Researchers have identified two new genetic risk factors for Alzheimer’s disease (AD) among African Americans.  The findings may lead to the development of new therapies specifically targeting those genes.

Despite the fact that AD is more common in African Americans than Caucasians, the AD genetic risk profile for African Americans is more poorly understood. While more than 20 genes have been identified as risk factors for AD in Caucasians, fewer than five have been identified for African Americans.

In 2013, a genome-wide association study of AD in more than 5,500 African Americans identified two genetic risk factors for AD. This study looked at genetic variants across subjects’ entire genome and compared their frequency in cases versus controls. Researchers from Boston University School of Medicine (BUSM) used these same subjects, but added additional AD risk information (smoking status, diabetes status, education level) to their statistical modelling to increase the power of the study. By doing so they were able to identify two new genes (COBL and SLC10A2) associated with risk of AD in African Americans.

Mez_Jesse-432×636-2“There are currently no medications for AD that slow or stop the progression of the disease. Genes that increase risk for AD are potential targets for new disease-modifying AD drug therapies. Our study identifies two potentially “drugable” targets,” explains corresponding author Jesse Mez, MD, MS, assistant professor of neurology  and associate director of the BU Alzheimer’s Disease & CTE Center Clinical Core.

According to the researchers the methodology they employed for this study allowed them to make an important discovery without investing more money in genotyping or more effort to recruit volunteers. They believe that a similar methodology could be used for many other diseases to make new genetic discoveries without new large investments.

“Despite the fact that Alzheimer’s disease is more common in African Americans than Caucasians, we understand less about the genes that influence risk of Alzheimer’s in African Americans. Our hope is that this study begins to eliminate that disparity and that ultimately these newly identified genes become targets for Alzheimer’s disease drug development,” added Mez.

Boston University Medical Center www.bumc.bu.edu/busm/2016/10/25/new-genes-responsible-for-alzheimers-among-african-americans-identified/

Researchers at the University at Buffalo Research Institute on Addictions have discovered how a gene in the brain’s dopamine system can play an important role in prolonging lifespan: it must be coupled with a healthy environment that includes exercise.

The study was led by Panayotis (Peter) K. Thanos, senior research scientist at RIA.

Thanos and his team studied the genes in dopamine to assess their impact on lifespan and behaviour in mice. Dopamine is a neurotransmitter that helps control the brain’s reward and pleasure centres and helps regulate physical mobility and emotional response.

The researchers found that the dopamine D2 receptor gene (D2R) significantly influences lifespan, body weight and locomotor activity, but only when combined with an enriched environment that included social interaction, sensory and cognitive stimulation and, most critically, exercise.

“The incorporation of exercise is an important component of an enriched environment and its benefits have been shown to be a powerful mediator of brain function and behaviour,” Thanos says.

The mice in the enriched environment lived anywhere from 16 to 22 percent longer than those in a deprived environment, depending on the level of D2R expression.

“These results provide the first evidence of D2R gene-environment interaction playing an important role in longevity and aging,” Thanos says. “The dichotomy over genes versus environment has provided a rigorous and long debate in deciphering individual differences in longevity. In truth, there exists a complex interaction between the two which contribute to the differences.”

Research exploring this genetic-environmental interaction should lead to a better understanding and prediction of the potential benefits of specific environments, such as those including exercise, on longevity and health during aging.

University at Buffalo Research Institute on Addictions www.buffalo.edu/ria/news_events/latest_news.host.html/content/shared/university/news/news-center-releases/2016/04/056.detail.html

Scientists at The University of Nottingham have demonstrated for the first time that it is possible to selectively sequence fragments of DNA in real time, greatly reducing the time needed to analyse biological samples.

A paper describes a novel technique for highly selective DNA sequencing, called ‘Read Until’.  The method, used with real-time nanopore sequencing, enables the user to analyse only DNA strands that contain pre-determined signatures of interest.

Dr Matt Loose, of the Cell and Developmental Biology Research Group in the University’s School of Life Sciences, has been working with the MinION, a new portable DNA sequencing technology produced by biotech company Oxford Nanopore Technologies. All sequencing was carried out at The University of Nottingham Next Generation Sequencing Facility, DeepSeq.

“This is the first time that direct selection of specific DNA molecules has been shown on any device,” said Dr Loose. “We hope that it will enable many future novel applications, especially for portable sequencing. This makes sequencing as efficient as possible and will provide a viable, informatics based alternative to traditional wet lab enrichment techniques. The application of this approach to a wide number of problems from pathogen detection to sequencing targeted regions of the human genome is now within reach.”

The pocket-sized MinION device – the same technology which NASA recently sent to the International Space Station in an effort to investigate whether DNA sequencing is possible in microgravity – employs tiny molecular pores in a membrane that ‘sense’ the sequence of DNA fragments passing through these nanopores, producing minute fluctuations in a current trace. These current traces, termed ‘squiggles’ then need to be converted to DNA bases using base caller software, often located in the cloud. The University of Nottingham team used signal processing techniques to map these squiggles to reference sequences, by passing this step.

In the paper, the Nottingham team go further, showing that this squiggle matching technique can be performed at a rate that enables decisions to be made about the fragment of DNA that is being sequenced before it has completely passed through the nanopore. Depending on the sequence, individual nanopores within the MinION can then be instructed to continue sequencing or to eject the current DNA fragment and start sequencing another. The Nottingham team show that this ‘real-time selective sequencing’, or as some have called it ‘DNA tasting’, can reduce the time needed to sequence key DNA fragments or enable the analysis of pathogen samples where there is host and other DNA present in the sample.

The Read Until method/technique was developed by applying dynamic time warping to match short query current traces to references, demonstrating selection of specific regions of small genomes, individual amplicons from a group of targets, or normalisation of amplicons in a set.

