The Children’s Medical Center Research Institute at UT Southwestern (CRI) has identified a biomarker that enables researchers to accurately characterise the properties and function of mesenchymal stem cells (MSCs) in the body. MSCs are the focus of nearly 200 active clinical trials registered with the National Institutes of Health, targeting conditions such as bone fractures, cartilage injury, degenerative disc disease, and osteoarthritis.

The finding, published in the journal Cell Stem Cell on June 19, significantly advances the field of MSC biology, and if the same biomarker identified in CRI’s studies with mice works in humans, the outlook for clinical trials that use MSCs will be improved by the ability to better identify and characterize the relevant cells.

“There has been an increasing amount of clinical interest in MSCs, but advances have been slow because researchers to date have been unable to identify MSCs and study their normal physiological function in the body,” said Dr. Sean Morrison, Director of the Children’s Research Institute, Professor of Paediatrics at UT Southwestern Medical Center, and a Howard Hughes Medical Institute Investigator. “We found that a protein known as leptin receptor can serve as a biomarker to accurately identify MSCs in adult bone marrow in vivo, and that those MSCs are the primary source of new bone formation and bone repair after injury.”

In the course of their investigation, the CRI researchers found that leptin receptor-positive MSCs are also the main source of factors that promote the maintenance of blood-forming stem cells in the bone marrow.

“Unfortunately, many clinical trials that are testing potential therapies using MSCs have been hampered by the use of poorly characterized and impure collections of cultured cells,” said Dr. Morrison, senior author of the study and holder of the Mary McDermott Cook Chair in Pediatric Genetics at UT Southwestern. “If this finding is duplicated in our studies with human MSCs, then it will improve the characterization of MSCs that are used clinically and could increase the probability of success for well-designed clinical trials using MSCs.” Children’s Medical Center Research Institute at UT Southwestern 

UCLA researchers led by Dr. Brigitte Gomperts have discovered the inner workings of the process thought to be the first stage in the development of lung cancer. Their study explains how factors that regulate the growth of adult stem cells that repair tissue in the lungs can lead to the formation of precancerous lesions.

Findings from the three-year study could eventually lead to new personalized treatments for lung cancer, which is responsible for an estimated 29 percent of U.S. cancer deaths, making it the deadliest form of the disease.

The study collaborated with Manash Paul and Bharti Bisht, postdoctoral scholars and co-lead authors of the study.

Adult stem cells in lung airways are present specifically to repair the airways after injury or disease caused by smoking, pollution, viruses or other factors. Gomperts and her team found that this reparative process is tightly regulated by molecules called reactive oxygen species, or ROS.

Recent research has shown that low levels of ROS are important for signalling the stem cells to perform important functions — such as repairing tissue damage — while high levels of ROS can cause stem cells to die. But the level of ROS needed for repair to be initiated has remained a subject of debate among researchers.

The UCLA study found that the dynamic flux of ROS from low to moderate levels in the airway stem cells is what drives the repair process, and that the increase in ROS levels in the repairing cell is quickly reduced to low levels to prevent excessive cell proliferation.

Gomperts’ lab found that disrupting this normal regulation of ROS back to low levels is equivalent to pulling the brakes off of the stem cells: They will continue to make too many of themselves, which causes the cells not to mature and instead become precancerous lesions. Subsequent progressive genetic changes to the cells in these lesions over time can eventually allow cancerous tumours to form.

‘Low ROS is what keeps stem cells primed so that your body is poised and ready to respond to injury and repair,’ said Gomperts, who also is an associate professor in the department of paediatrics at UCLA. ‘Loss of this ROS regulation leads to precancerous lesions. Now, with this precancerous model in place, we can begin looking for what we call ‘driver mutations,’ or those specific changes that take the precancerous lesions to full-blown cancer.’

Gomperts said that because many different factors — including cigarette smoke, smog and inflammation — could potentially trigger an increase in ROS in the airway stem cells, researchers might eventually be able to customize treatments based on the cause. ‘There are likely multiple ways for a person to get to a precancerous lesion, so the process could be different among different groups of people. Imagine a personalized way to identify what pathways have gone wrong in a patient, so that we could target a therapy to that individual.’

The research’s ultimate goal is to develop a targeted strategy to prevent pre-malignant lesions from forming by targeting the biology of these lesions and University of California – Los Angeles

Researchers at the University of California, San Diego School of Medicine have identified a new biomarker that predicts whether glioblastoma – the most common form of primary brain cancer – will respond to chemotherapy.

“Every patient diagnosed with glioblastoma is treated with a chemotherapy called temozolomide. About 15 percent of these patients derive long-lasting benefit,” said Clark C. Chen, MD, PhD, vice-chairman of Academic Affairs, Division of Neurosurgery, UC San Diego School of Medicine and the study’s principal investigator. “We need to identify which patients benefit from temozolomide and which another type of treatment. All therapies involve risk and the possibility of side-effects. Patients should not undergo therapies if there’s no likelihood of benefit.”

