Analysing a puzzling multisystem disorder in three children, genetic experts have identified a new syndrome, shedding light on key biological processes during human development. The research also provides important information to help caregivers manage the disorder, and may offer clues to eventually treating it.

“This syndrome illuminates a very important pathway in early human development — a sort of master switch that controls many other genes,” said study leader Ian D. Krantz, MD, co-director of the Individualized Medical Genetics Center at The Children’s Hospital of Philadelphia (CHOP). Krantz, a medical geneticist, is an attending physician in CHOP’s comprehensive human genetics program.

The investigators named the disorder CHOPS syndrome, with the acronym representing a group of symptoms seen in the affected children: cognitive impairment and coarse facies (facial features), heart defects, obesity, pulmonary involvement, short stature and skeletal dysplasia (abnormal bone development).

The central research finding is that mutations in the gene AFF4 disrupt a crucial group of proteins called the super elongation complex (SEC). The SEC controls the transcription process by which DNA is copied into RNA, enabling genes to be expressed in a developing embryo. The timing of this biological process is tightly regulated, so anything that interferes with this timing can disturb normal development in a variety of ways.

“Because the SEC involves such a crucial process in cell biology, it has long been a focus of study, particularly in cancer,” said Krantz. “CHOPS syndrome is the first example of a human developmental disorder caused by germline mutations in the SEC.”

Originating in the embryo, germline mutations are passed along to every cell in a developing organism, with harmful effects in multiple organs and biological systems. The mutated AFF4 gene produces mutated proteins, which then accumulate and cause a cascade of abnormalities in other genes controlled by AFF4.

“AFF4 has a critical role in human development, regulating so many other genes,” said Krantz. “When it is mutated, it can damage the heart and skeleton, and lead to intellectual disability, among other effects.”

The current study sequenced the exomes (the protein-coding portions of DNA) of three unrelated children treated at CHOP for a complex developmental disorder. All three patients had some symptoms similar to those found in patients with Cornelia deLange syndrome (CdLS), a rare multisystem disease long studied at CHOP. Krantz led research that discovered the first causative gene for CdLS in 2004.

The research team’s DNA analysis and studies of gene expression patterns determined that the new syndrome is genetically distinct from CdLS, even while sharing some common molecular mechanisms. Although only the three children in the study are known to definitely have CHOPS syndrome, Krantz expects diagnoses to increase with the dissemination of this discovery and the ongoing spread of faster, lower-cost gene-sequencing technology.

The research findings offer practical and emotional benefits for families, said Krantz. Physicians may now order more appropriate tests to monitor and manage specific medical issues arising from CHOPS syndrome. “This also means families and children can end their ‘diagnostic odyssey’ — the frustrating procession of tests and unsuccessful treatments that often occurs in trying to find an answer for families who have a child affected by a complex, undiagnosed disorder,” he added. CHOP Research Institute

