Researchers funded by the Canadian Cancer Society have discovered eight similar genes that, when mutated, appear to be responsible for medulloblastoma – the most common of childhood brain cancers. The findings are published in the online edition of the journal Nature Genetics.

“This discovery is very promising and may help researchers develop better, more targeted treatments so that more of these children will survive and fewer will suffer debilitating side effects,” says Dr. Christine Williams, Director of Research Programs, Canadian Cancer Society Research Institute.

Dr. Michael Taylor, who has a $600,000 research grant from the Canadian Cancer Society, led the study: “When these eight genes are functioning normally, we believe their role is to make a protein which tells the developing brain when it’s time to stop growing. But when the genes are mutated, the brain may continue to grow out of control, leading to cancer.

“Drugs are already being developed that target these types of proteins,” he says. “Our hope is that some of these drugs may be adapted and used effectively to treat medulloblastomas.” Dr. Taylor is a pediatric brain surgeon at Toronto’s Hospital for Sick Children:

In the study, the largest of its kind, researchers looked at more than 200 tumour samples. The samples came from children in countries all over the world including Canada, the US, England, Poland and Saudi Arabia. Paul Northcott, a PhD student in Dr Taylor’s lab, analyzed and interpreted all the data over a period of 3 ½ years. “We’ve learned more from this study about the genetic basis of this disease than from any other previous study,” Northcott says. The gene mutations they found had not been suspected as culprits in cancer formation.

About 250 Canadian children are diagnosed with various types of brain cancer every year. About 70 per cent of these survive. Brain tumours are the leading cause of childhood cancer deaths. The most common childhood brain cancer is medulloblastoma – a tumour that occurs at the back of the brain in the cerebellum. It is primarily a disease of very young children and is particularly deadly among babies under 18 months of age. In Canada, about 40 children are diagnosed with medulloblastoma every year and half of these will survive.

Many survivors experience serious physical and neurological problems from the disease itself and from the effects of very aggressive treatments on the developing brain. Treatments include surgery, radiation and chemotherapy.

Notes:

The Canadian Cancer Society is a national community-based organization of volunteers whose mission is the eradication of cancer and the enhancement of the quality of life of people living with cancer. It is the largest national charitable funder of cancer research in Canada. Last year, the Society funded close to $49.5 million in leading-edge research projects across the country. To know more about cancer, visit the website at http://www.cancer.ca/.

Giving patients with glioblastoma-the most common and aggressive form of primary brain tumour-the chemotherapy drug temozolomide in combination with radiotherapy increases their survival compared with those receiving radiotherapy alone and this improvement persists for up to 5 years, according to the final results of the EORTC-NCIC trial*, published Online first and in the May edition of The Lancet Oncology.

For over 30 years, post-operative radiotherapy was the standard treatment for glioblastoma, but offered only modest survival benefits to patients. The average life-expectancy of patients with glioblastoma was 9-12 months.

In 2004, after many disappointing attempts with drug therapy, the large international phase III EORTC-NCIC trial finally showed some promising results in this difficult setting where use of combined treatment with radiotherapy and temozolomide reduced the risk of dying from glioblastoma by 37% (HR for death 0.63, CI 0.53-0.75) compared with radiotherapy alone. At 2 years, 27% of patients receiving temozolomide in combination with radiotherapy (TMZ/RT) were alive, compared with just 10% of patients being treated with radiotherapy (RT) alone. However, whether this survival benefit would persist over time was unknown.

In this study, Roger Stupp and colleagues report the long-term 5-year outcomes of patients involved in the original EORTC-NCIC trial. The authors also examined whether clinical factors and the molecular profile of the tumours would identify patients with particularly good survival or response to chemotherapy.

Findings showed that at 3 years, 16% of patients receiving TMZ/RT were alive compared with only 4% of patients having RT alone. At 4 years, overall survival data after combined treatment were 12.1% compared with 3% for RT alone and at 5 years, 9.8% vs 1.9%, respectively. Importantly, improvement in survival was seen across all clinical prognostic subgroups, even in patients considered to have a poor diagnosis-such as more elderly patients or patients whose tumour could not be removed.

In exploratory analyses, overall survival data were best in patients being treated with TMZ/RT whose tumours carried an inactivated MGMT gene (0-6-methylguanine-DNA methyltransferase). Almost half of these patients were alive after 2 years and they also showed a persistent survival advantage at 3, 4, and 5 years. The authors suggest that testing tumours for the methylation status of the MGMT gene would allow the selection of patients most likely to benefit from this treatment.

