Genetic signature helps distinguish latent autoimmune diabetes in adults from pediatric-onset T1D

A multi-center team of researchers led by Children's Hospital of Philadelphia (CHOP) has discovered a genetic signature that could help distinguish an adult-onset form of diabetes sharing many type 1 diabetes (T1D) characteristics from pediatric-onset T1D, opening the door to potentially more straightforward diagnostic tests for the adult condition and improving responses by ensuring patients receive the most appropriate treatment.

This is our first insight into genetic differences between latent autoimmune diabetes in adults and T1D in children that may be diagnostically useful. We have found a genetic means of discriminating between the two conditions without expensive and cumbersome anti-autobody screening."

Latent autoimmune diabetes in adults (LADA) is sometimes referred to as "type 1.5 diabetes" because it shares characteristics of both T1D and type 2 diabetes (T2D). Like T1D, LADA produces autoantibodies that attack the body's insulin-producing beta cells in the pancreas. However, like those with T2D, patients with LADA are diagnosed in adulthood and do not require insulin at the time of diagnosis. For this reason, LADA is often misdiagnosed as T2D; studies have shown that up to 10% of T2D diagnoses are, in fact, LADA, and as a result patients do not respond to the commonly inappropriate treatments prescribed to them.

An earlier genome-wide association study led by CHOP found that, from a genetic perspective, LADA has more in common with T1D than with T2D. Researchers wanted to take a deeper dive and look for genetic differences that could help discriminate between LADA and T1D, meaning the diagnosis of LADA could potentially begin with a simple genotype array, rather than with a more complex and expensive auto-antibody screening.

To do so, the team decided to look at the major histocompatibility complex (MHC), a highly variable region of the genome that helps drive the immune system and is implicated in T1D. Earlier studies have shown that when researchers control for T1D genetic variants in one part of the MHC, other variants associated with T1D appear in another part of the MHC.

The study team applied that methodology to both a set of T1D data as well as a cohort of LADA patients. They found that when it came to the T1D group, the results from the earlier studies held: controlling for genetic variants in one part of the MHC revealed variants in another part of the MHC.

However, researchers did not find the same effect with LADA patients. When controlling for genetic variants in the MHC in those patients, the additional association was not observed within this key region - an important genetic distinction between the two conditions. When a sensitivity test was applied to the two cohorts, researchers still saw the effect only in T1D patients, not in those with LADA.

"This suggests that these MHC class associations may be a genetic discriminator between LADA and childhood-onset T1D," said Diana Cousminer, PhD, a geneticist at CHOP and a joint-first author of the study. "The next step is to look at this association in different ethnicities, particularly African ancestry, where the prevalence of adult-onset diabetes can be significantly higher in certain parts of the world."

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New app can detect early signs of eye cancer in kids

Researchers have developed a smartphone app to help parents detect early signs of various eye diseases in their children such as retinoblastoma, an aggressive pediatric eye cancer.

The CRADLE app (Computer-assisted detector leukocoria) searches for traces of abnormal reflections from the retina called leukocoria or "white eye", a primary symptom of retinoblastoma, as well as other common eye disorders. 

The app can be downloaded for free and can be found under the name "White Eye Detector."
The study, published in the journal Science Advances, found that the app is an effective tool to augment clinical leukocoria screenings, allowing parents to efficiently and effectively screen their children more often throughout their development.

"We suspected that the app would detect leukocoria associated with other more common disorders and some rare ones," said study researcher.

"We were right. So far parents, and some doctors have used it to detect cataract, myelin retinal nerve fibre layer, refractive error, Coats' disease and of course retinoblastoma," he added.

Researchers determined the sensitivity, specificity and accuracy of the prototype by analysing more than 50,000 photographs of children taken before their diagnosis. 

For children with diagnosed eye disorders, CRADLE was able to detect leukocoria for 80 per cent of the kids. 

The app detected leukocoria in photos that were taken on an average of 1.3 years prior to their official diagnosis.

CRADLE's sensitivity for children age 2 and younger surpassed 80 per cent. 

Researchers found the CRADLE app to be more effective simply by the breadth and frequency of its sample sizes: everyday family photos. 

Given the number of photos taken by family and friends and the variety of environments, there is a variety of opportunities for light to reflect off the ocular lesions regardless of its location in the eye.
As the app's algorithm has become more sophisticated, its ability to detect even slight instances of leukocoria has improved.

