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.

One way to tackle a tumor is to take aim at the metabolic reactions that fuel their growth. But a report in the February Cell Metabolism, a Cell Press Publication, shows that one metabolism-targeted cancer therapy will not fit all. That means that metabolic profiling will be essential for defining each cancer and choosing the best treatment accordingly, the researchers say.

The evidence comes from studies in mice showing that tumors' metabolic profiles vary based on the genes underlying a particular cancer and on the tissue of origin.

"Cancer research is dominated now by genomics and the hope that genetic fingerprints will allow us to guide therapy," said J. Michael Bishop of the University of California, San Francisco. "The issue is whether that is sufficient. We argue that it isn't because metabolic changes are complex and hard to predict. You may need to have the metabolome as well as the genome."

Just as a cancer genome refers to the complete set of genes, the metabolome refers to the complete set of metabolites in a given tumor.

The altered metabolism of tumors has been considered a target for anticancer therapy. For instance, tumors and cancer cell lines consume more glucose than normal cells do, a phenomenon known as the Warburg effect. There has often been the impression that such changes in metabolism are characteristic of cancers in general, but cancer is a genetically heterogeneous disease. The team led by Bishop and Mariia Yuneva wondered how metabolism might vary with the underlying genetic causes of cancer.

They found in mice that liver cancers driven by different cancer-causing genes (Myc versus Met) show differences in the metabolism of two major nutrients: glucose and glutamine. What's more, the metabolism of Myc-induced lung tumors is different from Myc-induced liver tumors.

"Our work shows that different tumors can have very different metabolisms," Yuneva said. "You can't generalize."

Bishop and Yuneva say their findings also highlight glutamine metabolism as a potential new target for therapy in some tumors, noting that the focus has been primarily on glucose metabolism. Interestingly, the data shows that a version of a glutaminase enzyme normally found in kidney cells turns up in cancerous liver cells. That means there might be a way to attack the metabolism of the cancer without damaging normal liver tissue.

"We shouldn't lose sight of the rather immediate therapeutic potential," Bishop said.

The researchers will continue to inventory metabolic variation in mouse models. Ultimately, they say it will be important to catalogue the metabolic variation in the much more complex, human setting

The future of disease diagnosis may lie in a "breathalyzer"-like technology currently under development at the University of Wisconsin-Madison.

New research published online in February in the peer-reviewed journal Metabolism demonstrates a simple but sensitive method that can distinguish normal and disease-state glucose metabolism by a quick assay of blood or exhaled air.

Many diseases, including diabetes, cancer, and infections, alter the body's metabolism in distinctive ways. The new work shows that these biochemical changes can be detected much sooner than typical symptoms would appear - even within a few hours - offering hope of early disease detection and diagnosis.

"With this methodology, we have advanced methods for tracing metabolic pathways that are perturbed in disease," says senior author Fariba Assadi-Porter, a UW-Madison biochemist and scientist at the Nuclear Magnetic Resonance Facility at Madison. "It's a cheaper, faster, and more sensitive method of diagnosis."

The researchers studied mice with metabolic symptoms similar to those seen in women with polycystic ovary syndrome (PCOS), an endocrine disorder that can cause a wide range of symptoms including infertility, ovarian cysts, and metabolic dysfunction. PCOS affects approximately 1 in 10 women but currently can only be diagnosed after puberty and by exclusion of all other likely diseases - a time-consuming and frustrating process for patients and doctors alike.

"The goal is to find a better way of diagnosing these women early on, before puberty, when the disease can be controlled by medication or exercise and diet, and to prevent these women from getting metabolic syndromes like diabetes, obesity, and associated problems like heart disease," Assadi-Porter says.

The researchers were able to detect distinct metabolic changes in the mice by measuring the isotopic signatures of carbon-containing metabolic byproducts in the blood or breath. They injected glucose containing a single atom of the heavier isotope carbon-13 to trace which metabolic pathways were most active in the sick or healthy mice. Within minutes, they could measure changes in the ratio of carbon-12 to carbon-13 in the carbon dioxide exhaled by the mice, says co-author Warren Porter, a UW-Madison professor of zoology.

One advantage of the approach is that it surveys the workings of the entire body with a single measure. In addition to simplifying diagnosis, it could also provide rapid feedback about the effectiveness of treatments.

"The pattern of these ratios in blood or breath is different for different diseases - for example cancer, diabetes, or obesity - which makes this applicable to a wide range of diseases," explains Assadi-Porter.

The technology relies on the fact that the body uses different sources to produce energy under different conditions. "Your body changes its fuel source. When we're healthy we use the food that we eat," Porter says. "When we get sick, the immune system takes over the body and starts tearing apart proteins to make antibodies and use them as an energy source."

That shift from sugars to proteins engages different biochemical pathways in the body, resulting in distinct changes in the carbon isotopes that show up in exhaled carbon dioxide. If detected quickly, these changes may signal the earliest stages of disease.

The researchers found similar patterns using two independent assays - nuclear magnetic resonance spectroscopy on blood serum and cavity ring-down spectroscopy on exhaled breath. The breath-based method is particularly exciting, they say, because it is non-invasive and even more sensitive than the blood-based assays.

In the mice, the techniques were sensitive enough to detect statistically significant differences between even very small populations of healthy and sick mice.

