A computer science and engineering associate professor and her doctoral student graduate are using a genetic computer network inference model that eventually could predict whether a person will suffer from bipolar disorder, schizophrenia or another mental illness.

The findings are detailed in the paper “Inference of SNP-Gene Regulatory Networks by Integrating Gene Expressions and Genetic Perturbations,” which was recently published. The principal investigators were Jean Gao, an associate professor of computer science and engineering, and Dong-Chul Kim, who recently earned his doctorate in computer science and engineering from UT Arlington.

“We looked for the differences between our genetic computer network and the brain patterns of 130 patients from the University of Illinois,” Gao said. “This work could lead to earlier diagnosis in the future and treatment for those patients suffering from bipolar disorder or schizophrenia. Early diagnosis allows doctors to provide timely treatments that may speed up aid to help affected patients.”

The UT Arlington researchers teamed with Jiao Wang of the Beijing Genomics Institute at Wuhan, China; and Chunyu Liu, visiting associate professor at the University of Illinois Department of Psychiatry, on the project.

Gao said the findings also could lead to more individualized drug therapies for those patients in the early stages of mental illnesses.

“Our work will allow doctors to analyse a patient’s genetic pattern and apply the appropriate levels of personalized therapy based on patient-specific data,” Gao said.

One key to the research is designing single nucleotide polymorphism or SNP networks, researchers said.

“SNPs are regulators of genes,” said Kim, who joins the University of Texas-Pan American this fall as an assistant professor. “Those SNPs visualize how individual genes will act. It gives us more of a complete picture.” UT Arlington

During breast-tissue development, a transcription factor called SLUG plays a role in regulating stem cell function and determines whether breast cells will mature into luminal or basal cells.

Studying factors, such as SLUG, that regulate stem-cell activity and breast-cell identity are important for understanding how breast tumours arise and develop into different subtypes. Ultimately, this knowledge may help the development of novel therapies targeted to specific breast-tumour subtypes.

Background: Stem cells are immature cells that can differentiate, or develop, into different cell types. Stem cells are important for replenishing cells in many tissues throughout the body. Defects that affect stem-cell activity can lead to cancer because mutations in these cells can cause uncontrollable growth. Some transcription factors regulate the differentiation or ‘programming’ of breast stem cells into the more mature cells of the breast tissue. Abnormal expression of these transcription factors can change the normal programming of cells, which can lead to imbalances in cell types and the over-production of cells with enhanced properties of stem cells.

Breast tissue has two main types of cells: luminal cells and basal cells. Transcription factors, like SLUG, help control whether cells are programmed to become luminal cells or basal cells during normal breast development. In cancer, transcription factors can become deregulated, influencing what type of breast tumour will form. In aggressive basal-type breast tumours, SLUG is often over-expressed.

Previous work led by Charlotte Kuperwasser, principal investigator and senior author, determined that some common forms of breast cancer originate from luminal cells, whereas rare forms of breast cancer originate from basal cells. This difference in origins suggests that genes that affect the ability of a cell to become luminal or basal may also affect the formation of breast tumours. Because SLUG can regulate breast-cell differentiation, Kuperwasser’s team investigated SLUG’s role in breast-cell differentiation and tumor growth.

The research team reduced the expression of the SLUG gene in human-derived breast cells and then used cell-sorting techniques to separate the cells into groups of luminal, basal, and stem cells. Next, they used mathematical modelling to measure the rate and frequency that each of the three cell types changed into another cell type. By comparing the rates between control cells and cells in which SLUG was reduced, the team was able to determine the role of SLUG in luminal-, basal-, and stem-cell transitions.

To test the result of their mathematical model, the research team examined and compared breast-tissue samples from mice in two groups: a control group with normal SLUG and an experimental group that did not express SLUG. Mammary glands from the experimental and control groups were analyzed for changes in structure, the amount and distribution of luminal and basal cells in the gland, and whether these cells had stem-cell activity.

The SLUG-deficient mice exhibited defects in breast-cell differentiation. The mammary glands of these mice had too many luminal cells and defective basal cells that had luminal-cell characteristics. The control group of normal mice had a normal ratio of luminal to basal cells.

The SLUG-deficient mice showed defects in stem-cell function: Specifically, tumour formation and tissue regeneration was inhibited, an indication of defective stem cells, suggesting that SLUG was necessary to maintain normal luminal and basal cells within the mammary gland.

Additionally, SLUG-deficient cells when transplanted could not regenerate the mammary gland of the mouse, suggesting that SLUG is necessary for mammary stem-cell function. Tumour formation was also inhibited in SLUG-deficient mice, suggesting that SLUG may affect stem-cell activity necessary for tumour formation. Tufts University

It has been some time in the making, but the newly designed Greiner Bio-One website was finally launched at the beginning of July along with our newly designed webshop.

