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Newswise NEW BRUNSWICK, N.J. The National Institute on Drug Abuse (NIDA) has awarded a five-year contract worth up to $19 million to RUCDR Infinite Biologics, a unit of Rutgers Human Genetics Institute of New Jersey. The worlds largest university-based biorepository, RUCDR Infinite Biologics is located on Rutgers Busch Campus in Piscataway.

Under the new contract, RUCDR will expand and enhance the services it provides through its NIDA Center for Genetic Studies, which it has supported for the past 15 years. The Center provides genomic services to NIDA-funded researchers.

Because the Rutgers operation has been continuously acquiring new equipment and systems, and refining the techniques its staff employs, the genomic testing and analysis for NIDA studies will be significantly more sophisticated than in previous years, according to Jay Tischfield, CEO and founder of RUCDR Infinite Biologics and the Duncan and Nancy Macmillan Distinguished Professor of Genetics at Rutgers.

Under this new contract with NIDA, we will be utilizing innovative technologies to support research, such as microarray typing and high-throughput sequencing for genomic and epigenomic analyses, Tischfield said. We also will support NIDA projects that employ induced pluripotent stem cells to facilitate the molecular and cellular study of brain development and addiction processes.

The NIDA Center for Genetic Studies is a scientific resource for informing the human molecular genetics of drug addiction. The center stores clinical and diagnostic data, pedigree information and biomaterials (including DNA, plasma, cryopreserved lymphocytes and/or cell lines) from human subjects participating in studies that form the NIDA Genetics Consortium.

The contract includes receiving data along with blood samples or other biospecimens from funded grants and/or contracts supporting research on the genetics of addiction and addiction vulnerability; processing these data and materials to create databases, serum, DNA, RNA and cell lines; distributing all data and materials in the NIDA Human Genetics Initiative to qualified investigators; and maintaining storage of data and biomaterials.

RUCDR has a similar agreement with the National Institute of Mental Health to support the NIMH Center for Collaborative Genomics Research on Mental Disorders, which provides services to NIMH-funded scientists studying mental disorders. A $44.5 million, five-year cooperative agreement renewal was awarded in 2013.

About RUCDR Infinite Biologics RUCDR Infinite Biologics offers a complete and integrated selection of biological sample processing, analysis and biorepository services to government agencies, academic institutions, foundations and biotechnology and pharmaceutical companies within the global scientific community. RUCDR Infinite Biologics provides DNA, RNA and cell lines with clinical data to hundreds of research laboratories for studies on mental health and developmental disorders, drug and alcohol abuse, diabetes and digestive, liver and kidney diseases. RUCDR completed an $11.8 million expansion and renovation of its facilities last year. Read more at http://www.rucdr.org.

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Rutgers' Human Genetics Institute Wins $19 Million Federal Contract

PUBLIC RELEASE DATE:

5-Mar-2014

Contact: Marta Garcia Gonzalo g.prensa@csic.es 34-915-681-476 Spanish National Research Council (CSIC)

The results, published in The New England Journal of Medicine and Human and Molecular Genetics journals, demonstrate for the first time that mutation in STAG3 gene is the major cause of human fertility disorders as it provokes a loss of function of the protein it encodes.

STAG3 encodes a meiosis-specific subunit of the cohesin ring, the biological process through which, from a diploid somatic cell, a haploid cell or gamete is produced. Cohesins are protein complexes that bind two straps of DNA and are implicated in its repair, replication and recombination, as well as in its chromosomal stability, transcription regulation, stem-cell pluripotency, and cell differentiation.

Alberto M. Pends, CSIC researcher at the Cancer Research Center (USAL/CSIC), states: "Our work enables us to causally relate mutations in a gene of the cohesin complex with human infertility. It also demonstrates for the first time in humans that POF and azoospermia, a disorder that impedes normal sperm production, are probably the two faces of the same genetic disease".

