Siemens Healthineers will expand the company’s existing manufacturing operations in Shanghai, China to include a new in vitro diagnostics facility. The China manufacturing facility will enable in-country manufacturing capabilities for clinical chemistry and immunoassay reagents. “This investment demonstrates the company’s continued commitment to address the evolving needs in the Chinese market and in healthcare markets across the globe,” said Franz Walt, President, Laboratory Diagnostics, Siemens Healthineers. China is the second largest market for Siemens Healthineers. According to George Chan, President, Greater China, Siemens Healthineers, “The opening of this facility strengthens our ability to support Chinese healthcare reform as we deliver better outcomes at a lower cost to our customers.” The company expects to employ hundreds of additional employees once the project is completed.

www.healthcare.siemens.com

Cancer is often driven by various genetic mutations that are acquired through changes to a person’s DNA over time. These alterations can occur at the chromosome level if the proteins are not properly organized and segregated as our cells divide and multiply.

Now, new research from The Wistar Institute demonstrates how two key proteins mediate the organization of chromosomes and our genome, shedding light on one of the key genetic processes for every person. With this key basic information in hand, scientists may now be able to pinpoint the origins of cancer due to genetic mutations.

“Understanding the three-dimensional structure of our genome is critical if we are to properly understand key functions like transcription, DNA replication and repair,” said Ken-ichi Noma, Ph.D., associate professor in the Gene Expression and Regulation program at Wistar and lead author of the study.

Each of our cells contains enough DNA that, if stretched out in a line, would total about six feet in length. Condensin and cohesin are two key protein complexes that properly preserve our DNA in our chromosomes. Condensin helps to compact the essential genetic information into our cells and facilitates chromosome formation. Cohesin helps regulate the chromatids – the two strands along which a chromosome divides – during cell division.

Noma has extensively studied the importance of the three-dimensional structure of our genomes, and while researchers know the roles of condensin and cohesin, their exact roles in how they are able to properly organize chromosomes has remained unclear. Noma and his colleagues studied fission yeast because it undergoes cell division very similar to that of humans. They were able to show that although condensin and cohesin bind to the exact same position on chromosomes, but the domains of chromatins – complexes of DNA and proteins that make up our chromosomes – vary in size and function depending on which protein complex is responsible for the organization.

Cohesin helps mediate associations between chromatins located close to one another whereas condensin mediates larger associations. These domains play critical roles in making sure each cell performs its key function, and if either cohesin or condensin does not organize these key genetic components properly, the consequences could be a host of genetic diseases, including cancer.

Specifically, the researchers pinpointed a mutation in the ace2Δ gene, which is responsible for encoding a transcription factor that is important for condensing, that can disrupt these key gene association domains. If this happens, it can lead to chromosomal segregation defects. This mutation revealed more information about the specific role of condensin as well. They proposed that condensin is recruited to chromosomes by transcription factors that regulate mitosis, or cell division. When condensin is recruited in this manner, chromosomes can be properly segregated.

“The more we know about the role of condensin and cohesin, the more we can learn about key processes involved in the cell cycle and how cancer can be controlled through processes like cellular senescence,” Noma said.

The Wistar Institute www.wistar.org/news-and-media/press-releases/two-key-proteins-preserve-vital-genetic-information

The formation of large numbers of polyps in the colon has a high probability of developing into colon cancer, if left untreated. The large-scale appearance of polyps is often due to a hereditary cause; in this case the disease can occur in multiple family members. Under the leadership of human geneticists of the University Hospital Bonn, a team of researchers discovered genetic changes in the MSH3 gene in patients and identified a new rare form of hereditary colon cancer.

Colon polyps form like mushroom-shaped growths from the mucosa and are several millimetres to several centimetres in size. They are benign and generally do not cause any symptoms – however, they can turn into malignant tumours (colon cancer). Physicians refer to the development of a large number of polyps in the colon as ‘polyposis.’ Scientists have already discovered several genes associated with a polyposis. ‘However, about one-third of families affected by the disease do not have any abnormalities in these genes,’ says Prof. Dr. Stefan Aretz, head of the working group at the Institute of Human Genetics at the University of Bonn Hospital. Therefore, there would have to be even more genes involved in the formation of polyps in the colon.

