Researchers at King’s College London and the University of Manchester, funded by Arthritis Research UK, have developed a new method to identify people that are at a very high-risk of developing rheumatoid arthritis, using a simple blood test and information about their smoking habits.
Rheumatoid arthritis is a potentially crippling autoimmune condition that causes pain and inflammation in the joints. It affects around 400,000 people in the UK and is at present incurable. Many factors are known to contribute to an individual’s risk of developing rheumatoid arthritis. These are divided into two categories: inherited genetic factors (46 genetic risk factors have been identified that increase someone’s risk of developing rheumatoid arthritis) and so called ‘environmental’ factors such as smoking.
This new computer-based technique of prediction modelling allows researchers to combine both genetic and environmental risk factors to estimate an individual’s lifetime risk of developing this disease.
According to the study’s lead researcher, Dr Ian Scott, Department of Genetics & Molecular Medicine at King’s College London, this new prediction modelling technique can also identify people of developing rheumatoid arthritis at a younger age.
‘This new computer-based technique of prediction modelling allows us to estimate someone’s risk of developing rheumatoid arthritis over their lifetime using genetic markers from a single blood test and information about their smoking habits’, explained Dr Scott.
‘I hope that, as we understand the risk factors for rheumatoid arthritis better, our prediction modelling method could be used to screen people for this disease before they develop any symptoms. This is an important first step in trying to develop ways to prevent the onset of rheumatoid arthritis.
‘Within the general population, few individuals that have clinically significant increased risks are likely to be identified using this approach. But targeted screening of people already at an increased risk of rheumatoid arthritis, such as relatives of patients, could identify enough high-risk people to allow researchers to look at ways to prevent rheumatoid arthritis from developing.’
Individuals classed as being high risk, using information from the most important gene associated with rheumatoid arthritis (the HLA-DRB1 gene), are more likely to develop rheumatoid arthritis at a younger age. They could be monitored for early signs of the disease. Treating rheumatoid arthritis early, before significant joint damage has occurred, increases the likelihood that the individual will go into remission (no joint pain or swelling) following treatment. King’s College London

A UC San Francisco-led research team has identified the likely genetic mechanism that causes some patients with multiple sclerosis (MS) to progress more quickly than others to a debilitating stage of the disease. This finding could lead to the development of a test to help physicians tailor treatments for MS patients.
Researchers found that the absence of the gene Tob1 in CD4+ T cells, a type of immune cell, was the key to early onset of more serious disease in an animal model of MS.
　
Senior author Sergio Baranzini, PhD, a UCSF associate professor of neurology, said the potential development of a test for the gene could predict the course of MS in individual patients.
The study was done in collaboration with UCSF neurology researchers Scott Zamvil, MD, and Jorge Oksenberg, PhD.
MS is an inflammatory disease in which the protective myelin sheathing that coats nerve fibres in the brain and spinal cord is damaged and ultimately stripped away – a process known as demyelination. During the highly variable course of the disease, a wide range of cognitive, debilitating and painful neurological symptoms can result.
In previously published work, Baranzini and his research team found that patients at an early stage of MS, known as clinically isolated syndrome, who expressed low amounts of Tob1 were more likely to exhibit further signs of disease activity – a condition known as relapsing-remitting multiple sclerosis – earlier than those who expressed normal levels of the gene.
The current study, according to Baranzini, had two goals: to recapitulate in an animal model what the researchers had observed in humans, and uncover the potential mechanism by which it occurs.
The authors were successful on both counts. They found that when an MS-like disease was induced in mice genetically engineered to be deficient in Tob1, the mice had significantly earlier onset compared with wild-type mice, and developed a more aggressive form of the disease.
Subsequent experiments revealed the probable cause: the absence of Tob1 in just CD4+ T cells. The scientists demonstrated this by transferring T cells lacking the Tob1 gene into mice that had no immune systems but had normal Tob1 in all other cells. They found that the mice developed earlier and more severe disease than mice that had normal Tob1 expression in all cells including CD4+.
‘This shows that Tob1 only needs to be absent in this one type of immune cell in order to reproduce our initial observations in mice lacking Tob1 in all of their cells,’ said Baranzini.
The researchers also found the likely mechanism of disease progression in the Tob1-deficient mice: higher levels of Th1 and Th17 cells, which cause an inflammatory response against myelin, and lower levels of Treg cells, which normally regulate inflammatory responses. The inflammation results in demyelination.
The research is significant for humans, said Baranzini, because the presence or absence of Tob1 in CD4+ cells could eventually serve as a prognostic biomarker that could help clinicians predict the course and severity of MS in individual patients. ‘This would be useful and important,’ he said, ‘because physicians could decide to switch or modify therapies if they know whether the patient is likely to have an aggressive course of disease, or a more benign course.’
Ultimately, predicted Baranzini, ‘This may become an example of personalised medicine. When the patient comes to the clinic, we will be able to tailor the therapy based on what the tests tell us. We’re now laying the groundwork for this to happen.’ University of California – San Francisco

