HORIBA Medical and NoemaLife announced in January a non-exclusive agreement, for the worldwide distribution of Halia, the web-based Laboratory Automation System by NoemaLife which allows central management of all pre-analytical, analytical and post-analytical instruments, making it possible to connect multiple sites, multiple Laboratory Information Systems and multiple instruments of various disciplines of the laboratory. “The addition of Halia to HORIBA Medical ’s Hematology product line makes it possible for a wide range of clinical laboratories to realize efficiencies resulting from a powerful yet very user friendly data management. NoemaLife is pleased to serve as HORIBA Medical‘s middleware provider in this effort” said Piero Tassoni, Diagnostic Marketing & Alliance Director NoemaLife, “HORIBA Medical equips more than 30,000 laboratories throughout the world, distributed in 110 countries in 5 continents. Not only we are proud to work with a partner who holds world records in its industry, but we are confident that this agreement has huge potential.” The specific version of the Halia middleware distributed by HORIBA Medical will soon integrate all the Hematology Expert validation station features that HORIBA Medical so far proposed exclusively in its “ABX Pentra ML” Work Station, the all-in-one validation system entirely dedicated to whole blood. “Halia is an important evolution to our hematology solution’s offer” said Olivier Pou, Corporate Marketing Director, HORIBA Medical. “The addition of a specific version of the Halia middleware to our product offer makes it possible for HORIBA Medical to provide a complete solution to our worldwide base of customers around the hematology expertise but also to facilitate the integrated management of hematology within the global IVD laboratory”.

The scientific community has made significant strides in recent years in identifying important genetic contributors to malignancy and developing therapeutic agents that target altered genes and proteins.  A recent approach to treat cancer called synthetic lethality takes advantage of genetic alterations in cancer cells that make them more susceptible to certain drugs. Alan F. List, MD, president and CEO of Moffitt Cancer Center, co-authored an article on synthetic lethality.

“Genetic alterations in cancer in humans may involve gene inactivation, amplification or inactivation,” said List.  These changes are not present in non-malignant cells. Common chemotherapeutic agents aggressively kill tumour cells irrespective of genetic alterations.  They also have a negative impact on normal cells and can cause significant side effects. Synthetic lethality harnesses the genetic differences between tumour cells and normal cells to minimize the effects on normal cells, and maximize a drug’s effects on cancer cells.

Synthetic lethality can target a variety of cellular defects, including alterations in DNA repair, cell-cycle control and metabolism.  This approach can also be used to target interactions between tumour cells and surrounding normal cells that promote tumour survival and oncogenes that drive tumorigenesis that are difficult to target directly.  Many of the synthetic lethal drugs and targets have been identified in large-scale drug screens of the entire human genome.

An example of synthetic lethality is the recent approach being investigated to treat breast cancer patients with BRCA1 and BRCA2 mutations. BRCA1 plays an important role is repairing damaged DNA.  Women who have mutations in BRCA1 or BRCA2 have an increased risk of developing breast and ovarian cancer because their cells cannot properly repair DNA. This suggests that BRCA mutated breast cancer cells may be more susceptible to drugs that target DNA.  Laboratory studies have confirmed this hypothesis by showing that agents that target another DNA repair protein called PARP significantly kill BRCA mutated cells. Several PARP inhibitors are now being investigated in clinical trials in breast cancer patients, and early results are promising.

“The goal of current anticancer approaches is to offer individualized and highly selective therapy. The treatment model for many anticancer approaches has been expanded, with movement away from dose-intensive, non-targeted cytotoxic agents to combination chemoimmunotherapy, new therapeutic combinations and targeted agents,” said List. Synthetic lethality approaches may provide an additional avenue for individualized patient treatment. Moffitt Cancer Center

Using a basic genetic difference between men and women, the Translational Genomics Research Institute (TGen) has uncovered a way to track down the source of a neurological disorder in a young girl.

