Cancer

A recent study published by the The Lancet Oncology indicates that children of women who received chemotherapy during their pregnancy suffer no adverse effects, developing as well as children in the general population. The study was led by Dr Frédéric Amant, Multidisciplinary Breast Cancer Center, Leuven Cancer Institute, Katholieke Universiteit Leuven, Belgium.

The researchers assessed 68 pregnancies of mothers who received an average of three to four cycles of chemotherapy - a total of 236 cycles. The average age of cancer diagnosis for the mothers was 18 weeks into pregnancy. The median gestation age of birth was at 36 weeks, with two thirds (47) of the women giving birth before 37 weeks. A total of 70 children were assessed, ranging from ages 1.5 to 18 years.

They carried out a series of tests on the children to examine their overall health and development, including: Bayley or intelligence quotient tests, electrocardiography and echocardiography, and a questionnaire on general health and development. Children above the age of 5 were given more tests such as the Auditory Verbal Learning Test, audiometry, the Test of Everyday Attention for Children, and their parents were to complete a 'Child Behavior Checklist'.

Neurocognitive outcomes were within normal ranges for children born at full term, children born preterm, however, had lower results, but the authors stress that this difference is found among the general population as well. The results of the tests indicated that the children's behavior, general health, heart dimensions/function, hearing, and growth were all equal to the average results of children in the general population.

It's been more than 50 years since James Watson and Francis Crick showed that DNA is a double helix of two strands that complement each other. But how does a short piece of DNA find its match, out of the millions of 'letters' in even a small genome? New work by researchers at the University of California, Davis, handling and observing single molecules of DNA, shows how it's done. The results are published online by the journal Nature.

Defects in DNA repair and copying are strongly linked to cancer, birth defects and other problems.

"This is a real breakthrough," said Stephen Kowalczykowski, professor of microbiology and co-author on the paper with postdoctoral researcher Anthony Forget. "This is an issue that has been outstanding in the field for more than 30 years."

"It's the solution of one of the greatest needle-in-the-haystack problems in biology," said Professor Wolf-Dietrich Heyer, a UC Davis molecular biologist who also studies DNA repair but was not involved in this research.

"How can one double-stranded DNA break find its match in an entire genome, five billion base pairs in humans? Now we know the fundamental mechanism," Heyer said.

Forget and Kowalczykowski used technology developed in Kowalczykowski's lab over the past 20 years to trap lengths of DNA and watch, in real time, as the proteins involved in copying and repairing DNA do their work.

The first step in repairing a damaged piece of normally double-stranded DNA by a process called recombination is to strip it to a single strand. That single-stranded DNA then looks for a complementary sequence within an intact chromosome to use as a template to guide the repair.

How does a short, single-stranded piece of DNA find its exact matching partner out of perhaps millions of possibilities? In the 1970s, scientists discovered a protein, called RecA in bacteria and Rad51 in humans, which binds to the single-stranded DNA, forms an extensive filament and guides it to the right place in the chromosome.

"This is a very important aspect of chromosome maintenance," Kowalczykowski said. "Without it, your genome will start to scramble very quickly."

Defects in some proteins associated with DNA repair are associated with an increased risk of cancer - for example BRCA2, the breast cancer gene. But animals with defects in Rad51 don't even survive as embryos.

But how this search for DNA sequence compatibility works has been unclear. The RecA/DNA complex has to bump into and sample different stretches of DNA until it finds the right one, but the number of sequences to search is huge - it's like finding the proverbial needle in the haystack.

One model would be for RecA and its attached single-stranded DNA to slide along the intact duplex DNA until it gets to the right place. Or, if the DNA is in a coiled up form like a bowl of spaghetti, the RecA/DNA filament might be able to touch several different stretches of DNA simultaneously and thus shorten the time for the search.

Forget set out to test these ideas by stretching single molecules of duplex DNA between two tiny beads to make a dumbbell shape. Both beads were held in place by laser beams, but one of the beads could be steered around using the laser. Then he added the RecA assembled on single-stranded DNA to the DNA-dumbbells and watched to see how well they attached to the target DNA when it was stretched out, or relaxed and allowed to coil up.

"These are very complicated experiments to perform," Kowalczykowski said.

They found that the RecA complex attached most efficiently to the target DNA when it was in a relaxed, coiled form.

"The most efficient homology search is when the local DNA density is higher and the RecA-DNA filament can contact more areas of duplex DNA at the same time," Kowalczykowski said. "RecA doesn't slide along the DNA looking for a partner."

Consider a bowl of spaghetti, Kowalczykowski said. If you were looking for one tiny region on just one piece of spaghetti in the bowl, you could grab several strands at once and quickly examine each. But if the spaghetti were stretched out in one long piece, you could only touch one part of one piece at a time.

Kowalczykowski began working on the system for studying single molecules of DNA in 1991 with the late Ron Baskin, professor of molecular and cellular biology at UC Davis. In 2001, they demonstrated the technique by filming an enzyme called a helicase at work in real time unwinding the double helix of DNA. Since then, they have used the method to get new insights into the complex of proteins that copy and repair DNA.

Kowalczykowski's lab was also one of two UC Davis groups to purify the protein made by the BRCA2 gene, strongly associated with breast cancer. BRCA2, it turns out, loads Rad51 - the human equivalent of RecA in bacteria - onto DNA to search the human DNA for the correct region to use for repair

With MRI scans becoming cheaper and more common, perhaps the days of the CT scan that does a similar function using X-Rays rather than magnetic fields, are numbered. A report shows that the cancer risk from CT scans, especially Brain Cancer and Leukemia can triple in some cases.

The Article published in The Lancet, and written by Dr Mark Pearce and Professor Sir Alan Craft, Newcastle University, UK; Professor Louise Parker, Dalhousie University, Halifax, NS, Canada; Dr Amy Berrington de González, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA, and colleagues, represents the culmination of almost two decades of research in this area, and is jointly funded by the UK Department of Health and NCI/NIH.

It shows that 2 or 3 computed tomography (CT) scans of a child's head (child meaning under 15 years old in this case), can triple the risk of brain cancer. The total dose of radiation would be around 60mGy, while 5 to 10 scans giving a dose of some 50mGy or more, triples the risk of leukemia.

The researchers go on to point out that the risks are still miniscule as the diseases are not particularly common, thus an increased risk is far from absolute certainty of contracting the disease. The CT scan is a useful and sometimes necessary diagnostic tool, and therefore physicians must weigh the risks and make patients and their parents aware.

The retrospective study used records from the radiology departments of some 70% of the UK's hospitals, and gathered data from 180,000 patients who underwent CT scans between 1985 and 2002. By looking at the number and types of CT scan from the records, the researchers estimated the dose absorbed in milli-Grays (mGy) by the brain and bone marrow in patient for each scan. The data was then cross-checked with cancer incidence and mortality reports in the UK National Health Service Registry between 1985 and 2008. It was then possible to show if a person having scans was more likely to develop cancer. From this, they calculated excess incidence of leukemia and brain tumors.

The UK has relatively low usage of CT scans due to a nationalized health service and the Ionising Radiation (Medical Exposure) Regulations, that make sure scans are only done when medically justified.