The current cavity ring-down spectroscopy analysis uses a machine about the size of a shoebox, but the researchers envision a small, hand-held "breathalyzer" that could easily be taken into rural or remote areas. They co-founded a company, Isomark, LLC, to develop the technology and its applications. They hope to explore the underlying biology of disease and better understand whether the distinctive biochemical changes they can observe are causative or side effects.

A University of Minnesota-led research team has proposed a mechanism for the control of whether embryonic stem cells continue to proliferate and stay stem cells, or differentiate into adult cells like brain, liver or skin.

The work has implications in two areas. In cancer treatment, it is desirable to inhibit cell proliferation. But to grow adult stem cells for transplantation to victims of injury or disease, it would be desirable to sustain proliferation until a sufficient number of cells have been produced to make a usable organ or tissue.

The study gives researchers a handle on how those two competing processes might be controlled. It was performed at the university's Hormel Institute in Austin, Minn., using mouse stem cells. The researchers, led by Hormel Institute Executive Director Zigang Dong and Associate Director Ann M. Bode, have published a report in the journal Nature: Structure and Molecular Biology.

"This is breakthrough research and provides the molecular basis for development of regenerative medicine," said Dong. "This research will aid in the development of the next generation of drugs that make repairs and regeneration within the body possible following damage by such factors as cancer, aging, heart disease, diabetes, or paralysis caused by traumatic injury."

The mechanism centers on a protein called Klf4, which is found in embryonic stem cells and whose activities include keeping those cells dividing and proliferating rather than differentiating. That is, Klf4 maintains the character of the stem cells; this process is called self-renewal. The researchers discovered that two enzymes, called ERK1 and ERK2, inactivate Klf; this allows the cells to begin differentiating into adult cells.

The two enzymes are part of a "bucket brigade" of signals that starts when a chemical messenger arrives from outside the embryonic stem cells. Chemical messages are passed to inside the cells, resulting in, among other things, the two enzymes swinging into action.

The researchers also discovered how the enzymes control Klf4. They attach a small molecule - phosphate, consisting of phosphorus and oxygen - to Klf4. This "tag" marks it for destruction by the cellular machinery that recycles proteins.

Further, they found that suppressing the activity of the two enzymes allows the stem cells to maintain their self-renewal and resist differentiation. Taken together, their findings paint a picture of the ERK1 and ERK2 enzymes as major players in deciding the future of embryonic stem cells--and potentially cancer cells, whose rapid growth mirrors the behavior of the stem cells.

Klf4 is one of several factors used to reprogram certain adult skin cells to become a form of stem cells called iPS (induced pluripotent stem) cells, which behave similarly to embryonic stem cells. Also, many studies have shown that Klf4 can either activate or repress the functioning of genes and, in certain contexts, act as either an oncogene (that promotes cancer) or a tumor suppressor. Given these and their own findings reported here, the Hormel Institute researchers suggest that the self-renewal program of cancer cells might resemble that of embryonic stem cells

A recent discovery by Van Andel Research Institute (VARI) scientists enables the prediction of patient sensitivity to proposed drug therapies for glioblastoma - the most common and most aggressive malignant brain tumor in humans.

The study, published in the Proceedings of the National Academy of Science, investigated glioblastoma models characterized by cell signaling activation and gene amplification for their susceptibility to inhibitors of both the human MET oncogene and the epidermal growth factor receptor (EFGR).

An oncogene is a gene with the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels. High MET levels often occur in human tumors, and cells with inappropriate MET signaling produce activity that potently affects the spread of cancer. This signaling is implicated in most types of human cancers and high MET expression often correlates with poor prognosis. Mutations affecting EGFR expression or activity are also linked to cancer.

"Because oncogene MET and EGFR inhibitors are in clinical development against several types of cancer, including glioblastoma, it is important to identify predictive markers that indicate patient subgroups suitable for such therapies," said VARI Research Scientist Qian Xie, Ph.D., lead author of the study.

"Studies have shown that targeting MET signaling can have potent antitumor effects," said Co-Author George F. Vande Woude, Ph.D., Head of the VARI Laboratory of Molecular Oncology. "Therefore, it is important to understand the mechanisms leading to HGF/MET sensitivity and to identify the patient subgroups most likely to benefit from MET-targeted therapeutics."

Dr. Vande Woude's career can be characterized by the uniquely broad scope of his work with MET and its molecular partner hepatocyte growth factor (HGF) - from the original cloning and characterization of the gene, through explaining the role of the HGF/ MET signaling pathway in human cancers, and then to applying that knowledge toward the identification of inhibitors of this important cancer pathway. Because MET and HGF play such an integral role in the process of cell survival, growth, blood vessel formation, and metastasis, they are a significant target in the development of anti-cancer drugs.

Dr. Vande Woude is also the co-author of an article published last week in Nature Reviews Cancer entitled "Targeting MET in cancer: rationale and progress," which updates the progress of MET and HGF as targets in the development of anti-cancer drugs.

"Progress in understanding this vital process has led to the successful development of blocking antibodies and a large number of small-molecule MET kinase inhibitors," said Vande Woude. "Results from recent clinical studies demonstrate that inhibiting MET signaling in several types of solid human tumors has major therapeutic value."