TGen’s discovery relies on a simple genetic fact: Men have one X and one Y chromosome, while women have two X chromosomes. This women-only factor was leveraged by TGen investigators to develop a highly accurate method of tracking down a previously unrecognized disorder of the X-chromosome. 

The study was of a pre-teen girl, who went years with an undiagnosed neurobehavioral condition.

TGen’s findings were made within its Dorrance Center for Rare Childhood Disorders, where investigators and clinicians apply the latest tools of genomic medicine to provide answers for parents seeking to identify the disease or disorder affecting their child.

The scientists sequenced, or spelled out in order, the complete genetic codes of DNA and RNA of the girl. Because girls inherit an X chromosome from each of their parents (boys inherit a Y chromosome from their father), they also sequenced her mother and father. On average, about half of all X chromosomes active in a female come from the mother and the other half from the father.

‘We now have the tools to significantly accelerate the diagnostic process, reducing the need for children to undergo multiple tests that can be emotionally and physically taxing for the entire family,’ said Dr. David Craig, TGen’s Deputy Director of Bioinformatics, Co-Director of the Dorrance Center and the paper’s senior author.

Sequencing would reveal the proportion of X chromosomes, and if disproportionate, whether the more abundant of the two were damaged in some way, which often leads to X-linked genetic conditions.

‘At the time of enrollment, we suspected the girl had a complex neurobehavioral condition, based on her attention deficit, and delays in development and learning,’ said Dr. Vinodh Narayanan, Medical Director of the Dorrance Center. ‘Her brain MRI scans were normal. We needed to find out more – at the genetic level – about what might be causing her disorder.’

By sequencing the DNA and RNA, TGen investigators were able to precisely identify which cells contained active X chromosomes from the girl’s mother, which contained active X chromosomes from the father, in what proportions, and whether they were associated with any known disorders.

They discovered that the X chromosome from the father contained a segment shown to be associated with neurobehavioral conditions. Interestingly, however, the proportion of X chromosomes active in the girl’s cells skewed toward the normal X inherited from her mother. This skewing may have led to a milder, harder to diagnose condition undetected by conventional methods.

‘This study shows the power sequencing holds when scanning for potential disease causing and disease-modifying genetic variations,’ said Dr. Matt Huentelman, the other Co-Director of the Dorrance Center and an author of the paper. TGen

Copy number variations (deletions or duplications of large chunks of the genome) are a major cause of birth defects, intellectual disability, autism spectrum disorder and other developmental disorders. Still, geneticists can definitively say how a CNV, once discovered in someone’s DNA, leads to one of these conditions in just a fraction of cases.

To aid in the interpretation of CNVs, researchers at Emory University School of Medicine have completed detailed maps of 184 duplications found in the genomes of individuals referred for genetic testing.

‘Ours is the first study to investigate a large cohort of clinically relevant duplications throughout the genome,’ says senior author Katie Rudd, PhD, assistant professor of human genetics at Emory University School of Medicine. ‘These new data could help geneticists explain CNV test results to referring doctors and parents, and also reveal mechanisms of how duplications form in the first place.’

Despite advances in ‘next generation’ DNA sequencing, the first step for patients who are referred to a clinical geneticist is currently a microarray. This is a scan using many probes across the genome, testing if someone’s DNA has one, two, three or more copies of the DNA corresponding to the probe. (Two is the baseline.) From this scan, geneticists will have a ballpark estimate of where a deletion or duplication starts and ends, but won’t know the breakpoints exactly.

‘In a few years, advances in sequencing will make it possible to routinely capture data on copy number variation and breakpoints at the same time,’ Rudd says. ‘But for now, we have to do this extra step.’

In addition, in comparison with deletions, duplications are more complicated. The extra DNA has to land somewhere, sometimes resulting in the disruption or warped regulation of nearby genes, which make it more difficult to pinpoint particular genes responsible for the individual’s medical condition.

