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ITN Type 1 Diabetes Study Identifies Subset of Patients with Strong Response to Therapy

Primary results from a new clinical trial show that patients with type 1 diabetes treated with the monoclonal antibody teplizumab (MacroGenics, Inc.) exhibit greater preservation of C-peptide, a biomarker of islet cell function, compared to controls. Further analyses identified a discrete subset of the treatment group that demonstrated especially robust responses (“responders”), suggesting that these patients could be identified prior to treatment. The trial, entitled “Autoimmunity-Blocking Antibody for Tolerance in Recently Diagnosed Type 1 Diabetes” (AbATE), was conducted by the Immune Tolerance Network (ITN). The results are available online and will be published in the November issue of the journal Diabetes.

The AbATE study, led by Kevan Herold, MD (Yale University), tested teplizumab, which targets the CD3 receptor found on T cells, in patients with new-onset type 1 diabetes. CD3 is required for T-cell activation, which can lead to the destruction of insulin-producing beta cells. A previous ITN study with teplizumab showed that a single course of the drug slowed C-peptide decline in new-onset patients for a year, after which the effects waned. The aim of the AbATE study was to test whether C-peptide preservation could be prolonged by administering two courses of teplizumab, one year apart.

In this open-label, Phase II study, 77 new-onset patients (ages 8 to 30 years old) were randomized to receive either teplizumab or a control. Those in the treatment arm received the scheduled treatment consisting of two 14-day courses of teplizumab, one year apart. Both arms received intensive diabetes care from certified diabetes educators and were followed for two years. The primary endpoint compared C-peptide preservation between the two groups.

After two years, the teplizumab-treated group showed significantly greater preservation of C-peptide (75-percent higher responses compared to the control group).

Further analysis revealed that within the treatment arm two groups of patients could be distinguished based on their C-peptide levels: one group, considered “responders” (22/49), showed very little C-peptide decline over the course of the study (only a 6 percent reduction from baseline), while the “non-responders” (27/49) exhibited a similar rate of C-peptide decline as the control group (less than 40-percent reduction from baseline).

Investigators measured various biomarkers and cell types that might distinguish between these two groups. They found that, at trial entry, “responders” had lower hemoglobin A1c levels (a marker of glucose concentration in the blood) and used less insulin at baseline, compared to “non-responders”. Differences in specific T-cell subsets also distinguished between the two groups at baseline, suggesting that immune status might contribute to drug responsiveness. However, further studies will be required to confirm these results.

“This overall approach to identifying characteristics of individuals most likely to respond to therapies shows great promise because the responders in this study experienced a robust and prolonged drug effect,” said Dr. Herold. “This type of response has not been seen in other studies of immune therapies.”

Type 1 diabetes is a disease marked by immune destruction of insulin-producing beta cells in the pancreas. New-onset patients usually have 20 to 40 percent of their normal beta cell mass remaining, which is still capable of producing insulin. Preserving this remaining mass, even temporarily, could improve long-term clinical outcomes.

Immune modulators, like teplizumab, represent a promising means of inducing tolerance; however, no drug has been shown to prevent or reverse disease, and only a few have temporarily delayed disease progression. The ability to identify a subgroup of patients who may be more responsive to therapy could greatly enhance the clinical use of immune modulators and improve outcomes for those patients. Further analyses with specimens collected from the AbATE study are ongoing to understand the mechanism of response.

Source: EurekAlert!

New Biomarker Could Reveal Alzheimer’s Disease Years Before Onset

A study published recently reported the identification of what may be the earliest known biomarker associated with the risk of developing Alzheimer’s disease (AD). The results suggest that this novel potential biomarker is present in cerebral spinal fluid (CSF) at least a decade before signs of dementia manifest.

“If our initial findings can be replicated by other laboratories, the results will change the way we currently think about the causes of Alzheimer’s disease,” said Dr. Ramon Trullas, research professor at the CSIC Institute of Biomedical Research of Barcelona and lead author of the study that was published in Annals of Neurology. “This discovery may enable us to search for more effective treatments that can be administered during the preclinical stage.”

Difficult Diagnosis

Alzheimer’s disease affects more than five million Americans and is the sixth leading cause of death in the United States. At present, the only way to accurately diagnose the disease is by post-mortem neuropathological analysis. The relationship of currently known biomarkers with the cause of the disease is unclear, making it nearly impossible to diagnose preclinical stages of the disease with any real certainty.