"This is one of the most critical parts of building the app," Shaw said. 

"We wanted to be able to detect all hues and intensities of leukocoria. As a parent of a child with retinoblastoma, I am especially interested in detecting the traces of leukocoria that appear as a 'gray' pupil and are difficult to detect with the naked eye," he added.


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Brain cancer in kids can be treated with leukemia drug

In a recent study, researchers suggested a new use of leukemia drug, nilotinib to heal a deadly pediatric brain cancer called medulloblastoma.

In the study, published in September -- the team demonstrated how use of a single drug, in this case nilotinib, specifically targets cancer cells that have an abnormal activation of a cell communication system, called the Hedgehog pathway, via two different mechanisms, making it more effective and less toxic than combining drugs.

"We discovered a previously unknown activity of nilotinib that may be leveraged to treat a large fraction of cases of medulloblastoma, a type of childhood brain cancer," said senior author.

"While more research is needed, this pharmaceutical could potentially be used for several cancer types with an overactive cell-signaling pathway," added the author.

Several types of basal cell carcinoma, myeloid leukemia, rhabdomyosarcoma, pancreatic adenocarcinoma, glioblastoma and one-third of medulloblastoma cases have impairment in the Hedgehog signaling pathway, a key cellular system that regulates embryonic development and adult tissue regeneration.

As a result of this impairment, the cancer cells overproduce a cell-surface receptor called Smoothened. Malignancies with this abnormality account for a quarter of all cancer deaths said Abagyan.

"Only a fraction of patients with this subtype of medulloblastoma respond well to current therapies that only target Smoothened," said the author.

"Knowing that dysregulation of the Hedgehog pathway is important to the maintenance of cancer stem cells and that it plays a critical role in several cancers, we wanted to find a single drug that inhibits this pathway in addition to several other essential anti-cancer activities," added Abagyan.

In the study, researchers discovered that mice bearing human medulloblastoma tumours saw tumour growth reduced and no drug resistance occurring. Nilotinib simultaneously inhibits Smoothened and several protein kinases critical for tumor growth.


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New drug combination shows promise for common pediatric brain tumor

A new combination treatment aimed at resistant and recurrent low-grade gliomas slowed tumor growth and killed tumor cells in laboratory and mouse models. 

Researchers combined carboplatin, a standard chemotherapy drug that works well against these brain tumours, and everolimus, which blocks an enzyme called mTOR that was shown in earlier research to fuel the growth of these tumors. The combination increased DNA damage and cell death in laboratory models. 

Pediatric low-grade glioma is the most common brain tumour in children and can often be treated with surgery alone. However, some patients have tumors in locations that make surgery too risky, such as near optic nerves or in the mid-brain area, or have their tumors grow back after surgery.

An associate professor of oncology and pediatric brain tumor expert, says tumors recur in about 50 percent of patients treated for low-grade glioma and require additional treatment with chemotherapy. Recurring tumors are often resistant to chemotherapy. The researchers wondered whether combining carboplatin and everolimus would be more effective.

When treated with carboplatin alone, four different human cell lines of low grade glioma cancer cells did not respond to the drug or kept growing. Similarly, some cell lines were resistant to everolimus alone.

When they treated the same cell lines with a combination of carboplatin and everolimus, the cells died or grew slower, and the researchers saw similar results in mouse models with no added toxicity.
"We saw dramatic growth inhibition after only a low concentration of everolimus was combined with the carboplatin," says the Prof. "We found that everolimus disrupted a key mechanism the cancer cells use to detoxify carboplatin. The ability of everolimus to increase the power of carboplatin suggests this combination could be used effectively in patients."

In a previous clinical study in 2014, the researchers were able to confirm the safety of the mTOR-blocking drug everolimus in patients with pediatric low-grade glioma and found some patients responded to the medicine. However, they never tested tumor tissue from those patients to understand the molecular role of mTOR.

"The current nationwide clinical study of everolimus in pediatric low-grade glioma requires that some tumor tissue from each patient be evaluated for expression of mTOR markers that might predict response to everolimus," the Prof. says. "In this way, we hope to figure out who is most likely to respond to the drug, so that we can move closer to our goal of giving the right medicine to the right patient at the right time. In the future, we may be able to give everolimus along with carboplatin to patients with high-level mTOR expression. Based on our research, we predict that these tumors will likely be resistant to carboplatin unless we simultaneously block mTOR."

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