cell type found in the central nervous system called the glial cell. Gliomas progress in severity over time and ultimately become highly invasive tumours known as glioblastomas, which are difficult to treat and almost invariably fatal. Current treatments, which include surgery, radiation therapy, and chemotherapy, can delay disease progression, but ultimately prove ineffective.
Cancer research has been transformed over the past several years by new concepts arising from stem cell biology. Scientists now appreciate that many cancers are the result of rogue stem cells or their offspring, known as progenitor cells. Traditional cancer therapies often do not prevent a recurrence of the disease since they may not effectively target and destroy the cancer-causing stem cells that lie at the heart of the tumours.
Gliomas are one such example. The source of the cancer is a cell found in the brain called the glial progenitor cell. The cells, which arise from and maintain characteristics of stem cells, comprise about three percent of the cell population of the human brain. When these cells become cancerous they are transformed into glioma stem cells, essentially glial progenitor cells whose molecular machinery has gone awry, resulting in uncontrolled cell division.
Goldman and his team have long studied normal glial progenitor cells. These cells produce glia, a category that includes both astrocytes – cells that support the function of neurons – and oligodendrocytes – cells that produces myelin, the fatty insulation that allows the long-distance conduction of neural impulses.
While Goldman’s group’s work has primarily focused on ways to use glial progenitor cells to treat neurological disorders such as multiple sclerosis, their understanding of the biology of these cells and mastery of the techniques required to sort, identify, and isolate these cells has also enabled them to explore the molecular and genetic changes that transform these cells into cancers.
Using human tissue samples representing the three principal stages of the cancer, the researchers were able to identify and isolate the cancer-inducing stem cells. Working with Goldman, lead authors Romane Auvergne, Ph.D. and Fraser Sim, Ph.D. then compared the gene expression profiles of these cancer stem cells to those of normal glial progenitor cells. The objective was to both pinpoint the earliest genetic changes associated with cancer formation and identify those genes that were unique to the cancer stem cells and were expressed at every stage of disease progression.
Out of a pool over 44,000 tested genes and sequences, the scientists identified a small set of genes in the cancerous glioma progenitor cells that were over-expressed at all stages of malignancy. These genes formed a unique ‘signature’ that identified the tumour progenitor cells and enabled the scientists to define a corresponding set of potential therapeutic targets present throughout all stages of the cancer.
‘One of the key things you are looking for in drug development in cancer is a protein or gene that is over-expressed, so that you can attempt to achieve therapeutic benefit by inhibiting it,’ said Goldman.
The researchers chose to test this hypothesis by targeting one such gene, called SIX1, which was highly over-expressed in the glioma progenitor cells. While this particular gene is active in the early development of the nervous system, it had not been observed in the adult brain before. However, SIX1 signalling has been associated with breast and ovarian cancer, raising the possibility of its contribution to brain cancer as well. This turned out to indeed be the case. When the researchers blocked – or knocked down – the expression of this gene, the tumour cells ceased growing, and implanted tumours shrank.
‘This study gives us a blueprint to develop new therapies,’ said Goldman. ‘We can now devise a strategy to systematically and rationally analyse – and eliminate – glioma stem and progenitor cells using compounds that may selectively target these cells, relative to the normal glial progenitors from which they derive. By targeting genes like SIX1 that are expressed at all stages of glioma progression, we hope to be able to effectively treat gliomas regardless of their stage of malignancy. And by targeting the glioma-initiating cells in particular, we hope to lessen the likelihood of recurrence of these tumours, regardless of the stage at which we initiate treatment.’ University of Rochester Medical Center