Genetic study in a family

Researchers have identified, through the analysis of samples obtained from a consanguineous Middle Eastern family, a region on chromosome 7q21 that has significant linkage with POF. In collaboration with US and French researchers, they have performed the whole-exome sequencing, the fraction of the genome that encodes proteins, of the DNA provided by two sisters within this family, being one of them healthy and the other one sterile. Through the combination of linkage data and exome sequencing, they have identified a deletion or loss of a single base in the gene encoding STAG3, which results in a prematurely truncated protein without function.

CSIC researcher adds: "We have confirmed that mutation is found in both copies of the gene, one inherited from the father and the other one inherited from the mother, in the four women affected by the disease, causing an absolute absence of STAG3 protein and meiotic cohesin complex in these women. Likewise, all the unaffected members have at least one of the two copies of the non-mutated STAG3 gene, which further supports that this is responsible for the POF".

The proof that STAG3 mutation is the cause of the disease has been achieved by generating mutant mice of this gene. The analysis of female mice has revealed that, same as the affected women, the absence of STAG3 provokes the disease.

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Genetic cause found for premature ovarian failure

Analyzing the genomes of twin 3-year-old sisters -- one healthy and one with aggressive leukemia -- led an international team of researchers to identify a novel molecular target that could become a way to treat recurring and deadly malignancies.

Scientists in China and the United States report their findings online Feb. 9 in Nature Genetics. The study points to a molecular pathway involving a gene called SETD2, which can mutate in blood cells during a critical step as DNA is being transcribed and replicated.

The findings stem from the uniquely rare opportunity to compare the whole genomes of the monozygotic twin sisters (which means they came from a single egg). This led to a series of follow up experiments in human samples from leukemia patients and mouse models of human disease. Those tests verified and extended initial findings researchers gleaned from the twin sisters' blood samples, according to Gang Huang, PhD, co-corresponding author and a researcher in the divisions of Pathology and Experimental Hematology and Cancer Biology at Cincinnati Children's Hospital Medical Center.

"We reasoned that monozygotic twins discordant for human leukemia would have identical inherited genetic backgrounds and well-matched tissue-specific events," Huang said. "This provided a strong basis for comparison and analysis. We identified a gene mutation involving SETD2 that contributes to the initiation and progression of leukemia by promoting the self-renewal potential of leukemia stem cells."

The twin sisters' genomes were compared at the laboratory of co-corresponding author Qian-fei Wang, PhD, Beijing Institute of Genomics, Chinese Academy of Sciences in Beijing, China. The sick sister had a particularly acute and aggressive form of the acute myeloid leukemia (AML) known as MLL, or multi-lineage leukemia.

Acute and aggressive leukemia like MLL develops and progresses rapidly in patients, requiring prompt treatment with chemotherapy, radiation or bone marrow transplant. These treatments can be risky or only partially effective. About 70 percent of people with AML respond initially to standard chemotherapy. Unfortunately, five-year survival rates vary between 15-70 percent, depending on the subtype of AML.

The researchers -- including co-corresponding author Tao Cheng, MD, Chinese Academy of Medical Sciences & Peking Union Medical College in Tianjin, China -- are searching for improved and more targeted treatment strategies. The authors show in their current study that the onset of aggressive and acute leukemia is fueled by a spiraling cascade of multiple gene mutations and what are called chromosomal translocations -- essentially incorrect alignments of DNA and genetic information during cell replication.

In comparing the blood cells of both twin sisters, these researchers identified a chromosomal translocation generated what is known as the MLL-NRIP3 fusion leukemia gene. When they activated the MLL-NRIP3 gene in laboratory mouse models, the animals developed the same type of leukemia, but it took a long period of time for them to do so. Researchers said this suggested that there had to be additional cooperative epigenetic and molecular events in play to induce full-blown leukemia.

