Thanks to effective vaccination, polio is considered nearly eradicated. Each year only a few hundred people are stricken worldwide. However, scientists of the University of Bonn, together with colleagues from Gabon, are reporting alarming findings: a mutated virus that was able to resist the vaccine protection to a considerable extent was found in victims of an outbreak in the Congo in 2010. The pathogen could also potentially have infected many people in Germany.
   
The polio epidemic in the Congo in 2010 was especially serious. 445 people were verifiably infected, mostly young adults. The disease was fatal for 209 of them. This high mortality rate is surprising. Also important was the fact that many of those affected had apparently been vaccinated: Surveys indicated that half of the patients remembered having received the prescribed three vaccination dosages. To date the vaccination has been considered a highly effective weapon for containing the polioviruses that cause the disease.

‘We isolated polio-viruses from the deceased and examined the viruses more closely’, explains Dr. Jan Felix Drexler, who is in the meantime working in the Netherlands. He carried out the study during his employment at the Institute for Virology of the University Hospital of Bonn under the supervision of Prof. Christian Drosten, together with his colleagues from Gabon, Dr. Gilda Grard and Dr. Eric Leroy. ‘The pathogen carries a mutation that changes its form at a decisive point.’ The result: the antibodies induced by the vaccination can hardly block the mutated virus and render it harmless.

The researchers have examined the success with which the new pathogen evades the immune system. To this purpose, they tested, among others, blood samples from 34 medical students of the University of Bonn. All of them were vaccinated in childhood with the usual methods against polio. And very successfully, as an initial test showed: The antibodies in the blood of the test subjects had no problem combating ‘normal’ polio viruses. The situation was different with the mutated virus; the immune reaction was much weaker here. ‘We estimate that one in five of our Bonn test subjects could have been infected by the new polio virus, perhaps even one in three’, says Prof. Drosten. University Hospital of Bonn

An international scientific collaboration led by Baylor College of Medicine has revealed clues about genetic alterations that may contribute to a rare form of kidney cancer, providing new insights not only into this rare cancer but other types as well.

The collaboration – part of The Cancer Genome Atlas initiative which is funded by the National Institutes of Health – completed the sequence completed the sequence of chromophobe renal cell carcinoma and have published the results.

“The Cancer Genome Atlas is a federally funded national effort that has already completed the sequence of many major types of cancer (breast, lung, ovarian, for example), but this project is now branching out to sequence more rare types of cancer,” said Dr. Chad Creighton, associate professor of medicine and a biostatistician in the NCI-designated Dan L. Duncan Cancer Center at Baylor and the lead and corresponding author on the report. “The idea is that with a better understanding of these more rare types of cancers, we gain new insight that might be relevant to how we study other types of cancer. The findings in this study are a perfect example of that.”

Chromophobe renal cell carcinoma is a rare type of kidney cancer, with approximately 2,000 new cases diagnosed each year in the United States. A majority of patients survive the disease.

“Although most patients are reassured when the pathology of their kidney tumour comes back as chromophobe, we all have cared for patients who developed and died from metastatic chromophobe kidney cancers,” said Dr. Kimryn Rathmell, associate professor of haematology and oncology in the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill and a co-senior author on the study. “This report is incredibly exciting for physicians who care for these patients because all of the treatment plans we have had to this point have been based on the biology of the more common kidney cancer type, as if chromophobe must be a close relative of that disease.”

The project shows with no uncertainty that chromophobe renal cell carcinoma represents a distinct cancer entity, and reveals exciting biology inherent to the disease that we hope in the future will allow new therapies to be developed specifically for the chromophobe type of kidney cancer, Rathmell said.

The team sequenced 66 tumor samples at Baylor’s Human Genome Sequencing Center. Other types of data were collected on these samples and integrated with the sequencing, including gene expression and epigenetic data. In addition to sequencing known genes, DNA from mitochondria and from the entire genome was also sequenced.

“Instead of just looking specifically at the exome, we also analysed the entire genome, something not typically done in these genomic studies,” said Creighton. The exome, the part of the genome used to make proteins, constitutes only 1 percent of the total genome, where the other 99 percent is often ignored in studies.

With whole exome analysis, scientists are just looking within the boundaries of known genes, to see which are broken and may have caused the disease, he explained.

“However, when you look outside of the genes, there is much more going on,” said Creighton. “For example, gene regulatory features of the genome can be altered.”

From whole genome analysis, the team observed a significant amount of structural rearrangements or breakpoints involving the promoter region of a gene called TERT, which encodes for the most important unit of the telomerase complex.

Telomerase represent the “clock” of the cell, Creighton said. “This plays a critical role in cell division, and with many cancer cells, telomerase levels are really high and time never really runs out, which allows the cell to never die. “

It was the promoter region, not the actual gene, that was affected, Creighton clarified. “Since there isn’t a breakdown in the actual gene, this malfunction is not picked up in whole exome analysis.”

The study also raised intriguing questions about the roles of mitochondrial DNA alterations and of the cell of origin involved in cancer initiation, the authors noted.

This could signify new approaches for how scientists should conduct molecular studies of cancer, he said. “We need to survey the regulatory regions for other cancer types as well.” Baylor College of Medicine

A study by researchers at the University of Kansas shows a new role for the protein adenomatous polyposis coli (APC) in suppressing colorectal cancer — the second-leading cause of cancer-related deaths in the U.S.

Lead author Kristi Neufeld, associate professor in the Department of Molecular Biosciences and co-leader of the Cancer Biology program at the KU Cancer Center, has spent the better part of her career trying to understand the various activities of APC, a protein whose functional loss is thought to initiate roughly 80 percent of all colon polyps, a precursor to colon cancer. Neufeld, along with her postdoctoral fellow Maged Zeineldin, undergraduate student Mathew Miller and veterinary pathologist Ruth Sullivan, now reports that APC found in a particular subcellular compartment, the nucleus, protects from inflammation as well as tumour development associated with chronic colitis.

