Posts Tagged ‘current’

Drug used for DNA repair defects could treat leukemia, other cancers more effectively

The new study suggests that treatment with poly (ADP-ribose) polymerase (PARP) inhibitors, together with standard chemotherapy drugs, could be more effective in combating leukemia. In the same study, researchers found that the inactivation of RUNX genes causes DNA repair defects and promotes the development of leukemia and other cancers. The study was first published online in the leading journal Cell Reports last month.

Unlike other cancers which are more commonly seen in the elderly, leukemia is notorious for its high prevalence among young people. There has been little advancement in the treatment of leukemia. Chemotherapy with or without hematopoietic stem cell transplantation remains the current standard of care, resulting in a cure rate of around 50 per cent. The RUNX family genes are among the most frequently inactivated genes in leukemia and other cancers. According to previous studies, RUNX1 is one of the most frequently mutated genes in leukemia and RUNX3 is associated with the development of the disease.

In this study, the research team also showed the link between the RUNX family genes and the pathway of a rare human congenital disease called Fanconi anemia for the first time. The disease is caused by mutations in one of the 15 genes responsible for the repair of a specific type of damaged DNA. In the early stages of this study, the researchers found that RUNX deficiency resulted in an inability to produce blood cells and a massive expansion of abnormal hematopoietic cells. They recognised that these clinical manifestations are symptoms of Fanconi anemia and started investigating RUNX functions in this DNA repair pathway.

Further research showed that RUNX proteins play a critical and central role in the Fanconi anemia pathway by facilitating the recruitment of a protein involved in the repair of DNA damage called FANCD2 to sites of DNA damage. This previously unknown relationship between RUNX and Fanconi anemia prompted the research team to test the possibility that PARP inhibitors, a drug originally designed for killing a limited type of cancer cells with DNA repair defects, could be applied in the treatment of leukemia and cancers with RUNX alterations. These types of cancer were previously not thought to have DNA repair defects. The researchers demonstrated that the drug was effective in the treatment of leukemia and other cancers in cell culture experiments.

Dr Osato said, “Common sense is often a veil that keeps us from understanding the truth. PARP inhibitors have been with us for quite some time, but nobody has realised their application for leukemia. Our study has shed light on the possibility of a more effective treatment using a combined therapy with PARP inhibitors which can potentially be extended to other types of common cancers.”

The team is currently conducting further drug efficacy testing with xenograft models, as a preclinical study.

source : http://www.sciencedaily.com/releases/2014/08/140825084450.htm

Lung cancer rarely detected by current X-ray procedures

In Norway, no other forms of cancer take as many lives as lung cancer. Each year, 2800 Norwegians develop the dreaded disease. Their prognosis is unpromising: six out of seven die within five years.

What is especially unfortunate about lung cancer is that the tumor has ample space to grow. It can thus grow for a long time before being detected.

Most patients have their first diagnosis made by X-ray imaging. Each year, Oslo University Hospital takes 30 000 chest X-rays. Nationwide, this number exceeds one million.

Nobody has ever investigated how well X-ray images function with a view to detecting lung cancer and other diseases of the chest region.

“X-ray technology has remained nearly unaltered for one hundred years,” says Trond Mogens Aaløkken at the Department of Radiology and Nuclear Medicine, Oslo University Hospital. In cooperation with a group of physicists at the Intervention Centre he has made a comparison of the proportion of patients who obtain a correct diagnosis with X-ray images and how many patients might have obtained a correct diagnosis with computer tomography (CT), which is a far more modern imaging technology.

While X-ray images are two-dimensional, CT images are three-dimensional. CT images can thus reveal the exact location of the tumor.

Too much radiation before

Until today, the radiation dose from examinations of lungs with CT has been one hundred times higher than from regular X-ray examinations. A CT scan is equivalent to five years of natural background radiation.

Radiologists have therefore been reluctant to use CT for an initial diagnosis of lung cancer.

If the X-ray examination is negative, some months may pass before the patient is referred for a CT scan. Then, it may already be too late.

“It’s sad that so many come to be treated too late because the hospitals are reluctant to use CT. The survival rate can be increased significantly if the lung cancer is initially detected by CT,” Aaløkken points out to the research magazine Apollon.

In recent years, CT scanners have become far more effective. The mathematical method for reconstructing pictures has changed completely. This means that the images now contain more information, while the radiation dose has decreased.

Little radiation now

Researchers at the Intervention Centre have now succeeded in producing CT images with the same low radiation dose as a regular X-ray image.

“We still cannot achieve the same high-quality images by replacing standard full-dose CT with ultralow-dose CT, but we have wondered whether the old low-quality X-ray examinations can be replaced by ultralow-dose CT. Although the CT dose is nearly as low as for a chest X-ray, we can obtain far more information from the images,” says associate professor Anne Catrine Trægde Martinsen, who works at the Intervention Centre and the Department of Physics, University of Oslo.