Kashin-Beck disease (KBD) and Keshan disease (KD) are major endemic diseases in China. Postgraduate Xi Wang et al., under the guidance of Professor Xiong Guo from the Institute of Endemic Diseases of the Faculty of Public Health, Medicine College of Xi’an Jiaotong University, Key Laboratory of Environment and Gene Related Diseases in Ministry of Education, Key Laboratory of Trace Elements and Endemic Diseases of Health Ministry, set out to tackle these two endemic diseases. After several years of innovative research, they have made significant progress in determining the etiology and pathogenesis of these diseases at a molecular level; in particular, the identification of some common differentially expressed genes.

KBD and KD are distributed from the northeast to the southwest of China, where the selenium content is low in the soil. In China, there are 660000 KBD and 40000 KD patients, and approximately 30 million people are at risk. KBD is an endemic osteoarthropathy, the pathologic changes of KBD included significant alterations in chondrocyte phenotype, necrosis, and apoptosis, and abnormal terminal chondrocyte differentiation. The mainly pathologic changes of KD are multifocal myocardial necrosis and fibrosis that can result in cardiogenic shock and congestive heart failure. KD is an endemic myocardosis that happened in women and pre-schoolers. Since osteoarthritis and myocardium deformities, the most of KBD and KD patients will partially or completely lose their abilities to work even self-care, which seriously reduces their quality of life, and also bring heavy medical burden to society; the etiology and pathogenesis of KBD and KD remain unclear. However, both diseases happened in the same area of China. Moreover, the living conditions of KBD and KD patients are similar, for example, most patients live in remote rural areas and the areas of awful transportation, have a meager income, and a simply diet. There is little research conducted to compare KBD and KD gene expression profiles. Therefore, the two diseases may have a further relationship at the molecular biology level.

In this study, the Agilent Human 1A Oligo microarray was used to compare gene expression profiles of peripheral blood mononuclear cells (PBMCs) between KBD or KD patients and healthy controls, and identified the common genes differentially expressed in both diseases groups. One hundred and thirty-six differentially expressed genes (53 up-regulated and 83 down-regulated) were identified between KBD and normal controls. Moreover, comparing KD and normal controls, 3310 differentially expressed genes (3154 up-regulated and 156 down-regulated) were identified. Comparing all identified differentially expressed genes, 16 genes showed differential expression in both diseases, including nine with synchronous and seven with asynchronous expression. These 16 genes were subdivided into 11 categories, namely metabolism, cytochrome enzymes, transcription-related, G-protein-related, receptor, cytokine factor, ion channel transport protein, signal transduction, hematopoietic related, interleukin, and immune-related.

The distribution of KBD and KD is in the similar geographical regions, although the clinical presentations and target pathological focus are not same. The common differentially expressed genes identified in both KBD and KD could be helpful to identify the potential mechanisms of the different organ lesions, caused by similar environmental risk factors, selenium deficiency. These findings make a great contribution towards clarifying the etiology and pathogenesis of KBD and KD. EurekAlert

