The team headed by Angel Rodríguez Nebreda, ICREA researcher at IRB, identifies for the first time in mice that the p38 MAPK protein is required for the survival and proliferation of colon cancer cells.

In the same study the scientists demonstrate that a p38 inhibitor that has been used in clinical trials for inflammatory diseases shrinks the tumours in mice.
A team headed by Angel R. Nebreda at the Institute for Research in Biomedicine (IRB) identifies a dual role of the p38 MAPK protein in colon cancer. The study demonstrates that, on the one hand, p38 is important for the optimal maintenance of the epithelial barrier that protects the intestine against toxic agents, thus contributing to decreased tumour development. Intriguingly, on the other hand, once a tumour has formed, p38 is required for the survival and proliferation of colon cancer cells, thus favouring tumour growth.

The protein p38 is a member of the MAPK family—molecules that transmit signals from outside the cell inside, thus allowing an appropriate and dynamic cell response. This protein is expressed in all cells of the body and it performs highly diverse functions depending on the context and tissue involved.

Nebreda’s group at IRB focuses on the function of p38 in cancer. Their work describes the essential role of p38 in tumour progression for the first time in vivo. Furthermore, the scientists demonstrate that the treatment of mice with a p38 inhibitor previously used in clinical assays causes a considerable reduction in tumour size. The study provides useful information for clinicians and pharmaceutical companies about the role of p38 in the context of colon cancer. Colorectal cancer is now the second leading cause of cancer-related death in the world.

‘p38 inhibitors may have clinical applications, but probably—and this forms part of the medicine of the future—these will be in combination with other drugs. We are trying to find out what p38 inhibitors should be combined with to make the tumour, which is now smaller, finally disappear,’ explains the Spanish scientist Nebreda, head of the Signalling and Cell Cycle Lab at IRB, BBVA Foundation Cancer Research Professor and ICREA research professor.

The role of p38 in cancer is not clear cut. In this same study, Indian-born Jalaj Gupta who recently obtained his PhD in Nebreda’s lab and is first author of the work, demonstrates that this same protein in a pre-tumoral context, favoured by inflammation of the colon—also known as colitis—impedes tumour development.

It is well-known that patients with chronic inflammation of the intestine, such as that caused by Crohn’s disease, have a greater incidence of colon tumours that the healthy population. In order to study the relationship between inflammation and cancer, Nebreda’s team use mouse models that reproduce this inflammatory context.

‘Given that p38 regulates inflammation and also functions as a tumour suppressor in some mouse models, our study addressed how these two functions are integrated during the colon tumorigenesis associated with inflammation’, says Gupta.

An important finding of the present study is related to the contribution of p38 to the maintenance of an intact epithelial barrier, a structure that protects the intestine from toxic agents and pathogens. Mice genetically depleted of p38 in the epithelial cells that form the intestinal barrier were subjected to a cancer-inducing protocol that causes mutations and inflammation.

These animals developed twice as many tumours as a group of p38-expressing mice subjected to the same protocol. The tumour-suppressing capacity of p38 has also been described in cancer of the liver and lung.

‘Our study highlights the complexity of p38 functions, both in cancer and in the normal maintenance of tissues, and shows why an inhibitor of this molecule could effectively have undesirable side effects. This is why it is necessary to study in depth the patients and contexts in which treatment with such inhibitors would be suitable,’ explains Gupta.

‘All drugs currently used to treat cancer have side effects,’ states Nebreda, ‘and in this regard p38 inhibitors would be no exception. However, the administration of such inhibitors to colon cancer patients may be a useful strategy to shrink the tumour in a few days before its surgical removal’.

Nebreda goes on to explain that the basic research performed in his lab seeks to understand better the biology of tumour cells, the roles of the molecules involved and the mechanisms that allow tumour progression. ‘We try to take this basic information a step further so that it becomes clinically useful when designing new treatments,’ says the researcher, who joined IRB, in Barcelona, in 2010, after working in USA, UK, Germany and the CNIO in Madrid. IRB Barcelona