To find out what works best, the researchers have undertaken a pilot study in which they made both X-ray images and ultralow-dose CT images of a small sample of patients for whom the researchers knew the correct answer beforehand.

The radiologists who examined the images did not know what ailed the patients, but they were aware of being part of a research project, and they were told to search for all possible diseases of the chest region.

From 18 to 89 percent hits

The results were remarkable. By studying the X-ray images, the radiologists found the correct answer in only 18 percent of the cases. In other words, they missed 82 percent of the diagnoses. With ultralow-dose CT, the radiologists made a correct diagnosis in 89 percent of the cases.

“X-rays are taken out of old habit, but with X-ray the cancer is detected too late. It’s therefore smart to use ultralow-dose CT to be able to detect the disease in time,” Aaløkken states.

Moreover, with X-ray images the radiologists detected fifteen times as many false positives. A false positive means that the patient is told that he is ill, even if he is as fit as a fiddle.

“False positives are a burden on the patient. They also entail unnecessary check-ups, which incur a high cost on society,” says Aaløkken, who concludes:

With an X-ray examination, there is a high likelihood that you will not have any answer as to whether you are ill, and an answer that says that you are ill even though you are healthy. Many are diagnosed too late. This is a dramatic consequence of the fact that the health services give priority to X-ray images above CT images.

Their research caused a stir at the world’s largest medical conference for radiology, RSNA, in 2012. Their academic article was nominated as one of the ten best from the conference.

“Even though our results are extremely convincing, we need to undertake a full-scale test to be absolutely certain.”

A question of economics

Before the diagnostic procedure is changed, the researchers must calculate the cost to society.

“A CT machine costs ten times more than an X-ray machine, but it is also costly to treat patients with advanced lung cancer.

Most people believe that X-ray is a quicker procedure than CT. This is not so.

“An X-ray check takes five minutes. A low-dose CT check goes almost as quickly; it takes seven minutes. On the other hand, the radiologists need two to three times longer to interpret a CT image,” Aaløkken and Martinsen underscore.

Odd Terje Brustugun, associate professor at the Department of Oncology at Oslo University Hospital and assistant professor at the Institute of Clinical Medicine, UiO, confirms that Aaløkken and Martinsen are on the right track.

“As far as I have understood, the method can be used on existing, modern CT machines. Before it can replace ordinary chest X-ray some work needs to be done in terms of the resource situation and training of radiographers and radiologists. The method should be tested on a greater number of patients and compared to other techniques on a larger scale before we can conclude how well it works,” Brustugun points out.

source : http://www.sciencedaily.com/releases/2014/08/140825084834.htm

Repurposing anti-depressant medication to target medulloblastoma

The multi-institutional group, led by scientists at Cancer and Blood Diseases Institute (CBDI) at Cincinnati Children’s Hospital Medical Center, publish their results in the journal’s online edition on Aug. 24. The researchers suggest their laboratory findings in mouse models of the disease could lead to a more targeted and effective molecular therapy that would also reduce the harmful side effects of current treatments, which include chemotherapy, radiation or surgery.

“Although current treatments improve survival rates, patients suffer severe side effects and relapse tumors carry mutations that resist treatment,” said lead investigator Q. Richard Lu, PhD, scientific director of the Brain Tumor Center, part of the CBDI at Cincinnati Children’s. “This underscores an urgent need for alternative targeted therapies, and we have identified a potent tumor suppressor that could help a subset of patients with an aggressive form of medulloblastoma.”

Using genetically-engineered mice to model human medulloblastoma, the authors identified a gene called GNAS that encodes a protein called Gsa. Gsa kicks off a signaling cascade that researchers found suppresses the initiation of an aggressive form of medulloblastoma driven by a protein called Sonic hedgehog — considered one of the most important molecules in tissue formation and development.

The scientists used an anti-depressant medication called Rolipram — approved for behavioral therapy for use in Europe and Japan — to treat mice that were engineered not to express the GNAS gene. Lack of GNAS allowed aggressive formation of medulloblastoma tumors in neural progenitor cells of the GNAS mutant mice.

Rolipram treatment in the mice elevated levels of a molecule called cAMP, which restored the GNAS-Gsa pathway’s tumor suppression function. This caused the tumors to shrink and subside. The study also suggests that elevating cAMP levels in cells enhances the potency of Sonic hedgehog inhibitors, currently being tested in clinical trials to fight tumor growth.

The scientists stressed that a significant amount of additional research is needed before their findings could become directly relevant to clinical treatment. The authors also caution that the effect of raising cAMP levels may depend on the type of cancer, and that laboratory results in mice do not always translate uniformly to humans.

source : http://www.sciencedaily.com/releases/2014/08/140824152337.htm