Most healthy people have a deletion or duplication of at least 100 kilobases in size. The individuals in the study were referred for clinical microarray testing with indications including intellectual disability, developmental delay, autism spectrum disorders, congenital anomalies, and dysmorphic features. Their CNVs were larger, with an average size of more than 500 kilobases.

Rudd’s team examined 184 duplications, and found that most are in tandem (head-to-tail) orientation and adjacent to the duplicated area. Most of the CNVs in the study were inherited from a parent. The researchers also found examples where a duplicated gene inserted into and disrupted another gene on a different chromosome.

In a few cases, a duplicated gene was fused together with another gene. This is a phenomenon often seen in cancer cells, where a DNA rearrangement leads to an abnormal activation of a growth- or survival-promoting gene. In these cases, the fusions were present in all cells in the body and not related to cancer, but could be responsible for the patient’s condition.

‘These fusion genes are intriguing but we don’t know, just from looking at the DNA, if the gene is expressed,’ Rudd says. ‘These findings could be the starting point for follow-up investigation.’ Emory University School of Medicine

Researchers at UT Southwestern Medical Center have found an “Achilles heel” in a metabolic pathway crucial to stopping the growth of lung cancer cells.

At the heart of this pathway lies PPARγ (peroxisome proliferation-activated receptor gamma), a protein that regulates glucose and lipid metabolism in normal cells. Researchers demonstrated that by activating PPARγ with antidiabetic drugs in lung cancer cells, they could stop these tumour cells from dividing.

“We found that activation of PPARγ causes a major metabolic change in cancer cells that impairs their ability to handle oxidative stress,” said Dr. Ralf Kittler, Assistant Professor in the Eugene McDermott Center for Human Growth and Development, the Department of Pharmacology, the Harold C. Simmons Cancer Center, and the Cecil H. and Ida Green Center for Reproductive Biology Sciences at UT Southwestern.

“The increased oxidative stress ultimately inhibits the growth of the tumour. We found that activation of PPARγ killed both cancer cells grown in a dish and tumours in mice, in which we observed near complete tumour growth inhibition,” said Dr. Kittler, the John L. Roach Scholar in Biomedical Research of UT Southwestern’s Endowed Scholars Program.

The study builds on a large body of work showing that metabolism in cancer cells is altered when compared to normal cells. Changes in metabolism can make cancer cells more vulnerable to therapeutic agents, which make them a good target to investigate for cancer therapy.  The new research also extends earlier observations made by Dr. Steven Kliewer, Professor of Molecular Biology and Pharmacology, who first identified that thiazolidinediones target PPARγ. Dr. Kliewer holds the Nancy B. and Jake L. Hamon Distinguished Chair in Basic Cancer Research.

Dr. Kittler and his team determined that PPARγ activation triggers changes in glucose and lipid metabolism that cause an increase in the levels of reactive oxygen species (ROS). ROS are highly reactive oxygen-containing molecules that damage cells when present at high levels, a phenomenon known as oxidative stress. It is this increase in ROS that eventually stops the cancer cells from dividing.

“The abnormal metabolism in cancer cells frequently causes increased oxidative stress, and any further increase can ‘push’ cancer cells over  the cliff,” said Dr. Kittler, UT Southwestern’s first Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research.

The findings suggest that targeting PPARγ could be a promising new therapeutic approach for lung cancer and potentially other cancers. The researchers saw that activating PPARγ caused similar molecular changes in breast cancer cells.

“This is an important finding because the drugs that activate PPARγ include FDA-approved antidiabetic drugs that are relatively well tolerated compared to chemotherapy. Knowing their mechanism of action provides us with clues for selecting tumours that may be responsive to this treatment, for combining these drugs with anti-cancer drugs to make therapy more effective, and for developing markers to measure the response of tumours to these drugs in patients,” said Dr. Kittler, Director of the McDermott Next-Generation Sequencing Core at UT Southwestern.

“Of course, further study will be required to determine the therapeutic effectiveness of PPARγ-activating drugs for lung cancer treatment,” he added. UT Southwestern Medical Center