The authors went on to demonstrate that activation of the MLL-NRIP3 fusion leukemia gene cooperated with the molecular cascade (including mutations in SETD2) to cause the multi-lineage form of acute myeloid leukemia (AML). The scientists' initial clue came by looking for additional genomic alterations in the leukemic blood cells of the sick twin sister. They discovered activation of the MLL-NRIP3 fusion leukemia started the molecular cascade that led to bi-allelic (two mutations) in the gene SETD2 -- a tumor suppressor and enzyme that regulates a specific histone modification protein called H3K36me3.

During a process called transcriptional elongation, SETD2 and H3K36me3 normally mark the zone for accurate gene transcription along the DNA. In the case of the sick twin sister, the gene mutations and molecular cascade disrupted the H3K36me3 mark, leading to abnormal transcription and the multi-lineage form of acute leukemia.

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Clues for battling aggressive cancers from twin sisters study

PUBLIC RELEASE DATE:

9-Feb-2014

Contact: Nick Miller nicholas.miller@cchmc.org 513-803-6035 Cincinnati Children's Hospital Medical Center

CINCINNATI Analyzing the genomes of twin 3-year-old sisters one healthy and one with aggressive leukemia led an international team of researchers to identify a novel molecular target that could become a way to treat recurring and deadly malignancies.

Scientists in China and the United States report their findings online Feb. 9 in Nature Genetics. The study points to a molecular pathway involving a gene called SETD2, which can mutate in blood cells during a critical step as DNA is being transcribed and replicated.

The findings stem from the uniquely rare opportunity to compare the whole genomes of the monozygotic twin sisters (which means they came from a single egg). This led to a series of follow up experiments in human samples from leukemia patients and mouse models of human disease. Those tests verified and extended initial findings researchers gleaned from the twin sisters' blood samples, according to Gang Huang, PhD, co-corresponding author and a researcher in the divisions of Pathology and Experimental Hematology and Cancer Biology at Cincinnati Children's Hospital Medical Center.

"We reasoned that monozygotic twins discordant for human leukemia would have identical inherited genetic backgrounds and well-matched tissue-specific events," Huang said. "This provided a strong basis for comparison and analysis. We identified a gene mutation involving SETD2 that contributes to the initiation and progression of leukemia by promoting the self-renewal potential of leukemia stem cells."

The twin sisters' genomes were compared at the laboratory of co-corresponding author Qian-fei Wang, PhD, Beijing Institute of Genomics, Chinese Academy of Sciences in Beijing, China. The sick sister had a particularly acute and aggressive form of the acute myeloid leukemia (AML) known as MLL, or multi-lineage leukemia.

Acute and aggressive leukemia like MLL develops and progresses rapidly in patients, requiring prompt treatment with chemotherapy, radiation or bone marrow transplant. These treatments can be risky or only partially effective. About 70 percent of people with AML respond initially to standard chemotherapy. Unfortunately, five-year survival rates vary between 15-70 percent, depending on the subtype of AML.

The researchers including co-corresponding author Tao Cheng, MD, Chinese Academy of Medical Sciences & Peking Union Medical College in Tianjin, China are searching for improved and more targeted treatment strategies. The authors show in their current study that the onset of aggressive and acute leukemia is fueled by a spiraling cascade of multiple gene mutations and what are called chromosomal translocations essentially incorrect alignments of DNA and genetic information during cell replication.

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Study involving twin sisters provides clues for battling aggressive cancers

Public release date: 13-Nov-2012 [ | E-mail | Share ]

Contact: Chris Chipello christopher.chipello@mcgill.ca 514-398-4201 McGill University

As they develop, vertebrate embryos form vertebrae in a sequential, time-controlled way. Scientists have determined previously that this process of body segmentation is controlled by a kind of "clock," regulated by the oscillating activity of certain genes within embryonic cells. But questions remain about how precisely this timing system works.