Researchers have identified a set of genes that allow melanoma cells, a type of cancer cell, to change rapidly between two shapes to escape from the skin and spread around the body. This new research – funded by the Wellcome Trust, Cancer Research UK and the US National Institutes of Health – could pave the way for scientists to develop desperately needed drugs for malignant melanoma, the deadliest form of skin cancer, which kills more than 2200 people every year.
The most dangerous aspect of melanoma is its ability to spread, or become malignant, to other parts of the body in the later stages of disease. This most often includes the liver, lungs and brain.
Dr Chris Bakal, a Wellcome Trust research fellow at the Institute of Cancer Research, London, explains: ‘We already knew that metastatic melanoma cells, or cells that are able to spread through the body, have to be able to adopt different shapes so that they can squeeze their way between healthy cells and move around the body.
‘The cells have to become rounded to travel through the bloodstream or invade soft tissues such as the brain, but they take on an elongated shape to travel through harder tissues like bone. But until now, we knew hardly anything about how the cells assume either of these shapes and how they switch between the two.’
To investigate this, researchers at the Institute of Cancer Research, London, and Weill Cornell Medical College in Houston started out by looking at fruit fly cells. They found that under normal conditions, the fruit fly cells grew in five different shapes. By switching off specific genes, they were able to change the mix of shapes among the fruit fly cells and identify several different genes that control a cell’s shape-shifting ability.
When they looked in human melanoma cells, they found that the human versions of these genes had a similar effect. In particular, they noted that switching off a gene called PTEN increased the proportion of cells that were elongated rather than rounded.
PTEN is a gene that is also involved in stopping healthy cells from becoming cancer cells, a so-called ‘tumour suppressor’ gene. This particular gene is switched off in around 1 in 8 melanoma patients and in almost half of melanoma patients who carry a mutation in another cancer gene called BRAF.
‘We think that metastatic melanoma cells lose their PTEN function so that they can increase their shape-shifting ability, which in turn enables them to move to many different tissues within the body. It’s early days, but taken together our findings offer new opportunities to develop drugs to try and stop the spread of melanoma,’ Dr Bakal added.
Dr Julie Sharp, Senior Science Communications Manager at Cancer Research UK, said: ‘This is still early research, but it gives us a better grasp of the way cancer cells behave in the body. By mimicking these conditions, our researchers are learning more about melanoma and bringing us closer to beating it. Wellcome Trust

Researchers from King’s College London and the University of Nottingham have identified neuroimaging markers in the brain which could help predict whether people with psychosis respond to antipsychotic medications or not.
In approximately half of young people experiencing their first episode of a psychosis (FEP), the symptoms do not improve considerably with the initial medication prescribed, increasing the risk of subsequent episodes and worse outcome. Identifying individuals at greatest risk of not responding to existing medications could help in the search for improved medications, and may eventually help clinicians personalise treatment plans.
In a study, researchers used structural Magnetic Resonance Imaging (MRI) to scan the brains of 126 individuals – 80 presenting with FEP, and 46 healthy controls. Participants had an MRI scan shortly after their FEP, and another assessment 12 weeks later, to establish whether symptoms had improved following the first treatment with antipsychotic medications.
The researchers examined a particular feature of the brain called ‘cortical gyrification’ – the extent of folding of the cerebral cortex and a marker of how it has developed. They found that the individuals who did not respond to treatment already had a significant reduction in gyrification across multiple brain regions, compared to patients who did respond and to individuals without psychosis. This reduced gyrification was particularly present in brain areas considered important in psychosis, such as the temporal and frontal lobes. Those who responded to treatment were virtually indistinguishable from the healthy controls.
The researchers also investigated whether the differences could be explained by the type of diagnosis of psychosis (eg. with or without affective symptoms, such as depression or elated mood). They found that reduced gyrification predicted non-response to treatment independently of the diagnosis.
Dr Paola Dazzan from the Department of Psychosis Studies at King’s College London’s Institute of Psychiatry, and senior author of the paper, says: ‘Our study provides crucial evidence of a neuroimaging marker that, if validated, could be used early in psychosis to help identify those people less likely to respond to medications. It is possible that the alterations we observed are due to differences in the way the brain has developed early on in people who do not respond to medication compared to those who do.’
She continues:’There have been few advances in developing novel anti-psychotic drugs over the past 50 years and we still face the same problems with a sub-group of people who do not respond to the drugs we currently use. We could envisage using a marker like this one to identify people who are least likely to respond to existing medications and focus our efforts on developing new medication specifically adapted to this group. In the longer term, if we were able to identify poor responders at the outset, we may be able to formulate personalised treatment plans for that individual patient.’
Dr Lena Palaniyappan from the University of Nottingham adds: ‘All of us have complex and varying patterns of folding in our brains. For the first time we are showing that the measurement of these variations could potentially guide us in treating psychosis. It is possible that people with specific patterns of brain structure respond better to treatments other than antipsychotics that are currently in use. Clearly, the time is ripe for us to focus on utilising neuroimaging to guide treatment decisions.’ King’s College London