Researchers at Okayama demonstrate that injection of a virus solution followed by tumour removal can eradicate cancer metastasis in lymph nodes without the need for preventative surgery.
While early-stage gastrointestinal cancers can be treated non-surgically, once the cancer has invaded to a particular depth, preventative – ‘prophylactic’ – surgery is routine. The frequency of lymph node metastasis increases significantly once the cancer has penetrated the submucosal layers, and as there is no way of determining whether the cancer has metastasized in the lymph nodes they will be surgically removed just in case. Now researchers at Okayama University and the University of California in San Diego have demonstrated that injection of a viral solution can eradicate lymph node metastasis making prophylactic surgery unnecessary.
To treat early stage cancers a saline solution is injected creating a fluid cushion, which raises and isolates the tumour. The tumour is then readily removed by equipment through a standard endoscopic viewing tube inserted in the gastrointestinal tract. However if the cancer has already penetrated the submucosal layer it will be prone to relapse in the lymphatic system.
Toshiyoshi Fujiwara and his colleagues adapted the standard endoscopic treatment by injecting a solution of Telomelysin – a virus known to kill epithelial and mesenchymal malignant cells – instead of saline solution.  They tested the treatment in a mouse model, injecting green-fluorescent-protein-labelled cancer cells into the submucosal layers of the rectum, which developed lymph node metastasis. Fluorescence imaging showed that cancer cells were successfully eliminated by the treatment with virus solution, in contrast to mice treated with saline solution instead. In addition, treated mice showed no relapse four weeks after the treatment
In their report of the results the researchers conclude, “From a clinical view point, this new, simple, and robust strategy is a more realistic and promising bench-to-bedside translation than prophylactic surgery for ablation of potential lymph node metastases in early gastrointestinal cancer patients.”
Early stage gastrointestinal cancers are defined by the level of the cancer invasion reaching no further than the submucosa. Endoscopic treatment removes these tumours by dissecting the submucosal layers.
For esophageal gastric and colorectal submucosally invaded cancers, the frequency at which the cancer is found to metastasize in the lymph nodes is approximately 10 to 20%. The lymphatic system distributes fluids, proteins, chemicals, cells and drugs. This makes it a major pathway for the spread of metastatic cancers so that cancerous invasion of the lymphatic system is particularly problematic. It is very difficult to determine whether the cancer has metastases in the lymph nodes. As a result lymph node surgery just in case is routine when treating esophageal gastric and colorectal submucosal cancers, even though in many cases it may not have been necessary.
Previous research has demonstrated that certain viruses replicate in cancer cells and break them down, and may be developed for cancer treatments. The researchers further exploited the role of the lymph system in mediating proteins and fluids, a function which makes it more prone to exposure to a virus injected in the surrounding area. They experimented with Telomelysin – a telomerase-dependent, tumour-killing replicating adenoviral agent (OBP-301). The virus is known to kill epithelial and mesenchymal malignant cells.  
The researchers first tested the virus on green-fluorescent-protein-labelled colorectal cancer cell lines with. Using fluorescence imaging, they observed rapid cell death in response to injection with the virus while there was no such response in cell lines treated with mutant strains of the virus that had replication deficiencies.
The researchers demonstrated how their treatment exploited the lymph node function using mouse models injected with red-fluorescent-protein-labelled lymph node metastasized cancer cells. After six days the virus labelled with green fluorescent protein was injected and fluorescence images showed the position of the virus coincided with the metastatic foci in the lymph nodes.

Kikuchi S, Kishimoto H, Tazawa H, Hashimoto Y, Kuroda S, Nishizaki M, Nagasaka T, Shirakawa Y, Kagawa S, Urata Y, Hoffman RM, Fujiwara T: Biological Ablation of Sentinel Lymph Node Metastasis in Submucosally Invaded Early Gastrointestinal Cancer. Mol Ther. 2014 Dec 19.

Beckman Coulter Diagnostics has received 510(k) clearance from the U.S. Food and Drug Administration (FDA) for the Access 25(OH) Vitamin D Total assay. Offering state-of-the-art performance, the new assay is an important addition to the company’s bone metabolism assay menu and is available for use on its Access 2 and UniCel DxI series of immunoassay systems.  “FDA clearance of our 25(OH) Vitamin D Total assay allows us to provide laboratories with the tools needed to confidently diagnose and manage vitamin D deficiency-related diseases,” said Arnd Kaldowski, president, Beckman Coulter Diagnostics. “The new assay delivers increased accuracy in patient results through traceability to the gold standard 25(OH) vitamin D reference measurement procedure (RMP) from Ghent University and equimolar detection of 25(OH) vitamin D2 and 25(OH) vitamin D3.”  The Ghent RMP is the reference procedure utilized by the Vitamin D Standardization Program (VDSP), an international collaboration established by the Office of Dietary Supplements at the National Institutes of Health, with the goal of promoting standardized laboratory measurements of 25(OH) vitamin D around the world.  The new assay also provides excellent stability, greater ease-of-use and convenient storage through innovative new packaging designed to prevent light-induced reagent degradation.

Protagen AG has recently entered into a long-term collaboration agreement with QIAGEN targeting the development of novel protein-based companion diagnostics for autoimmune disorders. Under the terms of the agreement, QIAGEN will gain access to the proprietary SeroTag technology platform of Protagen, which enables the discovery and validation of novel protein-based marker panels. Such markers hold great promise for the development into companion diagnostics to guide treatment decisions in various autoimmune disorders. The synergistic combination of the unique expertise of QIAGEN and Protagen in the development and commercialization of companion diagnostics will offer a complete solution for pharmaceutical and biotech companies targeting the development of new therapeutic compounds, diagnostic or companion diagnostic tests in the area of autoimmune disorders.

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”.