Despite this improvement-with a substantial proportion of patients surviving for several years after treatment with TMZ/RT-most still died. The authors noted no difference in the pattern of recurrence between patients treated with RT alone or TMZ/RT, and caution that upfront combined therapy may be effective in reducing tumour bulk and aggressiveness, but it does not truly modify the natural behaviour of the disease, and thus is unlikely to lead to a cure.

*The EORTC-NCIC (European Organisation for Research and Treatment of Cancer and the National Cancer Institute of Canada Clinical Trials Group) trial was a randomised trial in which standard post-operative radiotherapy and standard post-operative radiotherapy combined with temozolomide followed by up to six cycles of temozolomide were compared in 573 patients with newly diagnosed glioblastoma.

The combination of two drugs produces a critical improvement in the treatment of certain brain tumours. This has been demonstrated by researchers at Bonn University working in co-operation with German and Swiss colleagues in a current study. They treated 39 patients who had been diagnosed with a so-called gliablastoma. The patients survived on average 23 months; with the standard therapy the mean would have been 14.6 months. Glioblastomas are the most aggressive and the commonest brain tumours. Left untreated, they prove fatal within just a few weeks. The study has been published in the Journal of Clinical Oncology (doi: 10.1200/JCO.2008.19.2195).

Even today, glioblastomas are untreatable – something which even the new combination therapy cannot change. Nevertheless, Professor Dr. Ulrich Herrlinger of Bonn University´s Schwerpunkt Klinische Neuroonkologie speaks of an outstanding success: “This unusually manifest extension of the survival time has surprised even us. Our results offer the opportunity to improve our grip on this aggressive form of cancer. Now, further investigations involving a larger number of patients are needed to optimise this therapy. Planning for this is already in hand in Bonn”.

Up to now, doctors have treated glioblastomas using radiotherapy with concomitant chemotherapy. The “gold standard” for this for the last few years has been the active agent temozolomide. This is still celebrated as the most important breakthrough in the treatment of glioblastomas. The researchers combined this preparation with the drug lomustine. At the same time, the patients were given radiotherapy. The 39 patients thus treated survived the tumour for an average of 23.1 months. With the standard therapy, this time is over one third shorter. Seven patients even survived for over four years.

Genes decide the Success of the Therapy

It would appear that certain changes in the genotype are critical for the success of this therapy. “With eleven participants in the study, the information of one gene had been subjected to a characteristic modification”, Ulrich Herrlinger declares. “These patients survived on average a good 34 months. With the other patients, these drugs appeared to bring no apparent advantage vis-à-vis pure radiotherapy – at least, not in the dosage we tested. It is possible that a simple gene test could decide for whom a concomitant chemotherapy might be of benefit”. One disadvantage of the new method are the side-effects. However, these mostly occur during the several months of the treatment phase. “After that they normally disappear completely, and the patients have no further complaints about them”, Herrlinger stresses.

Working in co-operation with the Life&Brain-Zentrum in Bonn, the search is now on for more compatible, more effective, drugs. “Amongst other things, we now want to use cell cultures from original tumours to study precisely what the preparations we used in the study really effect”, Dr. Martin Glas, one of the authors of the study, declares.

Notes:

Long-Term Survival of Patients With Glioblastoma Treated With Radiotherapy and Lomustine Plus Temozolomide. Martin Glas, Caroline Happold, Johannes Rieger, Dorothee Wiewrodt, Oliver Bähr, Joachim P. Steinbach, Wolfgang Wick, Rolf-Dieter Kortmann, Guido Reifenberger, Michael Weller, and Ulrich Herrlinger. Journal of Clinical Oncology, February 2009 The combination of two drugs produces a critical improvement in the treatment of certain brain tumours. This has been demonstrated by researchers at Bonn University working in co-operation with German and Swiss colleagues in a current study. They treated 39 patients who had been diagnosed with a so-called gliablastoma. The patients survived on average 23 months; with the standard therapy the mean would have been 14.6 months. Glioblastomas are the most aggressive and the commonest brain tumours. Left untreated, they prove fatal within just a few weeks. The study has been published in the Journal of Clinical Oncology (doi: 10.1200/JCO.2008.19.2195).

Even today, glioblastomas are untreatable – something which even the new combination therapy cannot change. Nevertheless, Professor Dr. Ulrich Herrlinger of Bonn University´s Schwerpunkt Klinische Neuroonkologie speaks of an outstanding success: “This unusually manifest extension of the survival time has surprised even us. Our results offer the opportunity to improve our grip on this aggressive form of cancer. Now, further investigations involving a larger number of patients are needed to optimise this therapy. Planning for this is already in hand in Bonn”.

