Porous polymer scaffolds fabricated to support the growth of biological tissue for implantation may hold the potential to greatly accelerate the development of cancer therapeutics.

Researchers at Rice University and the University of Texas MD Anderson Cancer Center in Houston and Mount Sinai Medical Center in New York reported this week that three-dimensional scaffolds used to culture Ewing’s sarcoma cells were effective at mimicking the environment in which such tumours develop.
‘The scaffolds better recapitulate the micro-environment in which tumours grow, as compared with two-dimensional plastic surfaces typically used in cancer research to test anti-cancer drugs,’ said Rice bioengineer Antonios Mikos, who led the research team with Joseph Ludwig, an assistant professor and sarcoma medical oncologist at MD Anderson.

‘We’ve been working to investigate how we can leverage our expertise in engineering normal tissues to cancerous tissues, which can potentially serve as a better predictor of anti-cancer drug response than standard drug-testing platforms,’ Mikos said.

By growing cancer cells within a three-dimensional scaffold rather than on flat surfaces, the team of researchers found that the cells bore closer morphological and biochemical resemblance to tumours in the body. Additionally, engineering tumours that mimic those in vivo offers opportunities to more accurately evaluate such strategies as chemotherapy or radiation therapies, he said.

The project ‘provides a path forward to better evaluate promising biologically targeted therapies in the pre-clinical setting,’ Ludwig said.

Scaffolds fabricated in the Mikos’ lab facilitate the development and growth of new tissue outside the body for subsequent implantation to replace defective tissues.

The team found 3-D scaffolds to be a suitable environment for growing Ewing’s sarcoma, the second most-common pediatric bone malignancy. The tumour growth profile and protein expression characteristics were ‘remarkably unlike’ those in 2-D, Mikos said.

These differences led them to hypothesise that 2-D cultures may mask the mechanisms by which tumours develop resistance to anti-cancer therapeutics, and ‘may lead to erroneous scientific conclusions that complicate our understanding of cancer biology,’ they wrote.

The next challenge is to customise scaffolds to more accurately match the actual conditions in which these tumors are found. ‘Tumors in vivo exist within a complex microenvironment consisting of several other cell types and extracellular matrix components,’ Mikos said. ‘By taking the bottom-up approach and incorporating more components to this current model, we can add layers of complexities to make it increasingly reliable.

‘But we believe what we currently have is very promising,’ he said. ‘If we can build upon these results, we can potentially develop an excellent predictor of drug efficacy in patients.’ Rice University

A new study led by University of Pennsylvania researchers involves a classic case of evolution’s fickle nature: a genetic mutation that protects against a potentially fatal infectious disease also appears to increase the risk of developing a chronic, debilitating condition.

Such a relationship exists between malaria and sickle cell anaemia. Individuals who carry a gene to resist the former are carriers for the latter. And recently scientific evidence has suggested that individuals who are resistant to human African trypanosomiasis, or sleeping sickness, are predisposed to developing chronic kidney disease. That could explain why African-Americans, who derive much of their ancestry from regions where sleeping sickness is endemic, suffer from kidney disease at high rates.

In a study Penn researchers and colleagues offer further insights into the unfinished story of the sleeping sickness-kidney disease connection by looking at a variety of African populations which had not been included in prior studies. Sequencing a portion of a gene believed to play a role in both diseases, the scientists discovered new candidate variants that are targeted by recent natural selection. Their findings lend support to the idea that the advantages of resistance to sleeping sickness, a disease which continues to affect tens of thousands of sub-Saharan Africans each year, may have played a role in the evolution of populations across Africa.

The research was led by Wen-Ya Ko and Sarah Tishkoff of the Department of Genetics in Penn’s Perelman School of Medicine. Tishkoff, a Penn Integrates Knowledge professor, also has an appointment in the School of Arts and Sciences’ Department of Biology. Ko now holds a research position at the Universidade do Porto in Portugal.

Earlier research had shown that African-Americans with kidney disease frequently had one of two mutations in the gene that codes for the ApoL1 protein, endowing it with the ability to kill the parasite species that causes the form of sleeping sickness found in eastern Africa. But, puzzlingly, these variants were found at high frequencies in the Yoruba, who live in western Africa’s Nigeria.

‘That was an interesting finding, but nobody had ever done a sequencing analysis of this gene across other African populations,’ Tishkoff said. ‘We wanted to know if we would find the same variants and would they be as common.’

Using the earlier findings as a starting point, the Penn-led study expanded the sequencing effort to look at a region of the ApoL1 gene in 10 different African populations, encompassing groups from both eastern and western Africa.

They found the G1 and G2 haplotypes in some of the other populations but only at low frequencies, suggesting there may be other variants playing a similar role. Sure enough, the researchers also turned up another variant shared across groups, which they called G3.

‘This novel G3 was quite common in some of the populations but surprisingly absent in the Yoruba,’ Tishkoff said.

Not only was this variant present in the other nine groups studied, but the Ko-Tishkoff team found signs that it had been positively selected, or ferried through generations at a rate above chance, perhaps because it exerted a protective effect against sleeping sickness.

And interestingly, G3 was most common in the Fulani, a pastoralist group which lives in western and central Africa. The authors note that human African sleeping sickness, which is typically transmitted by tse tse flies, might have been an important factor driving the migration patterns of the Fulani throughout history.

Because the Fulani ‘practice cattle herding, tse tse flies and the parasites they carry may have been more of a problem … than for some other groups,’ Ko said. ‘It may have been particularly advantageous for them to be able to resist the disease.’

