The discovery of a gene that causes a form of hereditary spastic paraplegia may provide scientists with an important insight into what causes axons, the stems of our nerve cells, to degenerate in conditions such as multiple sclerosis.An international team of scientists led by Dr Evan Reid at the University of Cambridge and Dr Stephan Zuchner from the University of Miami reports that mutations in the gene known as reticulon 2 on chromosome 19 cause a form of hereditary spastic paraplegia (HSP). HSP is characterised by progressive stiffness and contraction (spasticity) of the legs, caused by selective and specific degeneration of axons.
The team identified three mutations in the reticulon 2 gene as causing a type of HSP – in one case, this mutation included an entire deletion of the gene. In addition, the researchers showed that reticulon 2 interacts with another gene, spastin. Mutations in this gene cause the most common form of hereditary spastic paraplegia.
Reticulon 2 provides the genetic code for a reticulon protein that is a member of a family of proteins recently shown to have a key role in shaping the endoplasmic reticulum. The endoplasmic reticulum is a network of interconnected sheets and tubules that extends throughout the cytoplasm in nearly all cells.
The endoplasmic reticulum has several functions, including protein synthesis, calcium signalling and the regulation of other components of the cell. Recent data suggest the sheets are involved in protein synthesis, whereas the tubules are specialised to carry out the other functions.
This new study provides the most direct evidence to date that defects in how the endoplasmic reticulum is shaped and formed could underlie axon degeneration. When axons degenerate, signals are unable to pass through the nerve cells, leading to a breakdown of communication within the central nervous system. This is common in degenerative diseases of the nervous system, such as multiple sclerosis.
‘Our work highlights important new disease mechanisms, which may provide a platform for us to study how axons are damaged in devastating illnesses such as HSP, and perhaps even in multiple sclerosis, which in some cases is very similar to HSP,’ explains Dr Reid, a Wellcome Trust Senior Research Fellow in Clinical Science. ‘But we must not forget how this work may immediately directly benefit families affected by HSP, for whom the discovery now opens up the possibility of genetic counselling and testing.’ Wellcome Trust

A recent analysis of clinical trial results performed by the Radiation Therapy Oncology Group (RTOG) demonstrate that a chromosomal abnormality—specifically, the absence (co-deletion) of chromosomes 1p and 19q—have definitive prognostic and predictive value for managing the treatment of adult patients with pure and mixed anaplastic oligodendrogliomas. The presence of the chromosomal abnormality was associated with a substantially better prognosis and near-doubling of median survival time when treatment with combined chemotherapy and radiation therapy was compared to treatment with radiation therapy alone.
Oligodendrogliomas are uncommon tumours that represent approximately 4.0% of all brain tumours. Mixed oliogdendrogliomas (those also containing astrocytic elements) account for 1.0% of all brain tumours. Pure and mixed oligodendrogliomas that contain anaplastic (malignant) cells typically grow more rapidly than non-anaplastic tumours.

The RTOG 9402 trial A Phase III Intergroup Randomized Comparison of Radiation Alone vs. Pre-Radiation Chemotherapy for Pure and Mixed Anaplastic Oligodendrogliomas was conducted with four other National Cancer Institute (NCI)-supported co-operative groups. Trial participants had a pathologically confirmed pure or mixed anaplastic oligodendroglioma and were randomly assigned into one of two treatment arms. The 148 participants randomised to Arm 1 were treated with PCV (procarbazine, CCNU [lomustine] and vincristine) chemotherapy and radiation therapy (RT), and the 143 participants randomised to Arm 2 were treated with RT alone.

RTOG 9402 study results showed no survival benefit for patients treated with early PVC chemotherapy plus RT over RT alone. Although a significant impact on median progression-free survival time was realised (2.6 years versus 1.7 years for RT alone), the regimen was associated with significantly more adverse side effects. The study authors also reported that study participants in both arms whose tumour lacked chromosomes 1p and 19q had longer median survival times as compared with participants without these deletions (> 7 vs. 2.8 years, respectively). This led the study authors to conclude that ‘tumours with 1p and 19q co-deletion are less aggressive or more responsive to PCV chemotherapy or both.’

A recent analysis undertaken of the RTOG 9402 data (at a median study participant follow-up time of 11 years) is planned for submission to the 2012 American Society of Clinical Oncology Annual Meeting. However, due to the finding’s significance for patient care, results are reported here in advance of submission. Radiation Therapy Oncology Group

New research from Queen Mary, University of London has uncovered a gene which plays a key role in the development of oesophageal cancer (cancer of the gullet).
The researchers studied families who suffer a rare inherited condition making them highly susceptible to the disease and found that a fault in a single gene was responsible. Initial studies suggest that the gene could play a role in the more common, non-inherited form of the disease, revealing a new target for treating this aggressive type of cancer.
Oesophageal cancer affects more than 8,000 people each year in the UK and rates are rising. It is more common in the UK than anywhere else in Europe.
Survival rates are poor compared to other types of cancer with only eight per cent of people alive five years after diagnosis. Scientists know little about how oesophageal cancer develops and very few drugs for targeting the disease are currently available.
The new study was led by Professor David Kelsell from Barts and the London Medical School, Queen Mary, University of London with collaborators from the University of Dundee and the University of Liverpool.
The research concentrated on three families with a hereditary condition called tylosis with oesophageal cancer. This condition affects the skin and mouth and sufferers have a 95 per cent chance of developing oesophageal cancer by the age of 65.
The research revealed that all three families carried a faulty version of a gene called RHBDF2.
Experiments showed that this gene plays an important role in how cells that line the oesophagus, and cells in the skin, respond to injury. When the gene is functioning normally it ensures that cells grow and divide in a controlled fashion to help heal a wound.
However, in tylosis patients’ cells, and in cells from oesophageal cancers, the gene malfunctions. This allows cells to divide and grow uncontrollably, causing cancer.
Professor Kelsell explains: ‘In studying this relatively rare condition, we have made an important discovery about a cancer that is all too common. Finding a genetic cause for this aggressive cancer, and understanding what that gene is doing, is an enormous step forward.
‘By analysing the complex biology which causes a particular type of cancer we begin to understand which treatments might be effective and also which treatments are unlikely to help.’ Queen Mary University of London