Up to now, doctors have treated glioblastomas using radiotherapy with concomitant chemotherapy. The “gold standard” for this for the last few years has been the active agent temozolomide. This is still celebrated as the most important breakthrough in the treatment of glioblastomas. The researchers combined this preparation with the drug lomustine. At the same time, the patients were given radiotherapy. The 39 patients thus treated survived the tumour for an average of 23.1 months. With the standard therapy, this time is over one third shorter. Seven patients even survived for over four years.

Genes decide the Success of the Therapy

It would appear that certain changes in the genotype are critical for the success of this therapy. “With eleven participants in the study, the information of one gene had been subjected to a characteristic modification”, Ulrich Herrlinger declares. “These patients survived on average a good 34 months. With the other patients, these drugs appeared to bring no apparent advantage vis-à-vis pure radiotherapy – at least, not in the dosage we tested. It is possible that a simple gene test could decide for whom a concomitant chemotherapy might be of benefit”. One disadvantage of the new method are the side-effects. However, these mostly occur during the several months of the treatment phase. “After that they normally disappear completely, and the patients have no further complaints about them”, Herrlinger stresses.

Working in co-operation with the Life&Brain-Zentrum in Bonn, the search is now on for more compatible, more effective, drugs. “Amongst other things, we now want to use cell cultures from original tumours to study precisely what the preparations we used in the study really effect”, Dr. Martin Glas, one of the authors of the study, declares.

Notes:

Long-Term Survival of Patients With Glioblastoma Treated With Radiotherapy and Lomustine Plus Temozolomide. Martin Glas, Caroline Happold, Johannes Rieger, Dorothee Wiewrodt, Oliver Bähr, Joachim P. Steinbach, Wolfgang Wick, Rolf-Dieter Kortmann, Guido Reifenberger, Michael Weller, and Ulrich Herrlinger. Journal of Clinical Oncology, February 2009

Schering-Plough Corporation (NYSE: SGP) announced that the European Commission and the US FDA both approved the intravenous (IV) formulation of temozolomide as an alternative to the already approved oral form of the drug. Temozolomide is marketed as TEMODAL(R) in the EU and as TEMODAR(R) in the US. The EU Commission Decision was based on the positive opinion from the European Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) in November 2008. On January 22, 2009, the Commission approved a sachet packaging presentation for TEMODAL Capsules. This new presentation provides greater patient convenience and flexibility. On February 17, 2009, the Commission approved an IV formulation of TEMODAL. On February 27, 2009, Schering-Plough received approval from the US FDA for the TEMODAR IV formulation.

TEMODAL is a chemotherapy agent approved in the EU for treatment of patients with newly diagnosed glioblastoma multiforme (GBM) concomitantly with radiotherapy and subsequently as monotherapy, and for patients with malignant gliomas, such as GBM or anaplastic astrocytoma (AA), showing recurrence or progression after standard therapy. In the US, TEMODAR is approved for the treatment of adult patients with newly diagnosed GBM concomitantly with radiotherapy and then as maintenance treatment, as well as for refractory AA, i.e., patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

“TEMODAR is a well recognized, effective treatment for patients with newly diagnosed GBM. The newly approved IV formulation of TEMODAR provides patients with an important alternative method of administration, and the European TEMODAL sachet presentation offers flexibility and a convenient alternative form of packaging,” said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. “These two new options recognize Schering-Plough’s commitment to providing effective treatments in a variety of presentations for specific patient needs and patient convenience.”

About Malignant Gliomas

The worldwide incidence rate of primary malignant brain and central nervous system tumors, using the world standard population, is 3.7 per 100,000 person in males and 2.6 per 100,000 person in females(1). The most common type of primary malignant brain tumors are gliomas, with AA and GBM being the most common and among the most serious types.

About temozolomide

In addition to the new presentations, TEMODAL (temozolomide), a cytotoxic agent, is currently approved in oral form as 5mg, 20mg, 100mg, 140mg, 180mg and 250mg capsules in Europe. Cytotoxic agents are designed to impact the replication of cells that divide rapidly, such as those in tumors.

TEMODAL was initially approved in the EU in 1999 for the treatment of patients with malignant glioma, such as GBM or AA, showing recurrence or progression after standard therapy. In June 2005, TEMODAL received marketing approval in the EU for the treatment of patients with newly diagnosed GBM concomitantly with radiotherapy and subsequently as monotherapy treatment. The TEMODAL IV formulation approved by the EU Commission was developed for cancer patients who are unable to take TEMODAL Capsules and has shown bioequivalence to the oral product. The sachet packaging presentation for TEMODAL Capsules was created to provide greater patient convenience and flexibility.