A new international cross-disciplinary collaboration between physicists and molecular genetics researchers advances scientists' understanding of this crucial biological timing system. The study, co-authored by McGill University Prof. Paul Franois and Ohio State University Prof. Sharon L. Amacher and published in Developmental Cell, sheds light on the clock mechanism by providing the first real-time, visual evidence of how it operates at the level of individual cells.

While previous scientific studies have examined the oscillation phenomenon in the tissue of mouse embryos, the McGill and Ohio State researchers were able to observe and analyze it in single cells. To do so, they genetically modified zebrafish a freshwater fish whose body is nearly transparent during early development, making its anatomy easy to observe. The researchers used a fluorescent marker in the transgenic fish and developed software tools to monitor the concentration of a certain "cyclic" protein, whose production rises and falls with the oscillating expression of the molecular clock genes.

It is known that cells communicate with neighboring cells through a messaging system known as the Notch signaling pathway. In their experiments with the zebrafish, the researchers cut off this inter-cellular communication network enabling them to see how that would affect the oscillation pattern in individual cells and their neighbors.

These experiments revealed that cyclic protein concentrations in individual cells of the zebrafish continued to rise and fall, indicating that they continued to oscillate. With the inter-cellular signaling pathway blocked, however, the oscillations were no longer synchronized among neighboring cells. The cellular clocks were still ticking, in other words, but not in unison. This finding confirms that the Notch pathway serves to coordinate timing among cells a crucial role, since the cells must act in concert in order to form vertebrae.

By observing normal zebrafish embryos, the researchers were also able to show that cells desynchronize their oscillations while performing cellular division, then later resynchronize with their neighbors as they proceed collectively to form vertebrae.

"In humans, defects in Notch signaling are associated with congenital developmental disorders called spondylocostal dysostosis, that are typified by scoliosis and trunk dwarfism caused by malformed ribs and vertebrae," Amacher notes. "Studies such as ours may provide insight into potential therapies for human disease. It is likely that many cells in our bodies - stem cells, cancer cells - have similar molecular oscillators that regulate response to environmental signals. By unraveling such molecular clocks, we can understand how to modify them and thus change the number of oscillating cells that respond to differentiating signals, providing tremendous insight for studies in stem cell and cancer biology and tissue engineering."

"The formation of the vertebral column is very important, because everything follows from that" in the development of vertebrates, Franois adds. A physicist, he developed the computer tools used to analyze video footage of the zebrafish embryos. Francois's research focuses on the modeling of physical properties of gene networks and their evolution a field that has emerged at the nexus of biology and physics in recent years, following sequencing of the human genome and rapid growth in scientists' understanding of the processes inside cells.

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Study sheds light on genetic 'clock' in embryonic cells

Public release date: 15-Oct-2012 [ | E-mail | Share ]

Contact: Jennifer Hilliard Scott jscott1@georgiahealth.edu 706-721-8604 Georgia Health Sciences University

AUGUSTA, Ga. Georgia Health Sciences University researchers have developed a mouse that errs on the side of making bone rather than fat, which could eventually lead to better drugs to treat inflammatory diseases such as rheumatoid arthritis.

Drugs commonly used to treat those types of conditions called glucocorticoids work by turning down the body's anti-inflammatory response, but simultaneously turn on other pathways that lead to bone loss. The result can lead to osteoporosis and an accumulation of marrow fat, says Dr. Xingming Shi, bone biologist at the GHSU Institute of Molecular Medicine and Genetics.

The key to the body developing bone instead of fat, a small protein called GILZ, was shown in cell cultures in 2008. Now, with work by GHSU Graduate Student Guodong Pan, the work has been replicated in an animal model. Pan received the American Society for Bone and Mineral Research's Young Investigator Award for his work at the society's annual meeting Oct. 12-15 in Minneapolis.

Bone and marrow fat come from the same biological precursor mesynchymal stem cells. "The pathways for bone and fat have a reciprocal relationship, so we needed to find the key that disrupts the fat production pathway, which would then instead encourage bone growth," Shi says.