Together with pathologists from the University Hospital Bonn, scientists from the Yale University School of Medicine in New Haven (USA), and the Frankfurt University Hospital, the team working with Prof. Aretz investigated the genetic material (DNA) of more than 100 polyposis patients using blood samples. In each patient, all of the about 20,000 protein-coding genes known were simultaneously examined. In this process, the scientists filtered the rare, possibly relevant genetic changes out of the gigantic quantity of data, like the proverbial needle in a haystack. In two patients, genetic changes (mutations) were discovered in the MSH3 gene on chromosome 5.

Proof of causes is like a trial based on circumstantial evidence

‘The challenge is proving the causal connection between the mutations in this gene and the disease,’ says Prof. Aretz. The process is similar to that of a trial based on circumstantial evidence. Family members also play a role here: The siblings with the disease have to have these same MSH3 mutations as the patient who was first examined, but not the healthy relatives. That was the case. In addition, the scientists investigated the consequences for patients resulting from the loss of function of the MSH3 gene. ‘It involves a gene for the repair of the genetic material,’ reports Dr. Ronja Adam, one of the two lead authors from Prof. Aretz’s team. ‘The mutations cause the MSH3 protein to not be formed.’ Since the protein is missing in the cell nucleus of the patient´s tissues, there is an accumulation of genetic defects. The mutations which are not repaired then predispose to the more frequent occurrence of polyps in the colon.

The newly discovered type of polyposis, in contrast to many other forms of hereditary colon cancer, is not inherited dominantly, but instead recessively. ‘This means that siblings have a 25 percent chance of developing the disease; however, the parents and children of affected persons only have a very low risk of developing the disease,’ explains Dr. Isabel Spier from the Institute of Human Genetics, who was also very involved in the study.

The annual colonoscopy is the most effective cancer screening method for polyposis patients. As a result, the development of colon cancer can be effectively prevented. By investigating the MSH3 gene, a clear diagnosis can be made prospectively in some other, previously unexplained polyposis cases. Afterwards, healthy persons at risk in the family can be tested for the mutations. ‘Only proven carriers would need to take part in the intensive surveillance program,’ says the human geneticist. In addition, science would gain new insights into the development and biological foundations of tumours through the identification of mutations in the MSH3 gene. Prof. Aretz: ‘The knowledge about molecular mechanisms which lead to cancer is also a precondition for the development of new targeted drugs.’

University of Bonn www.uni-bonn.de/Press-releases/discovery-of-a-novel-gene-for-hereditary-colon-cancer

Microcephaly is a rare disorder that stunts brain development in utero, resulting in an abnormally small head. The Zika virus is one environmental cause of this devastating condition, but genetic defects can cause microcephaly, too. A new Duke University study examining three genetic causes of microcephaly in mice suggests one common mechanism through which the disorder could arise.

The study offers a new window into early, critical stages of brain development, and may improve understanding of the diverse causes of microcephaly and other neurodevelopmental disorders, including autism.

“We’re excited about this study because, by stepping back and looking at the basic mechanistic routes to microcephaly, we hope to understand how Zika infection causes microcephaly,” said the study’s senior investigator Debra Silver, an assistant professor of molecular genetics and microbiology at the Duke University School of Medicine.

In the new study, Hanqian Mao, a graduate student in Silver’s lab, created three mouse models of microcephaly by cutting the levels of each of three genes — Magoh, Rbm8a and Eif4a3 — by half during a critical time in brain development. All three types of mice developed a smaller cerebral cortex, the part of the brain responsible for memory and thought.