TEMODAR capsules (temozolomide) received accelerated approval from the US Food and Drug Administration (FDA) for adult patients with refractory AA in 1999 and full approval in March 2005 for refractory AA, i.e., patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine, and for the treatment of newly diagnosed GBM concomitantly with radiotherapy and then as maintenance treatment.

Important Information Regarding US Labeling for TEMODAR and TEMODAR Intravenous Formulation

TEMODAR(R) (temozolomide) is indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment. TEMODAR is indicated for the treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

TEMODAR(R) is contraindicated in patients who have a history of hypersensitivity (such as urticaria, allergic reaction including anaphylaxis, toxic epidermal necrolysis and Stevens-Johnson syndrome) to any of its components, or to DTIC.

Patients treated with TEMODAR(R) Capsules may experience myelosuppression including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medications associated with aplastic anemia including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim complicates assessment. Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have also been observed.

Prophylaxis against Pneumocystis carinii pneumonia is required for all patients receiving concomitant TEMODAR(R) and radiotherapy for the 42-day regimen. There may be a higher occurrence of PCP when temozolomide is administered during a longer dosing regimen. However, all patients receiving temozolomide, particularly patients receiving steroids, should be observed closely for the development of PCP regardless of the regimen.

TEMODAR(R) can cause fetal harm when administered to a pregnant woman. In nursing women, a decision should be made whether to discontinue nursing or to discontinue TEMODAR(R), taking into account the importance of the drug to the mother. The safety and effectiveness of TEMODAR(R) in children have not been established.

As bioequivalence between TEMODAR Capsules and TEMODAR for Injection has been established only when TEMODAR for Injection was given over 90 minutes, infusion over a shorter or longer period of time may result in suboptimal dosing. Additionally, the possibility of an increase in infusion related adverse reactions cannot be ruled out.

TEMODAR(R) Capsules should not be opened or chewed. If capsules are accidentally opened or damaged, rigorous precautions should be taken with the capsule contents to avoid inhalation or contact with the skin or mucous membranes.

Caution should be exercised when administered to those with severe hepatic or renal impairment.

In newly diagnosed patients with glioblastoma multiforme, the adverse event profile was similar in patients <65 years of age and those greater than or equal to 65 years.

In newly diagnosed glioblastoma multiforme the most common adverse reactions in clinical studies in the Concomitant Phase (Radiotherapy + TEMODAR(R)) and the Maintenance Phase (TEMODAR(R) alone), respectively, were alopecia 69%, 55%; fatigue 54%, 61%; nausea 36%, 49%; vomiting 20%, 29%; anorexia 19%, 27%; headache 19%, 23%; rash 19%, 13%; constipation 18%, 22%; with the following important adverse events also reported: convulsions 6%, 11% and thrombocytopenia 4%; 8%. Of these adverse events, those grade greater than or equal to 3 in clinical studies in the Concomitant Phase (Radiotherapy + TEMODAR) and the Maintenance Phase (TEMODAR alone), respectively, were fatigue 7%, 9%; nausea 1%, 1%; vomiting <1%, 2%; anorexia 1%, 1%; headache 2%, 4%; constipation 1%, 0%; convulsions 3%, 3%; thrombocytopenia 3%, 4%.

In the newly diagnosed GBM population, when laboratory abnormalities and adverse events were combined, Grade 3 or 4 neutropenia occurred in 8% and Grade 3 or 4 platelet abnormalities including thrombocytopenic events occurred in 14% of patients treated with temozolomide.

Most common adverse reactions in the trial in AA patients overall and Grade 3/4, respectively, were: nausea 53%, 10%; vomiting 42%, 6%; headache 41%, 6%; fatigue 34%, 4%; constipation 33%, 1%; convulsions 23%, 5%; with the following important adverse events also reported: hemiparesis 18%, 6%; asthenia 13%, 6%.

Adverse hematologic effects (Grade 3 to 4) in the AA trial in adults were lymphopenia (55%); platelets (19%); neutrophils (14%); WBC (11%); and hemoglobin (4%).

7% and 9.5% of patients over age 70 experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients less than or equal to age 70, 7% and 5.5% experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively.

Adverse reactions reported from intravenous formulation studies that were not reported in TEMODAR capsule studies were: pain, irritation, pruritus, warmth, swelling, and erythema at infusion site as well as the following adverse reactions: petechiae and hematoma.