The different variants, therefore, may reflect a variety of selective pressures, including population movements around Africa and the historical and ongoing evolutionary arms race between the sleeping sickness parasite and the human immune system. The fact that the Yoruba can resist a form of the disease that is no longer present in the area in which they live might be the result of changes either in the parasite or in the movement patterns of the Yoruba themselves. Kidney disease might thus be considered an evolutionary trade-off, the unintended consequence of a battle to resist a powerful and prevalent infectious disease. University of Pennsylvania

Johns Hopkins researchers say that by measuring levels of certain proteins in cerebrospinal fluid (CSF), they can predict when people will develop the cognitive impairment associated with Alzheimer’s disease years before the first symptoms of memory loss appear.
Identifying such biomarkers could provide a long-sought tool to guide earlier use of potential drug treatments to prevent or halt the progression of Alzheimer’s while people are still cognitively normal.
To date, medications designed to stop the brain damage have failed in clinical trials, possibly, many researchers say, because they are given to those who already have symptoms and too much damage to overcome.
‘When we see patients with high blood pressure and high cholesterol, we don’t say we will wait to treat you until you get congestive heart failure. Early treatments keep heart disease patients from getting worse, and it’s possible the same may be true for those with pre-symptomatic Alzheimer’s,’ says Marilyn Albert, Ph.D., a professor of neurology at the Johns Hopkins University School of Medicine. ‘But it has been hard to see Alzheimer’s disease coming, even though we believe it begins developing in the brain a decade or more before the onset of symptoms,’ she adds.
For the new study, the Hopkins team used CSF collected for the Biomarkers for Older Controls at Risk for Dementia (BIOCARD) project between 1995 and 2005, from 265 middle-aged healthy volunteers. Some three-quarters of the group had a close family member with Alzheimer’s disease, a factor putting them at higher than normal risk of developing the disorder. Annually during those years and again beginning in 2009, researchers gave the subjects a battery of neuropsychological tests and a physical exam.
They found that particular baseline ratios of two proteins — phosphorylated tau and beta amyloid found in CSF — were a harbinger of mild cognitive impairment (often a precursor to Alzheimer’s) more than five years before symptom onset. They also found that the rate of change over time in the ratio was also predictive. The more tau and the less beta amyloid found in the spinal fluid, the more likely the development of symptoms. And, Albert says, the more rapidly the ratio of tau to beta amyloid goes up, the more likely the eventual development of symptoms.
Researchers have known that these proteins were in the spinal fluid of patients with advanced disease. ‘But we wondered if we could measure something in the cerebral spinal fluid when people are cognitively normal to give us some idea of when they will develop difficulty,’ Albert says. ‘The answer is yes.’ John Hopkins Medicine

A little bit of learned fear is a good thing, keeping us from making risky, stupid decisions or falling over and over again into the same trap. But new research from neuroscientists and molecular biologists at USC shows that a missing brain protein may be the culprit in cases of severe over-worry, where the fear perseveres even when there’s nothing of which to be afraid. In a study, researchers examined mice without the enzymes monoamine oxidase A and B (MAO A/B), which sit next to each other in a human’s genetic code as well as on that of mice.
Prior research has found an association between deficiencies of these enzymes in humans and developmental disabilities along the autism spectrum, such as clinical perseverance, the inability to change or modulate actions along with social context. ‘These mice may serve as an interesting model to develop interventions to these neuropsychiatric disorders,’ said University Professor and senior author Jean Shih, Boyd & Elsie Welin Professor of Pharmacology and Pharmaceutical Sciences at the USC School of Pharmacy and the Keck School of Medicine of USC. ‘The severity of the changes in the MAO A/B knockout mice compared to MAO A knockout mice supports the idea that the severity of autistic-like features may be correlated to the amounts of monoamine levels, particularly at early developmental stages.’
Shih is a world leader in understanding the neurobiological and biochemical mechanisms behind such behaviours as aggression and anxiety. In this latest study, Shih and her co-investigators — including lead author Chanpreet Singh, a USC doctoral student at the time of the research who is now at the California Institute of Technology (Caltech), and Richard Thompson, USC University Professor Emeritus and Keck Professor of Psychology and Biological Sciences at the USC Dornsife College of Letters, Arts and Sciences — expanded their past research on MAO A/B, which regulates neurotransmitters known as monoamines, including serotonin, norepinephrine and dopamine. Comparing mice without MAO A/B with their wild-type littermates, the researchers found significant differences in how the mice without MAO A/B processed fear and other types of learning. Mice without MAO A/B and wild mice were put in a new, neutral environment and given a mild electric shock. All mice showed learned fear the next time they were tested in the same environment, with the MAO A/B knockout mice displaying a greater degree of fear. But while wild mice continued to explore other new environments freely after the trauma, mice without the MAO A/B enzymes generalised their phobia to other contexts — their fear spilled over onto places where they should have no reason to be afraid. ‘The neural substrates processing fear in the brain is very different in these mice,’ Singh said. ‘Enhanced learning in the wrong context is a disorder and is exemplified by these mice. Their brain is not letting them forget. In a survival issue, you need to be able to forget things.’
The mice without MAO A and MAO B also learned eye-blink conditioning much more quickly than wild mice, which has also been noted in autistic patients but not in mice missing only one of these enzymes. Importantly, the mice without MAO A/B did not display any differences in learning for spatial skills and object recognition, the researchers found, ‘but in their ability to learn an emotional event, the [MAO A/B knockout mice] are very different than wild types,’ Singh said. He continued: ‘When both enzymes are missing, it significantly increases the levels of neurotransmitters, which causes developmental changes, which leads to differential expression of receptors that are very important for synaptic plasticity — a measure of learning — and to behavior that is quite similar to what we see along the autism spectrum.’ University of Southern California