Then, Mao screened for any changes in mRNA and protein levels that could also contribute to the underdeveloped brains. One change that stood out involved a protein called p53, which accumulated in each of the mutant brains. The group hypothesized that too much p53 could cause developing cells to die.

To test the involvement of p53 in microcephaly, Duke postdoctoral fellow John McMahon suppressed it in each of the three types of mice. By blocking p53 at a crucial point in development, the team was able to trigger the brains to partially or fully recover to normal size, suggesting that p53 or its signalling partners might be considered as new therapeutic targets for microcephaly.

“What we don’t know yet is exactly how our microcephaly-causing genes are regulating p53 and other changes in the brain, and that’s going to be the next big question,” Silver said.

The genes Magoh, Rbm8a and Eif4a3 are related to one another in that they bind together on specific spots on RNA and affect its processing to become protein. Although the triad is expressed in every cell of the body, it is more abundant in brain tissue.

“Our results suggest that the molecular complex is a master regulator of cortical development, because it’s regulating critical genes in stem cells, which must divide and then start making neurons,” said Silver, who is also a member of the Duke Institute for Brain Sciences.

“If you have problems at this early stage, you don’t get enough stem cells. And then the stem cells themselves can’t go on to make neurons. That’s where you get microcephaly,” Silver added.

Importantly, disruptions in the genes Rbm8a and Eif43 have already been linked to human cases of intellectual disability, and Rbm8a has been associated with microcephaly and autism in people.

“That’s another reason that identifying the downstream molecules of these genes is really important,” Silver said, adding that her team has some of the only mouse models in which it is possible explore those questions.

Duke University today.duke.edu/2016/09/genetic-causes-small-head-size-share-common-mechanism

A new device for studying tumour cells can trap 10,000 individual cells in a single chip.

The technique, developed at the University of Michigan, could one day help screen potential cancer treatments based on an individual patient’s tumour and help researchers better understand so-called cancer stem cells. It also sheds light on a controversy: are large cells or small cells more likely to be cancer stem cells?

Cancer cells are not all the same, and one theory holds that no more than 5 percent of the cells in a tumour are cancer stem cells. These few may be the only cells capable of causing a relapse or metastasis.

‘Most normal cells will die if they are not anchored to something, but cancer stem cells can survive. They can become circulating tumour cells and come to another area of the body,’ said Euisik Yoon, professor of electrical engineering and computer science, and biomedical engineering.

The team led by Yoon designed and made a device that takes advantage of this ability in hopes of understanding cancer stem cells better: how to identify them, what causes them to grow or die, and how to target them with cancer treatments. Their chip contains up to 12,800 wells for catching individual cancer cells. The team tested the chip with breast cancer cells, donated by researchers in the U-M Comprehensive Cancer Center.

They mixed the cells into a solution and ran the liquid through tiny channels in a plastic chip. Each channel was lined with chambers for trapping single cells.

The chambers have small openings to a parallel channel, which creates a draft that draws cells in — sort of like the drain in a sink. Once a cell is trapped, it blocks that opening and stops the draft. This ensures that, most of the time, only one cell is pulled into each chamber.

The walls of the chamber are coated so that the cell can’t latch on. As a result, normal cells that can’t cause metastases die over the course of a few days, leaving behind just the cancer stem cells. These cells reproduce in their chambers, forming tiny floating colonies, or tumorspheres.

While the ability to isolate 10,000 individual cells is impressive, it wouldn’t be useful if the team had to manually record every one, as required by most devices that capture cancer cells. The key is their computer algorithm, capable of combing through the microscope images and assessing the size and number of cells in each well. The algorithm’s particular talent is identifying cells no matter whether they show up dimly or brightly in the microscope image.

‘Our method is special because we really want to enable the study of many cells at once,’ said Yu-Heng Cheng, a doctoral student in electrical engineering and computer science. ‘Cancer cells have many different appearances, and our algorithm recognizes them.’

University of Michigan www.mcancer.org/news/archive/cancer-stem-cells-new-method-analyzes-10000-cells-once