About Schering Plough

Schering-Plough is an innovation-driven, science-centered global health care company. Through its own biopharmaceutical research and collaborations with partners, Schering-Plough creates therapies that help save and improve lives around the world. The company applies its research-and-development platform to human prescription, animal health and consumer health care products. Schering-Plough’s vision is to “Earn Trust, Every Day” with the doctors, patients, customers and other stakeholders served by its colleagues around the world. The company is based in Kenilworth, N.J., and its Web site is http://www.schering-plough.com.

SCHERING-PLOUGH DISCLOSURE NOTICE: The information in this press release includes certain “forward-looking statements” within the meaning of the Securities Litigation Reform Act of 1995, including statements relating to TEMODAL and the potential market for TEMODAL. Forward-looking statements relate to expectations or forecasts of future events. Schering-Plough does not assume the obligation to update any forward-looking statement. Many factors could cause actual results to differ materially from Schering-Plough’s forward-looking statements, including market forces, economic factors, product availability, patent and other intellectual property protection, current and future branded, generic or over-the-counter competition, the regulatory process, and any developments following regulatory approval, among other uncertainties. For further details about these and other factors that may impact the forward-looking statements, see Schering-Plough’s Securities and Exchange Commission filings, including Item 1A. “Risk Factors” in the 2008 10-K, filed February 27, 2009.

Also Included In: Neurology / Neuroscience; Regulatory Affairs / Drug Approvals; Clinical Trials / Drug Trials

While surviving cancer should be an occasion for rejoicing, many people who have undergone the standard or high-dose chemotherapy to defeat the disease unfortunately suffer from a physical and mental ailment known as “chemobrain.” This cognitively dysfunctional symptom ranges from fatigue and memory loss to serious learning impairment due to possible brain damage. In CHEMOBRAIN: HOW CANCER THERAPIES CAN AFFECT YOUR MIND (Prometheus Books, $18.98), a clear, concise guide for cancer patients, survivors, families, friends, and caregivers, noted science journalist Ellen Clegg provides the latest information on this much-discussed but poorly understood side effect of chemotherapy treatment, while also – in an objective journalistic fashion – giving voice to those medical professionals who remain skeptical of chemobrain.

Based on extensive and candid interviews with both those suffering from chemobrain and the physicians and scientists who have treated and studied this problem, Clegg cuts through the scientific jargon and explains in understandable terms how chemotherapy works at the most basic biological level. In doing so, she provides cancer survivors with the knowledge to understand what is happening to them and practical tips for coping with the aftermath of chemotherapy treatment.

Clegg’s extensive cross-analysis of chemotherapy survivors’ stories with the opinions of doctors who recognize the symptoms will provide the affirmation that so many who suffer from chemobrain so desperately need. She includes tactics for dealing with cognitive problems and other lingering side effects, strategies for multitasking at home and reentering the workforce, and even ways to deal with health insurance.

In addition to personal strategies and stories, Clegg also provides the history of the patient empowerment movement that brought chemobrain to the attention of the medical establishment in the first place. She also addresses the future of cancer research and the search for treatments that do less harm, and looks at chemobrain’s implications for the mental health of developing children.

Stewart B. Fleishman, MD, Director, Supportive Services, Continuum Cancer Centers of New York: Beth Israel and St. Luke’s-Roosevelt Hospitals, is a doctor at the forefront of a new movement to treat cognitive dysfunction as a real symptom with real potential solutions. “We will learn more about the causes of cognitive impairment soon, asking future patient generations to invest less of their quality of life to not only survive, but also thrive after diagnosis of cancer and its treatment,” he writes in the book’s foreword. “Many questions have yet to be answered. Further studies are now underway to do so.”

While survivor circles have acknowledged and debated chemobrain for years, this is the first and only book to delve into the cognitive problems many patients endure when they undergo chemotherapy. CHEMOBRAIN brings together cutting-edge science, the compelling stories of adults and children who have struggled for years with cognitive dysfunction, and the coping strategies being developed on the front lines of patient care. Clegg’s investigative study of chemobrain is both a required read for today’s upcoming medical professionals and a gospel for those suffering with this widespread symptom as well as for caring family members.

Notes:

About the Author: Ellen Clegg (Boston, MA) is a deputy managing editor of news operations at the Boston Globe, in charge of the Sunday paper. Her previous positions at the same paper include health and science editor, night news editor, and city editor.

People in the Northeastern U.S. are one-third more likely than those in the South or West to be hospitalized for treatment of brain cancer or to have brain cancer when they are hospitalized for another illness or complication, according to the latest News and Numbers from the U.S. Agency for Healthcare Research and Quality.