The CSIC researchers demonstrated that a decrease in the content of mitochondrial DNA (mtDNA) in CSF may be a preclinical indicator for Alzheimer’s disease; furthermore, there may be a directly causative relationship. The hypothesis is that decreased mtDNA levels in CSF reflect the diminished ability of mitochondria to power the brain’s neurons, triggering their death. The decrease in the concentration of mtDNA precedes the appearance of well-known biochemical Alzheimer’s biomarkers (the Aβ1-42, t-tau, and p-tau proteins), suggesting that the pathophysiological process of Alzheimer’s disease starts earlier than previously thought and that mtDNA depletion may be one of the earliest predictors for the disease.

In addition to enabling an investigation of the potential causal relationship of mtDNA and Alzheimer’s progression, the use of mtDNA as an index of preclinical Alzheimer’s disease provides an important advantage over previous biochemical markers: the detection of this novel nucleic acid biomarker is unhampered by the technical difficulties associated with protein detection. mtDNA can be readily quantified by real-time quantitative PCR (qPCR) or droplet digital PCR (ddPCR).

Quantitation of mtDNA

Prior to this study, researchers had not reported that circulating cell-free mtDNA could be detected in human CSF. But with this study, Dr. Trullas’ team was able to both detect and reproducibly quantitate mtDNA using qPCR, carefully optimized by adhering to the MIQE guidelines.

To validate their qPCR findings, Dr. Trullas’ team used Bio-Rad Laboratories’ QX100™ Droplet Digital™ PCR system. Unlike qPCR assays, the QX100 system provides an absolute quantification of target DNA molecules without the need for a standard curve. In addition, an important factor for their CSF analysis was that the Droplet Digital PCR system did not require sample purification to remove PCR inhibitors, as is necessary for qPCR assays.

“Droplet Digital PCR allowed us to validate our initial qPCR measurements because it provides absolute quantitation at the single-molecule level without relying on a standard curve,” said Dr. Trullas. “As the technology becomes more widely adopted, we anticipate that Droplet Digital PCR will be the future of detecting mtDNA in cerebral spinal fluid.”

Dr. Trullas hopes that other laboratories and hospitals will successfully replicate his group’s research results, confirming that reduced mtDNA levels should be investigated as a possible cause of Alzheimer’s disease. By finding a way to block this degeneration, clinicians may be able to diagnose and treat Alzheimer’s disease before symptoms appear.

Study: Low CSF concentration of mitochondrial DNA in preclinical Alzheimer’s disease [Annals of Neurology]

Source: Bio-Rad

Trio of Biomarkers May Help Identify Kidney Cancer in Early Stages

A new immunoassay that tests for the presence of three biomarkers appears to be a valid screening method for the early detection of malignant kidney cancer, according to data published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

“Renal cell carcinoma, a malignant tumor arising from the kidney, is one of the most difficult forms of cancer to detect and treat properly because it remains silent until disseminating to other organs,” said Nam Hoon Cho, M.D., of the Department of Pathology at Yonsei University Health System in Seoul, Korea. “Furthermore, because imaging, which is high-cost, is seldom performed without any specific reasons, developing a blood-tumor biomarker is a great chance to detect the silent killer.”

The new immunoassay developed by Cho and colleagues from Genomine Inc. measured the levels of three potential biomarkers for kidney cancer: nicotinamide N-methyltransferase (NNMT), L-plastin (LCP1) and nonmetastatic cells 1 protein (NM23A).

Using this assay, the researchers measured concentrations of NNMT, LCP1 and NM23A in 189 plasma samples from 102 healthy controls and patients with benign tumors and 87 patients with kidney cancer. Plasma levels indicated that all three biomarkers were highly elevated in patients with kidney cancer. For example, the median level of NNMT concentration in healthy controls was 68 pg/mL compared with 420 pg/mL for patients with kidney cancer.

Next, the researchers tested the ability of the immunoassay to distinguish plasma samples from healthy controls and patients with kidney cancer using the same 189 plasma samples already tested. The results indicated that the three-marker assay was highly accurate. When it correctly identified 90 percent of the samples from healthy controls, it also correctly identified 94.4 percent of the samples from patients with kidney cancer.