GILZ, Shi and Pan say, was already a known mediator of the anti-inflammatory response of glucocorticoids, and the protein also mediates bone production. Shi's early research had shown that glucocorticoids enhance bone formation in the lab because of a short "burst" of GILZ.

The protein works by inhibiting the way cells regulate fat production and turn on fat-producing genes, Shi says. "When you permanently express GILZ, the fat pathway is suppressed, so the body chooses to produce bone instead."

"We found that when we overexpressed the protein in these mice, it increased bone formation," Pan added. "This supports our original hypothesis that GILZ mediates the body's response to glucocorticoids and encourages bone growth." In fact, the genetically modified mice showed a significant increase in bone mineral density and bone volume as well, he found.

"That means GILZ is a potential new anti-inflammatory drug candidate that could spare people from the harmful effects associated with glucocorticoid therapy," Pan said

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Protein could be key for drugs that promote bone growth

BOLOGNA, Italy--(BUSINESS WIRE)--

Silicon Biosystems, S.p.A., a provider of specialized molecular and cellular biology technologies, will present at the Fourth World Circulating Tumour Cells Summit, April 25, 2012 at 3:30 p.m. at the Maritim Hotel in Berlin. Dr. Nicol Manaresi, founder and chief technology officer of Silicon Biosystems, will provide an overview of the DEPArray system, which uses image-based single-cell sorting to deliver pure populations of rare tumor cells.

As part of the presentation, Dr. Manaresi will also offer recent data demonstrating single-CTC molecular characterization based on Whole Genome Amplification using the companys proprietary Ampli1 WGA kit followed by sequencing with Ion Torrent.

Silicon Biosystems is a device manufacturer leading the field in the detection and isolation of single cells for cancer research and prenatal genetic testing. The companys DEPArray technology exploits microelectronics and the principles of dielectrophoresis to find, sort, isolate, and collect 100 percent pure populations of rare cells, such as CTCs, for single-cell based genomic and transcriptional profiling.

The collection of pure individual CTCs from biological samples is a game changer in the quest to obtain clinical utility of these cells as it enables individual cell-based molecular profiling for personalized therapy, going beyond existing cell counting approaches for prognostic purposes, said Manaresi. We show that 100 percent pure single-CTC sorting by DEPArray and DNA amplification with our Ampli1 WGA seamlessly integrates with Ion Torrent AmpliSeq Cancer Panel sequencing to deliver a comprehensive overview of the mutational status, cell-by-cell, in a streamlined and automated manner. To the best of our knowledge, it is the first time this has been achieved.

There are multiple large and expanding market opportunities for technology that find and isolate rare cells for molecular analysis. Silicon Biosystems DEPArray is used for translational medicine applications in metastatic cancer, cardiovascular disease, prenatal genetics, and stem cells research.

The World CTC Summit attracts important members across the CTC study community including diagnosticians, drug developers, technology providers and clinicians, said Manaresi. Silicon Biosystems is eager to join our peers and share the excitement of this achievement, and the impact of our unique method for CTC collection and analysis for the advancement of patient diagnosis and decision making.

About Silicon Biosystems

Silicon Biosystems, Inc. was formed in October 2010 as a wholly owned subsidiary of Silicon Biosystems, S.p.A. based in Bologna, Italy. The company manufactures and sells the DEPArray platform which is based on the principle of dielectrophoresis to isolate and manipulate cells in suspension with a microelectronic array. The approach, patented by Silicon Biosystems, offers the unique ability to control individual cells and micro-particles inside a disposable cartridge. The DEPArray platform makes it possible to find, sort, select and separate individual cells for further analysis or culturing. For more information on Silicon Biosystems visit http://www.siliconbiosystems.com.

Original post:
Silicon Biosystems to Present Single-Circulating Tumor Cell Molecular Characterization at the Fourth World CTC Summit