In 2006, about 30 of every 100,000 people in the Northeast were hospitalized with brain cancer. That compares to 23 per 100,000 for people in both the South and West. The rate was slightly higher for people in the Midwest 25 per 100,000.

AHRQ’s analysis also shows that in 2006:

– Nationally, the hospitalization rate for brain cancer remained stable since 1995 roughly about 35,000 hospital stays a year.

– An additional 38,000 hospital admissions were associated with brain cancer mostly for chemotherapy or radiotherapy to continue treatment, or for convulsions, pneumonia or other complication from the disease. These hospitalizations increased 18 percent since 1995.

– Among people over 65, men were 62 percent more likely to be hospitalized primarily for brain cancer and 55 percent more likely to be hospitalized with brain cancer as a secondary diagnosis than were women.

– While 6.2 percent of hospital patients admitted for brain cancer died while hospitalized in 1995, the rate dropped to 4.4 percent in 2006.

This AHRQ News and Numbers is based on data in Hospitalizations for Brain Cancer, 2006. The report uses statistics from the 2006 Nationwide Inpatient Sample, a database of hospital inpatient stays that is nationally representative of inpatient stays in all short-term, non-Federal hospitals. The data are drawn from hospitals that comprise 90 percent of all discharges in the United States and include all patients, regardless of insurance type, as well as the uninsured.

Cognitive neuroscientists at the Swedish medical university Karolinska Institutet (KI) have succeeded in making subjects perceive the bodies of mannequins and other people as their own. The findings are published in the online, open-access journal PLoS ONE, December 3.

In the first experiment, the head of a shop dummy was fitted with two cameras connected to two small screens placed in front of the subjects’ eyes, so that they saw what the dummy “saw.” When the dummy’s camera eyes and a subject’s head were directed downwards, the subject saw the dummy’s body where he/she would normally have seen his/her own.

The illusion of body-swapping was created when the scientist touched the stomach of both with two sticks. The subject could then see that the mannequin’s stomach was being touched while feeling (but not seeing) a similar sensation on his/her own stomach. As a result, the subject developed a powerful sensation that the mannequin’s body was his/her own.

“This shows how easy it is to change the brain’s perception of the physical self,” says Henrik Ehrsson, who led the project. “By manipulating sensory impressions, it’s possible to fool the self not only out of its body but into other bodies too.”

In another experiment, the camera was mounted onto another person’s head. When this person and the subject turned towards each other to shake hands, the subject perceived the camera-wearer’s body as his/her own.

“The subjects see themselves shaking hands from the outside, but experience it as another person,” says Valeria Petkova, who co-conducted the study with Dr Ehrsson. “The sensory impression from the hand-shake is perceived as though coming from the new body, rather than the subject’s own.”

The strength of the illusion was confirmed by the subjects’ exhibiting stress reactions when a knife was held to the camera wearer’s arm but not when it was held to their own.

The illusion also worked even when the two people differed in appearance or were of different sexes. However, it was not possible to fool the self into identifying with a non-humanoid object, such as a chair or a large block.

The object of the projects was to learn more about how the brain constructs an internal image of the body. The knowledge that the sense of corporal identification/self-perception can be manipulated to make people believe that they have a new body is of potential practical use in virtual reality applications and robot technology.

Citation:
” If I Were You: Perceptual Illusion of Body Swapping.”
Petkova VI, Ehrsson HH (2008)
PLoS ONE 3(12): e3832. doi:10.1371/journal.pone.0003832
Click here to view article online

About PLoS ONE

PLoS ONE is the first journal of primary research from all areas of science to employ a combination of peer review and post-publication rating and commenting, to maximize the impact of every report it publishes. PLoS ONE is published by the Public Library of Science (PLoS), the open-access publisher whose goal is to make the world’s scientific and medical literature a public resource.

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Most children are able to imagine their future selves as astronauts, politicians or even superheroes; however, many older adults find it difficult to recollect past events, let alone generate new ones. A new Harvard University study reveals that the ability of older adults to form imaginary scenarios is linked to their ability to recall detailed memories.

According to the study, episodic memory, which represents our personal memories of past experiences, “allows individuals to project themselves both backward and forward in subjective time.”

Therefore, in order to create imagined future events, the individual must be able to remember the details of previously experienced ones extract various details and put them together to create an imaginary event, a process known as the constructive-episodic-simulation.

Harvard psychologists Donna Rose Addis, Alana Wong and Daniel Schacter supported the hypothesis using an adapted version of the Autobiographical Interview in which young and older participants responded to randomly selected cue words with past and future scenarios.

When compared with young adults, the researchers found that the older adults displayed a significant reduction in the use of internal episodic details to describe both past memories and imagined future events.