The research of physician-scientist Katalin Susztak, MD, PhD, associate professor of Medicine in the Renal Electrolyte and Hypertension Division, at the Perelman School of Medicine, University of Pennsylvania, strives to understand the molecular roots and genetic predisposition of chronic kidney disease. In a recent Genome Biology paper, Susztak, and her co-corresponding author John Greally from the Albert Einstein College of Medicine, Bronx, NY, found, in a genome-wide survey, significant differences in the pattern of chemical modifications on DNA that affect gene expression in kidney cells from patients with chronic kidney disease versus healthy controls. This is the first study to show that changes in these modifications – the cornerstone of the field of epigenetics – might explain chronic kidney disease.
Epigenetics is the science of how gene activity can be altered without actual changes in the DNA sequence. DNA can be modified by different chemical groups. In the case of this study, these are methyl groups that, like using sticky notes as reminders, open or close up regions of the genome to make these areas more or less available to be ‘read’ as a gene.

Chronic kidney disease is a condition in which the kidneys are damaged and cannot adequately filter blood. This damage can cause wastes to build up, which leads to other health problems, including cardiovascular disease, anaemia, and bone disease. More than 10% of people, or more than 20 million, aged 20 years or older in the United States have chronic kidney disease, according to the Centers for Disease Control.
Past epidemiological studies have shown that adverse intrauterine and postnatal conditions have a long-lasting, over-a-lifetime role in the development of chronic kidney disease. Adverse intrauterine factors include small size of babies for gestational age due to a lack of nutrients, or conversely, a large size for gestational age, for example if mom had pregnancy-related diabetes.
Studies from the Diabetes Control and Complications trial also indicate that patients with diabetes who had poor diabetes control 25 years earlier still have an increased risk of kidney disease despite having a decade of excellent glucose control. ‘This is called the metabolic memory effect,’ says Susztak. ‘Kidney cells remember the past bad metabolic environment.’
Susztak’s lab used human kidney cells that looked almost the same under a microscope, but the way each cell type is affected by the methyl groups was very different. In general, an increase in the number of methyl groups on a gene turns off expression, and a decrease of methyl groups turns on a gene’s expression.
Specifically, they found that the differences in the methyl groups were not on promoter regions in the diseased kidney cells, but mostly on enhancer regions, and were also near sequences for important kidney transcription factors. ‘This all speaks to the importance of these regions in regulating gene expression,’ says Susztak.

Promoter regions are in front of genes and near the gene they influence. Enhancer regions are farther away from the gene of influence. This difference indicates that the two cell types would likely respond differently to stress.
‘The difference in methylation related to kidney fibrosis — genes encoding collagen and growth factors — at core kidney development sites in the genome raises the possibility that these differences are established early on in a person’s development because the genes Pax2 and Pax8 are active in the developing kidney in the fetus,’ explains Susztak.
‘Most of the research on kidney epigenetics so far has been on promoter regions on kidney cancer cells,’ says Susztak. ‘The difference we found in dysregulation between the two cell populations may indicate that dysregulation in cancer is different from dysregulation in chronic kidney disease. Five years ago there was no epigenetic information outside of cancer,’ says Susztak.

Overall, the findings raise the possibility that dysregulation of epigenetic marks plays a role in chronic kidney disease by affecting pathways that lead to more fibrosis. Identifying the genes and proteins associated with this system gone awry may help identify new biomarkers and targets for new drugs. Perelman School of Medicine