Whether APC reaches the nucleus may well affect the ability of intestinal stem cells to produce differentiated cells with specialized functions, Neufeld said.

“It’s not widely appreciated, but there is still plenty of cell growth going on in adults, with the colon being a good example,” she said. “On average, we shed and replace about 70 pounds of intestinal tissue annually, so you can imagine that this process requires exquisite control to prevent tumour formation.”

Regular renewal of the colon lining occurs through stem cells that are capable of constantly dividing. These cells produce descendants that take up specific roles: By secreting mucin, for instance, goblet cells generate a mucus layer that serves as the colon’s physical barrier against its many microbial tenants. But if APC can’t find its way to the nucleus, Neufeld and her team have noted far fewer goblet cells as one outcome.

“We introduced a specific APC mutation into mice that took away the nuclear zip code, so to speak, leaving APC stuck in the cytoplasm,” Neufeld said. The researchers studied this mouse model under conditions that induce ulcerative colitis, a form of inflammatory bowel disease that can be a prelude to colon cancer.

Observing significantly more colon tumours in these mice compared to those with normal APC in the same disease setting, they hypothesized that functional nuclear APC might somehow guard against inflammation and its downstream effects, including tumour development. Now, Neufeld thinks she and her team may have a clue as to how this happens.

“The drop in goblet cell numbers we observed was striking,” she said. “We then examined one of the proteins found in mucus, called Muc2, and found that its RNA levels were greatly decreased. If there are fewer goblet cells as a result of APC being unable to reach the nucleus, there will also be less mucus, which could increase the colon’s sensitivity to bacteria and other microorganisms in the gut that are capable of promoting inflammation.”

Neufeld said while there are still no quick fixes for mutant genes, perhaps tools could be developed to synthetically replace this less-than-ideally thick mucus layer in affected people.

One known function of APC is that it halts cell proliferation: by muzzling the canonical arm of the Wnt signaling pathway, which otherwise instructs cells to go forth and multiply. Neufeld and her group have already shown, using the same mouse model, that APC stationed in the nucleus is necessary to suppress Wnt and its signaling partners — particularly β-catenin, a key target of normal APC. With a role for nuclear APC in controlling goblet cell differentiation now supported, the researchers are probing possible mechanisms to learn if and how Wnt pathway members might be involved. Kansas University

Over the past several decades, malaria diagnosis has changed very little. After taking a blood sample from a patient, a technician smears the blood across a glass slide, stains it with a special dye, and looks under a microscope for the Plasmodium parasite, which causes the disease. This approach gives an accurate count of how many parasites are in the blood — an important measure of disease severity — but is not ideal because there is potential for human error.
A research team from the Singapore-MIT Alliance for Research and Technology (SMART) has now come up with a possible alternative. The researchers have devised a way to use magnetic resonance relaxometry (MRR), a close cousin of magnetic resonance imaging (MRI), to detect a parasitic waste product in the blood of infected patients. This technique could offer a more reliable way to detect malaria, says Jongyoon Han, a professor of electrical engineering and biological engineering at MIT.

“There is real potential to make this into a field-deployable system, especially since you don’t need any kind of labels or dye. It’s based on a naturally occurring biomarker that does not require any biochemical processing of samples” says Han, one of the senior authors of a paper describing the technique.

With the traditional blood-smear technique, a technician stains the blood with a reagent that dyes cell nuclei. Red blood cells don’t have nuclei, so any that show up are presumed to belong to parasite cells. However, the technology and expertise needed to identify the parasite are not always available in some of the regions most affected by malaria, and technicians don’t always agree in their interpretations of the smears, Han says.

“There’s a lot of human-to-human variation regarding what counts as infected red blood cells versus some dust particles stuck on the plate. It really takes a lot of practice,” he says.
The new SMART system detects a parasitic waste product called haemozoin. When the parasites infect red blood cells, they feed on the nutrient-rich haemoglobin carried by the cells. As haemoglobin breaks down, it releases iron, which can be toxic, so the parasite converts the iron into hemozoin — a weakly paramagnetic crystallite.
Those crystals interfere with the normal magnetic spins of hydrogen atoms. When exposed to a powerful magnetic field, hydrogen atoms align their spins in the same direction. When a second, smaller field perturbs the atoms, they should all change their spins in synchrony — but if another magnetic particle, such as hemozoin, is present, this synchrony is disrupted through a process called relaxation. The more magnetic particles are present, the more quickly the synchrony is disrupted.

“What we are trying to really measure is how the hydrogen’s nuclear magnetic resonance is affected by the proximity of other magnetic particles,” Han says.
For this study, the researchers used a 0.5-tesla magnet, much less expensive and powerful than the 2- or 3-tesla magnets typically required for MRI diagnostic imaging, which can cost up to $2 million. The current device prototype is small enough to sit on a table or lab bench, but the team is also working on a portable version that is about the size of a small electronic tablet.
After taking a blood sample and spinning it down to concentrate the red blood cells, the sample analysis takes less than a minute. Only about 10 microliters of blood is required, which can be obtained with a finger prick, making the procedure minimally invasive and much easier for health care workers than drawing blood intravenously.

“This system can be built at a very low cost, relative to the million-dollar MRI machines used in a hospital,” Peng says. “Furthermore, since this technique does not rely on expensive labelling with chemical reagents, we are able to get each diagnostic test done at a cost of less than 10 cents.” MIT