The results of the study, which appear in the January 2008 issue of Psychological Science, a journal of the Association for Psychological Science, not only reveal that there is a link between age-related memory deficits and future planning in older adults, but raise questions concerning the involvement of other types of memory, as well.

New research at Wake Forest University Baptist Medical Center suggests that a three-drug cocktail may one day improve outcomes in patients with glioblastoma multiforme (GBM), a type of brain tumor with a dismal prognosis. Two of the drug candidates have been developed, and the team is working on the third all targeted to kill or impair cancer cells and spare healthy brain.

Waldemar Debinski, M.D., Ph.D., senior researcher and director of the Wake Forest Brain Tumor Center of Excellence, predicts that the cocktail could be tested in patients within five years.

The treatment would be based on the first-ever documented “molecular signature” of GBM tumors. The researchers had previously reported that three different proteins are found in high levels individually in these cancers. In the current study, reported in Clinical Cancer Research, they examined 76 specimens of brain tumor, including 46 GBMs, and nine normal brain samples, to determine how frequently the markers appeared together.

Expression of all three markers was significantly higher in GBM tissue compared to normal brain and to brain tumors that aren’t as aggressive as GBM. Particularly important was that all GBM tumors had at least one of the markers present and 95 percent of tumors had at least two.

“This finding offers a unique opportunity for treatment,” said Debinski. “Without any pre-therapy testing, we would know for sure that at least one of these targets is highly present in each patient and that the patient is suitable for the combination of off-the-shelf drugs. It is like having a crystal ball.”

In a recent issue of Molecular Cancer Therapeutics, the researchers reported developing a potent treatment targeted to one of the proteins (EphA2). In addition, a drug targeted to a second protein, interleukin 13 receptor alpha 2 (IL-13R 2), is already being tested alone in a phase 3 clinical trial. In this trial, the second protein is showing significant benefits to patients, and newer generations are in development. The team is working to develop a drug to target a third marker (Fra-1). GBM tumors are often resistant to current treatments, including chemotherapy and radiation therapy. The mean survival rate of patients with GBM is about 14 months and has improved only slightly over the past decades.

“Developing molecularly targeted therapies using genetically engineered bacterial toxins represents an attractive option that may improve outcomes,” said Debinski.

The fact that the three markers were not found in healthy brain tissue suggests that the proteins are highly suited as targets for therapies designed to kill cancer cells and spare healthy brain tissue. In Molecular Cancer Therapeutics, the team reported success creating a drug to kill cancer cells that have high levels of EphA2. The drug, which would be delivered by catheters directly to the tumor, was created by chemically linking a protein that binds to EphA2 with a modified bacterial toxin. In the laboratory, the treatment potently killed all of the over-expressing EphA2 cells within 48 hours. It was also effective at reducing tumors in mice. The researchers compared the treatment’s potency to the drug Debinski had previously developed to target cells that express IL-13R 2.

“Both were extremely effective and highly potent,” said Debinski. “Some of the tumor cells responded to the IL-13 cytotoxin, some responded to EphA2-targeted cytotoxin and some responded to both. This illustrates why we need a cocktail to cover as many patients as possible.”

He said this combination treatment might also apply to breast, pancreas and prostate cancers, which also have high levels of these proteins.

The third marker, Fra-1, is believed to control the malignant features of brain tumor cells, such as the development new blood vessels to “feed” the tumor.

An additional benefit of targeting the three proteins is that the drug cocktail affects targets residing in the GBM cellular signaling pathways, including a pathway (epidermal growth factor receptor vIII) that is known to control the expression of all three proteins. These pathways are known to be important in tumor progression.

“With the drug cocktail we may be taking care of cancer cells that are really important for tumor survival,” said Debinski. “It may be the best of two worlds.”

The research was funded by the National Cancer Institute, National Institute of Neurological Disorders and Wake Forest Brain Tumor Center of Excellence. Co-researchers were Jill Wykosky, Ph.D. candidate, lead author of the two manuscripts, Denise M. Gibo, B.S., and Constance Staton, M.D., all with Wake Forest.

Wake Forest University Baptist Medical Center is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university’s School of Medicine. The system comprises 1,154 acute care, psychiatric, rehabilitation and long-term care beds and is consistently ranked as one of “America’s Best Hospitals” by U.S. News & World Report.