To validate the accuracy of the test, the researchers blind tested an additional 100 plasma samples from 73 healthy controls and 27 patients with kidney cancer. In this analysis, 67 of the samples from the 73 healthy controls and all of the samples from patients with kidney cancer were classified correctly.

“If this biomarker is truly valid and accurate to detect renal cell carcinoma, a number of patients with renal cell carcinoma could potentially be saved through early diagnosis,” Cho said.

Cho and colleagues hope that this biomarker will soon be commercially available. They are currently working toward approval by the U.S. Food and Drug Administration.

Study: Composite Three-Marker Assay for Early Detection of Kidney Cancer

Source: EurekAlert!

Office Workers Carry Biomarker of Potentially Harmful Flame Retardant, Study Finds

A flame retardant removed from children’s pajamas 30 years ago but now used in polyurethane foam is prevalent in office environments, especially in older buildings, where urine testing of workers turned up widespread evidence of its biomarker, a new study led by Boston University School of Public Health researchers has found.

The study, published in the journal Environment International, found that the chemical known as TDCPP — chlorinated tris(1,3-dichloro-2-propyl) phosphate, or ‘chlorinated tris’ — was present in 99 percent of dust samples taken from participants’ homes, vehicles and offices, “demonstrating the widespread presence of this flame retardant in the indoor environment.” The research team recruited 31 adults who worked and lived in the Boston area for the testing.

The study found that the office environment was the strongest predictor of metabolized TDCPP in urine, with significantly lower concentrations of the chemical among workers in a new office building than in older buildings. Similarly, the average concentration of TDCPP in dust was significantly lower in the new office building than in the older office buildings.

Urine samples were collected during the workday, which may explain why an association was found between the quickly metabolized chemical and characteristics of the office, rather than the vehicle or home.

“Overall, our findings suggest that exposure to TDCPP in the work environment is one of the contributors to the personal exposure for office workers. Further research is needed to confirm specific exposure sources (e.g., polyurethane foam), determine the importance of exposure in other microenvironments such as homes and vehicles, and address the inhalation and dermal exposure pathways,” the research team concluded.

TDCPP, an additive to polyurethane foam used in upholstered furniture, is found in dust, where it can likely lead to human exposure. Potential health effects remain a concern. In 2011, TDCPP was added to the Proposition 65 list of chemicals known by the State of California to cause cancer.

In vitro studies suggest TDCPP may be neurotoxic, and one study found that increased concentrations in dust were associated with decreased semen quality and reduced free thyroxine in men, suggesting possible effects on fertility and thyroid function. Animal studies show TDCPP is readily absorbed through both the skin and gastrointestinal tract.

The researchers said the high concentrations observed in dust from offices could reflect requirements by the City of Boston that office furniture meet California fire retardant standards, a rule that is not required of residential furniture in Boston. The state of California has proposed a draft furniture flammability standard that could reduce the need for flame retardant chemicals in polyurethane foam. However, the standard used for office furniture has yet to be revised.

“It is currently very difficult to avoid flame retardants. Hopefully, better options will become available in the near future,” said Courtney Carignan, a doctoral candidate in environmental health who co-authored the study. “Currently, the best advice we have for people is to wash your hands, especially before eating. Dust control, good ventilation and air purifiers may also be useful for reducing personal exposure.”

The low concentrations of TDCPP in the newer office building suggest that its newer furniture did not contain TDCPP, or that it had not yet had sufficient time to migrate out of the products, the researchers said. If the new furniture did not contain TDCPP, it likely contained a different flame retardant such as the controversial FireMaster 550. Other differences between exposures include the possibility of more efficient ventilation or HVAC systems or cleaning methods in the newer building.

The authors urged that “more research is needed to determine factors that influence TDCPP concentrations in dust, in relation to building contents and characteristics.”

Study: Predictors of tris(1,3-dichloro-2-propyl) phosphate metabolite in the urine of office workers

Source: EurekAlert!

Trio of Biomarkers May Help Identify Kidney Cancer in Early Stages

A new immunoassay that tests for the presence of three biomarkers appears to be a valid screening method for the early detection of malignant kidney cancer, according to data published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.