To pinpoint which patients were most likely respond to temozolomide, the researchers studied microRNAs that control the expression of a protein called methyl-guanine-methyl-transferase or MGMT. This protein dampens the cancer-killing effect of temozolomide. Tumours with high levels of MGMT are associated with a poor response to temozolomide therapy.

The scientists systematically tested every microRNA in the human genome to identify those that suppressed MGMT expression, with the expectation that high-levels of these microRNAs in the tumour would predict improved therapeutic response to temozolomide.

“We showed that a signature of the MGMT-regulating microRNAs predicted temozolomide response in a cohort of glioblastoma patients. Validation of these results should lead to diagnostic tools to enable us to determine which patients will benefit most from temozolomide therapy,” said Chen.

In the study, the scientists also discovered that injection of the MGMT-regulating microRNAs into glioblastoma cells increased tumour sensitivity to temozolomide treatment.

“These findings establish the foundation for microRNAs-based therapies to increase the efficacy of temozolomide in glioblastoma patients,” said lead author, Valya Ramakrishnan, PhD, postdoctoral researcher, UC San Diego School of Medicine. University of California – San Diego

A genomic analysis of clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, from 72 patients has uncovered 31 genes that are key to development, growth and spread of the cancer, say researchers from Mayo Clinic in Florida. Eight of these genes had not been previously linked to kidney cancer, and six other genes were never known to be involved in any form of cancer.

Their stud is the most extensive analysis to date of gene expression’s role in ccRCC tumor growth and metastasis. The ccRCC subtype accounts for 80 percent of all kidney cancer cases.
This study is a thorough analysis, because overexpressed genes were functionally tested in kidney cancer cells to ensure they were important to some aspect of the cancer process, says the study’s senior investigator, molecular biologist, John A. Copland, Ph.D.

“The power of this study is that we looked at genes discovered to be over-expressed in patients’ tumours and determined their function in kidney cancer, which has not been done on a large scale before,” he says. “This is a seminal step in identifying key pathways and molecules involved in kidney cancer so that specific therapies that target these new genes can be developed to treat this cancer.” Mayo Clinic

Use of exome sequencing improved the ability to identify the underlying gene mutations in patients with biochemically defined defects affecting multiple mitochondrial respiratory chain complexes (enzymes that are involved in basic energy production), according to a study in the July 2 issue of JAMA.

Defects of the mitochondrial respiratory chain have emerged as the most common cause of childhood and adult neurometabolic disease, with an estimated prevalence of l in 5,000 live births. Clinically these disorders can present at any time of life, are often seen in association with neurological impairment, and cause chronic disability and premature death. The diagnosis of mitochondrial disorders remains challenging, according to background information in the article. Examples of problems caused by mitochondrial diseases include a type of epilepsy; mitochondrial encephalopathy; lactic acidosis; and a syndrome that includes stroke-like episodes.

Robert W. Taylor, Ph.D., F.R.C.Path., of Newcastle University, Newcastle upon Tyne, U.K., and colleagues studied whether a whole-exome sequencing approach could help define the molecular basis of mitochondrial disease. Whole-exome sequencing is a complex laboratory process that determines the entire unique sequence of an organism’s exome (the collection of exons, which are relatively small lengths of a whole genome and contain instructions for the body to build proteins).

The study included 53 patients, referred to 2 national centres in the United Kingdom and Germany between 2005 and 2012, who had biochemical evidence of multiple respiratory chain complex defects. The majority (51/53 [96 percent]) of the patients presented during childhood (<15 years old) and most (66 percent) developed symptoms within the first year of life. The most frequent clinical features were muscle weakness, central neurological disease, cardiomyopathy, and abnormal liver function; a combination of these abnormalities was present in most cases. Following whole-exome sequencing, presumptive causal variants were identified in 28 patients (53 percent) and possible causal variants were identified in 4 (8 percent). Together these accounted for 32 patients (60 percent) and involved 18 different genes. Distinguishing clinical features included deafness and kidney involvement associated with one gene, and cardiomyopathy with two genes. In 20 patients with prominent heart disease, the causative mutation was detected in 80 percent, while the detection rate was much lower in patients with liver disease (33 percent). It was not possible to confidently identify the underlying genetic basis in 21 patients (40 percent). “In the pre-exome era, the systematic biochemical characterization of 53 patients with multiple respiratory chain complex defects led to detection of the underlying genetic basis in only 1 patient. The work presented herein demonstrates the effect of whole-exome sequencing in this context, which has defined the genetic etiology in 32 of 53 patients (60 percent) with a confirmed biochemical defect …,” the authors write. “Our findings contrast with large-scale candidate gene analysis using conventional and next-generation sequencing approaches, both of which had a lower diagnostic yield (10 percent-13 percent) and by definition did not discover new potential disease genes.” “Additional study is required to determine the utility of this approach compared with traditional diagnostic methods in independent patient populations,” the researchers conclude. JAMA Network