Product and order information for the business divisions Preanalytics (specimen collection), BioScience (products for the biotech industry), Diagnostics (DNA arrays) and OEM (customised developments for the Life Science industry) can be accessed at www.gbo.com.

The innovative design with cool Parallax Scrolling technology at various levels is not the only thing that is new. Alongside the range of improvements, there are also a number of technical innovations, making it even easier to find the information you are looking for.

Features include:

• A download menu divided into product groups, with downloads of flyers, brochures, etc. available in a range of languages
• FAQs for the various products are answered in the "Frequently Asked Questions" section
• The E-learning system "GBO Compass" and social media channels
  can now also be accessed via links
• The latest developments are shown in brief and with an eye-catching layout in Marketing Highlights
• Related content such as print material is shown directly on the various product pages in a separate box.

_{^{Greiner Bio-One International AG
Greiner Bio-One is specialized in the development, production and distribution of high quality laboratory products made from plastic. The company is a technological partner for hospitals, laboratories, universities, research institutes and the diagnostic, pharmaceutical and biotechnology industries. Greiner Bio-One consists of four business units: Preanalytics, BioScience, Diagnostics and OEM. Today the company generates a turnover of 373 Mio. Euro.  Greiner Bio-One is a member of the Greiner Group based in Kremsmünster (Austria).}}

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

Prostate cancer is a leading cause of cancer-related death in men in the United States. The development and progression of the disease depend on the actions of male sex hormones called androgens, which bind to the androgen receptor to activate signalling pathways involved in cell growth and survival. Therefore, there is a strong need to identify novel drug targets to alter androgen-receptor signalling and treat this often deadly disease.

Sanford-Burnham researchers have discovered that a protein called NWD1 affects androgen-receptor signalling to control the growth of prostate cancer cells. ‘A very limited number of proteins have been shown to specifically and exclusively affect androgen-receptor signalling, so our findings represent a major advance in the field,’ said lead study author Ricardo Correa, Ph.D., staff scientist at Sanford-Burnham. ‘NWD1 could represent a new biomarker for predicting patient prognosis as well as a therapeutic target for a novel class of prostate cancer drugs.’
High levels of androgens are critical for the growth of prostate cancer cells in early disease stages, and one major type of therapy focuses on inhibiting androgens. But over time, prostate cancer cells often respond to hormone therapy by expressing high levels of the androgen receptor, allowing these castration-resistant cells to grow even when androgen levels are low. Castration-resistant prostate cancer is an advanced form of the disease associated with poor survival rates. However, both early and advanced stages of prostate cancer depend on androgen-receptor signalling, highlighting the value of targeting this pathway for treating a broad range of patients.

While searching for novel modulators of androgen-receptor signalling, Correa and his team became interested in the nucleotide-binding domain and leucine-rich repeat (NLR) family of proteins. These proteins are involved in recognising pathogens and cell-injury signals and activating immune-defence pathways, but they have also been implicated in a variety of cancers. In particular, the researchers were intrigued by an NLR-related protein called NWD1, which was previously identified in zebrafish but had not yet been analyzed in humans.

In the new study, Correa and his colleagues found that the expression of the human NWD1 gene was very high in prostate tissue and other parts of the male reproductive system. Moreover, NWD1 expression was higher than normal in human prostate cancer cell lines, especially in castration-resistant and highly metastatic cell lines. Similarly, NWD1 protein levels were higher than normal in advanced-stage and castration-resistant prostate tumour tissue from patients.

Taken together, the findings suggest that NWD1 could be a potential prostate cancer biomarker because high levels of the protein are associated with malignant progression. ‘We believe that NWD1 could represent a promising biomarker because changes in NWD1 expression happen at stages where the levels of prostate-specific antigen (PSA), a protein that is widely used to screen men for prostate cancer, are not very accurate in the clinic,’ Correa said.
In addition to its potential use for predicting patient prognosis, NWD1 could represent a promising therapeutic target. When the researchers inhibited the activity of the NWD1 gene in prostate cancer cells, they noticed a drop in androgen-receptor levels as well as a decrease in cell growth and survival. On the other hand, an increase in NWD1 activity led to a rise in androgen-receptor levels in these cells.

Their experiments also shed light on the molecular mechanisms by which NWD1 affects androgen-receptor signalling. NWD1 silencing fed the activity of cancer-related genes such as PDEF (prostate-derived epithelial factor), which is known to bind to androgen receptors and belongs to a family of proteins that regulate cell growth and survival. Moreover, a protein called sex-determining region Y (SRY), which controls sex determination during fetal development, affected the activity of the NWD1 gene. Thus, the findings not only reveal a novel molecular pathway involved in prostate cancer, but also suggest that drugs targeting NWD1 could eventually become a new class of treatments for the disease. Sanford-Burnham