Today, heterosexuals in Europe are at particular risk of carrying HIV for so long that they remain undiagnosed until their immune system starts to fail and they become ill.
An international study under the leadership of the HIV in Europe initiative has now revealed that a number of diseases, including herpes zoster and certain forms of cancer, should be on the list of indicators for having HIV – and thus serve to prompt health care professionals to suggest an HIV-test to their patients.
The new results and guidelines are to be debated at a major international HIV conference in Copenhagen on 19th-20th March.
‘At the HIV in Europe conference we will be discussing how to disseminate knowledge of the new HIV indicator diseases to non-HIV doctors and health care professionals across Europe,’ says Jens Lundgren, Co-chair of the HIV in Europe initiative.
He’s also a Professor of Viral Diseases at Rigshospitalet and the Faculty of Health and Medical Sciences at the University of Copenhagen, where he heads the Copenhagen HIV Programme, one of the leading HIV/AIDS centres in the world.
Half of all people living with HIV are diagnosed very late in the course of their chronic HIV infection. People infected through heterosexual transmission now comprise 42 per cent of these late presenters, as a study of 90,000 Europeans tested HIV positive since 2.000 shows.
UNAIDS has estimated that 2,5 million Europeans carry an HIV infection, and as many as 900 000 of these, are still unaware of this. Inside EU the numbers are 800.000 infected with 250.000 undiagnosed.
Ton Coenen, co-chair of the HIV in Europe initiative, Director of Aids Funds and Soa AIDS Nederland suggests that since the HIV/AIDS issue is no longer high on the agenda in many European countries, and since people have to actively choose to be HIV-tested, many perhaps no longer consider going for a test if they have had unsafe sex.
However, the sooner HIV-infected individuals receive a diagnosis and start therapy, the greater are their chances of survival and their quality of life. And new research also shows therapy lowers the risk of passing the infection on to someone else.
‘The currently situation shows that we need more effective testing strategies and guidelines,’ Ton Coenen continues. ‘More than 300 doctors, health care professionals, NGOs and health politicians from 40 European countries will be discussing this need at the conference on 19th and 20th of March, so we have the ideal forum for it.’
‘We already have a list of Aids defining diseases, the vast majority of which indicate a weak immune system. This is a symptom of HIV and should lead to an immediate HIV test,’ Professor Lundgren explains. ‘We nned to find people living with HIV sooner than is currently the case, but to do so requires that doctors and other health care professionals offer tests to people presenting with diseases indicative of a hidden and undiagnosed HIV infection earlier in the course of the disease.’
The HIV in Europe initiative took up this challenge in 2009 and started the HIDES study (HIV Indicator Diseases Across Europe), which investigated eight new diseases and how often they proved to be signs of an undiagnosed HIV infection among the 3588 patients in the study.
‘We could see that if an adult had a sexually transmitted infection, malignant lymphoma, cervical or anal cancer/dysplasia, herpes zoster, hepatitis B or C, ongoing mononucleosis-like illness, inexplicable, persistent decline in the number of circulating white blood cells, or seborrheic dermatitis/exanthema, the risk of HIV infection was so high that it would be cost-effectiveness for society to routinely offer them a test,’ Professor Lundgren says. He also emphasises that the new indicator diseases do not necessarily mean that the patient has HIV.
‘But the incidence of HIV is greater for these eight indicator diseases and they should encourage health care professionals to offer the patient an HIV test. Draft guidelines on how to ensure this throughout Europe are one of the topics we need to debate and decide on, before they can be implemented.’ University of Copenhagen

UT Southwestern Medical Center cardiologists have uncovered how a specific protein’s previously unsuspected role contributes to the deterioration of heart muscle in patients with diabetes. Investigators in the mouse study also have found a way to reverse the damage caused by this protein.
Dr. Joseph HillThe new research was carried out in the laboratory of Dr. Joseph Hill, director of the Harry S. Moss Heart Center at UT Southwestern.
‘If we can protect the heart of diabetic patients, it would be a significant breakthrough,’ said Dr. Hill, the study’s senior author who also serves as chief of cardiology at the medical center. ‘These are fundamental research findings that can be applied to a patient’s bedside.’
Cardiovascular disease is the leading cause of illness and death in patients with diabetes, which affects more than 180 million people around the world, according to the American Heart Association. Diabetes puts additional stress on the heart – above and beyond that provoked by risk factors such as high blood pressure or coronary artery disease, Dr. Hill said.
‘Elevated glucose and the insulin-resistant diabetic state are both toxic to the heart,’ he said.
Dr. Hill and his colleagues in this study were able to maintain heart function in mice exposed to a high fat diet by inactivating a protein called FoxO1. Previous investigations from Dr. Hill’s laboratory demonstrated that FoxO proteins, a class of proteins that govern gene expression and regulate cell size, viability and metabolism, are tightly linked to the development of heart disease in mice with type 2 diabetes.
‘If you eliminate FoxO1, the heart is protected from the stress of diabetes and continues to function normally,’ Dr. Hill said. ‘If we can prevent FoxO1 from being overactive, then there is a chance that we can protect the hearts of patients with diabetes.’ UT Southwestern Medical Center