Bioengineers at Rice University and the University of Texas Medical Branch (UTMB) at Galveston have developed a simple, highly sensitive and efficient test for the diarrhoeal disease cryptosporidiosis that could have great impact on global health.
Results from the diagnostic developed by the lab of Rice bioengineer Rebecca Richards-Kortum are read from a paper strip that resembles a pregnancy test. Lines on the strip tell whether samples taken from the stool of a patient contain genetic DNA from the parasite that causes the disease.
‘Diarrhoeal illness is a leading cause of global mortality and morbidity,’ said Richards-Kortum, director of the Rice 360˚: Institute for Global Health Technologies. ‘Parasites such as cryptosporidium are more common causes of prolonged diarrhoea. Current laboratory tests are not sensitive, are time-consuming and require days before results are available. A rapid, affordable, accurate point-of-care test could greatly enhance care for the underserved populations who are most affected by parasites that cause diarrhoeal illness.’
A. Clinton White, director of the Infectious Disease Division at UTMB, asked Richards-Kortum to help develop a diagnostic test for the parasite. ‘I’ve been working with cryptosporidium for more than 20 years, so I wanted to combine her expertise in diagnosis with our clinical interest,’ he said. ‘Recent studies in Africa and South Asia by people using sophisticated techniques show this organism is a very common, under-appreciated cause of diarrhoeal disease in under-resourced countries.’
Current specialized tests that depend on microscopic or fluorescent analysis of stool samples or polymerase chain reactions (PCR) that amplify pathogen DNA are considered impractical for deployment in developing countries because of the need for expensive equipment and/or the electricity to operate it.
The Rice test depends on recent developments in a recombinase polymerase amplification (RPA) technique that gives similar ‘gold standard’ results to PCR but operates between room and body temperatures. In Rice’s experiments, samples were prepared with a commercial chemical kit that releases all the DNA and RNA in the small amount of stool tested. The purified nucleic acids are then combined with RPA primers and enzymes tuned to amplify the pathogen of interest, Crannell said.
‘If the pathogen DNA is present, these primers will amplify it billions of times to a level that we can easily detect,’ he said. The sample is then flowed over the detection strip, which provides a positive or negative result.
The RPA enzymes are stable in their dried form and can be safely stored at the point of care without refrigeration for up to a year, he said.
While current tests might catch the disease in samples with thousands of the pathogens, the Rice technique detects the presence of very few – even one – parasite in a sample. In their experiments, the researchers reported the presence or absence of the disease was correctly identified in 27 of 28 infected and control-group mice and all 21 humans whose stool was tested. Rice University

Researchers have explored the role of a master gene that controls the functioning of other genes involved in heart development. Variations in this gene – NR2F2 – are responsible for the development of severe forms of congenital heart disease.
Approximately one per cent of all babies are born with congenital heart disease, where the normal workings of the heart are affected. Because the damage to the heart is structural, most babies will need surgery to correct the problem. Although genetic causes are known to underlie the disease, these causes are not very well understood.
Scientists have previously shown that mice with a less active NR2F2 gene had abnormal heart development. To see if the gene was involved in severe forms of human congenital heart disease, the team looked at DNA sequences of parents and affected children and found that variation on the NR2F2 caused the structural damage that underlies these conditions.
The team found that these genetic variants were typically only present in the child and not the parents, revealing that congenital heart disease producing variants occur in the womb.
‘What we see is that these rare variants in the NR2F2 gene interfere with the normal heart development and cause severe forms of congenital heart disease during human development,’ says Saeed Al Turki, first author from the Wellcome Trust Sanger Institute.
NR2F2 is a master regulator for other genes involved in the development of a healthy functioning heart – once the activity of NR2F2 is affected it has a knock-on effect on these other genes affecting the healthy development of the heart.
The team found that different types of damage in the NR2F2 gene cause different types of heart defects. Genetic variants that completely deactivate the NR2F2 gene tended to cause damage to the left side of the heart. In contrast, genetic variants that alter activity of the gene but do not deactivate it more commonly caused a specific sub-type of holes in the hearts of patients. Wellcome Trust Sanger Institute

Scientists are a step closer to understanding how some of the brain’s 100 billion nerve cells co-ordinate their communication.

The University of Bristol research team investigated some of the chemical processes that underpin how brain cells co-ordinate their communication. Defects in this communication are associated with disorders such as epilepsy, autism and schizophrenia, and therefore these findings could lead to the development of novel neurological therapies.

Neurons in the brain communicate with each other using chemicals called neurotransmitters. This release of neurotransmitter from neurons is tightly controlled by many different proteins inside the neuron. These proteins interact with each other to ensure that neurotransmitter is only released when necessary. Although the mechanisms that control this release have been extensively studied, the processes that co-ordinate how and when the component proteins interact is not fully understood.

The School of Biochemistry researchers have now discovered that one of these proteins called ‘RIM1α’ is modified by a small protein named ‘SUMO’ which attaches to a specific region in RIM1α. This process acts as a ‘molecular switch’ which is required for normal neurotransmitter release.

Jeremy Henley, Professor of Molecular Neuroscience in the University’s Faculty of Medical and Veterinary Sciences and the study’s lead author, said: ‘These findings are important as they show that SUMO modification plays a vital and previously unsuspected role in normal brain function.’ Bristol University