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1. Neuron, Astrocyte, and Oligodendrocyte Transcriptomes

John D. Cahoy, Ben Emery, Amit Kaushal, Lynette C. Foo, Jennifer L. Zamanian, Karen S. Christopherson, Yi Xing, Jane L. Lubischer, Paul A. Krieg, Sergey A. Krupenko, Wesley J. Thompson, and Ben A. Barres

In this issue, Cahoy et al. describe a comprehensive database of quantitative gene expression data from neurons, astrocytes, and oligodendrocytes isolated from mouse forebrain at different developmental stages. To do this, the authors first developed a novel purification strategy, involving immunopanning and fluorescence-activated cell sorting, to obtain nearly pure samples of each cell type, including mature astrocytes. They then profiled the expression of >20,000 genes using GeneChip arrays. Besides providing a wealth of quantitative gene enrichment data for the neuroscience community, their analysis revealed that the transcriptomes of astrocytes and oligodendrocytes are as different from each other as they are from neurons and that cultured astrocytes are substantially different from mature astrocytes (the former may be more akin to reactive astrocytes). In addition, a new, highly specific, broadly expressed astrocyte marker, aldhL1, was identified. Finally, analysis of molecular pathway genes suggested that phagocytosis may be a major function of astrocytes.

2. Extended Period of Retinocollicular Synaptic Plasticity in â2-/- Mice

Ruchir D. Shah and Michael C. Crair

Spontaneous retinal waves, mediated by cholinergic synapses during the first postnatal week, are thought to drive refinement of the retinotopic map in the superior colliculus. This week, Shah and Crair use mice lacking the nicotinic acetylcholine receptor â2 subunit (â2-/-) to investigate mechanisms of synaptic plasticity in retinocollicular synapses. In normal mice, the AMPA/NMDA receptor ratio and the amplitude of AMPA currents increased from postnatal day 3 (P3) to P7, while the proportion of silent synapses decreased. These changes also occurred in â2-/- mice but only after the second postnatal week, when glutamate-mediated retinal waves occur. The delay in maturation of retinocollicular synapses in â2-/- mice was paralleled by an extended period in which long-term potentiation (LTP) could be elicited: a stimulation paradigm that mimicked retinal wave bursts elicited LTP in a majority of synapses in P3-P4 control mice, but not P6-P7 controls, whereas this stimulation produced LTP in â2-/- mice at both ages.

3. Antimanic Drugs and AMPA Receptors

Jing Du, Thomas K. Creson, Long-Jun Wu, Ming Ren, Neil A. Gray, Cynthia Falke, Yanling Wei, Yun Wang, Rayah Blumenthal, Rodrigo Machado-Vieira, Peixiong Yuan, Guang Chen, Min Zhuo, and Husseini K. Manji

Although lithium and valproate have long been used to treat manic disorder, the mode of action of these structurally dissimilar treatments is not fully understood. Du et al. now suggest that these drugs reduce trafficking of AMPA receptor GluR1/GluR2 tetramers to synapses. Chronic treatment of rats with therapeutic doses of lithium or valproate reduced levels of GluR2 in hippocampal synaptosomes, as had been shown previously for GluR1. The overall expression level of GluR2 in hippocampus was unchanged, however, suggesting that the reduction in membrane expression may result from decreased receptor trafficking. This hypothesis was supported by chronically treating rats with a fusion peptide that specifically blocks PKA phosphorylation of GluR1 at Ser 845, a site necessary for insertion of GluR1/2 tetramers into membranes. The treatment mimicked the effects of lithium and valproate on GluR1 and GluR2 localization, and it also decreased amphetamine-induced hyperactivity, a common model of mania.

4. Environmental Trigger for Alzheimer’s Disease

Jinfang Wu, Md. Riyaz Basha, Brian Brock, David P. Cox, Fernando Cardozo-Pelaez, Christopher A. McPherson, Jean Harry, Deborah C. Rice, Bryan Maloney, Demao Chen, Debomoy K. Lahiri, and Nasser H. Zawia

Early exposure to environmental toxins can lead to diseases much later in life. This week, Wu et al. report that primates exposed to lead as infants showed Alzheimer’s disease (AD)-like pathology years later. From birth to 400 d of age, monkeys were exposed to lead levels that produced no obvious sign of toxicity. Although by young adulthood blood lead levels in exposed monkeys were indistinguishable from those of controls, when examined at approximately 23 years of age, the brains of lead-exposed monkeys exhibited many hallmarks of AD, including Aâ plaques and neurofibrillary tangles, as well as increased expression of Aâ precursor protein (APP) and Sp1, a transcription factor that regulates APP expression. DNA methyl transferase I activity was reduced in lead-exposed monkeys, whereas oxidative damage to DNA was increased. These results indicate that lead exposure early in life can predispose animals to later neurodegenerative disease, possibly through alterations in DNA methylation and oxidation.