Nottingham University www.nottingham.ac.uk/news/pressreleases/2016/july/nottingham-researchers-show-novel-technique-that-can-‘taste’-dna.aspx

Researchers have identified a new pathway and with it a protein, BRD4, necessary for breast cancer cells to spread.

The findings may provide a new target to suppress breast cancer metastasis.

Triple-negative breast cancer is considered the worst subgroup of breast cancer. It is highly aggressive and responds poorly to the current therapeutic tools resulting in a dismal prognosis for patients. Furthermore, the lack of identified targets has limited the development of new drug strategies.

Researchers from Boston University School of Medicine (BUSM) used breast cancer cell lines that present the clinical characteristics of an aggressive breast cancer subtype (clinically described as a triple-negative breast cancer). They then used an experimental design to model cancer cell metastasis. By suppressing the expression of the protein BRD4 in these cell lines, they observed that their dissemination capabilities were blocked, indicating that BRD4 drives breast cancer dissemination. In addition, they conducted a screening analysis of human breast tumours and found that tumours with a high expression of BRD4 were more likely to metastasize.

“The current treatment options for a triple-negative cancer are unacceptably limited. It is crucial to identify new therapeutic targets to tackle challenging cancer types, including triple negative breast cancer. BDR4 targeting represents an innovative strategy to ablate breast cancer metastasis,” explained lead investigator Guillaume Andrieu, PhD, a post-doctoral research associate at Boston University School of Medicine.

Although obesity per se is not thought of as a carcinogen, the abnormal, inflamed microenvironments found in obesity are critical for progression, invasion and metastasis of triple negative breast cancer. “Bromodomain and ExtraTerminal domain (BET) proteins, which include BRD2, BRD3 and BRD4, are known to regulate production of inflammatory mediators. Our study proposes that BRD4 couples inflammation to breast cancer dissemination. Thus, small molecules that block BET proteins possess anti-inflammatory properties that can be useful for therapy,” he added.

Although these findings primarily focus on breast cancer and metastasis, the researchers plan to expand their results to the treatment of prostate cancer, which they believe has similar pathways involved in its metastasis.

Boston University Medial Center www.bu.edu/news/2016/11/15/researchers-identify-protein-required-for-breast-cancer-metastasis/

Ludwig researchers working in collaboration with colleagues in Australia and the US have shown that fragments of tumour DNA circulating in the blood can be used to gauge the risk of colorectal cancer recurrence and the efficacy of chemotherapy following surgery. The finding is an important step toward the development of a non-invasive and more effective test for the detection, monitoring and treatment of cancer.

‘Prior studies, including ones from our group, have shown that this technique is sensitive enough to detect tumour DNA fragments in patients with advanced cancer,” Bert Vogelstein, co-director of the Ludwig Center at Johns Hopkins and one of the study leaders. “But this new study gets us one major step closer to the real goal, because it suggests that it can detect residual disease in early stage patients well before conventional clinical or radiologic criteria can.’

The decision of whether a stage II colon cancer patient should be treated with adjuvant, or post-operation, chemotherapy remains one of the most challenging areas in colorectal oncology. Such assessments are currently made by combining a number of clinical and pathologic features—such as the tumour’s appearance under the microscope, including how far it has spread through the bowel wall—or looking for the presence of cancer-specific genetic markers that have prognostic significance.

However, current methods are imprecise, and as a result doctors tend to err on the side of caution. Currently, up to 40 percent of stage II patients undergo the rigors and risks of adjuvant chemotherapy even though only a small fraction of them are destined to experience a cancer relapse.

‘The routine procedure is to give six months of chemotherapy, but we don’t have any way of knowing if the treatment is effective,’ said Jeanne Tie, a Ludwig investigator at the Walter and Eliza Hall Institute of Medical Research (WEHI) in Victoria, Australia, and lead author of the study.

Cancer cells often shed their DNA into the blood when they die, and recent advances in technology have made it possible to capture and profile these relatively rare fragments of DNA. Mutations in such circulating tumour DNA (ctDNA) can serve as extremely specific cancer biomarkers.

‘We have to be able to pick out a single tumour DNA among ten thousand normal DNA fragments,’ Tie said. ‘That’s the level of sensitivity that we needed to get down to, and that wasn’t possible until now.’

For the current study, Tie and her colleagues collected tumour samples from 230 patients with stage II colorectal cancer. They analysed the DNA of the tumour specimens and then designed personalized assays to target each patient’s particular genetic mutations.

The assays were applied to blood samples taken from the patients four to 10 weeks after surgery to remove tumours. Twenty of the 230 patients tested positive for ctDNA, and of this group, 80 percent experienced cancer relapse within about two years. Of the 164 patients whose blood tested negative for ctDNA, only 10 percent relapsed.

‘A positive ctDNA test is an indicator that cancer cells from the original tumor are hiding somewhere in the body,’ said Peter Gibbs, a Ludwig investigator at WEHI who co-led the study with Tie and Vogelstein.

The team also looked at whether ctDNA could be used to gauge the impact of chemotherapy treatments. Six of the patients who tested positive for ctDNA following surgery also underwent adjuvant chemotherapy. The scientists continued to collect blood samples from these patients and found that in two patients, ctDNA readings changed from positive after surgery to negative following chemotherapy.

‘To an oncologist, that’s probably the most exciting aspect of a ctDNA screening test—that it can be used not only to determine the risk of recurrence, but also as a real-time marker of chemotherapy benefits,’ said Gibbs.

In the current study, the ctDNA assays were custom-tailored to each patient’s unique cancer mutations, but the scientists are also developing a ctDNA screening test that covers frequently occurring colorectal cancer mutations.

‘When such a generic test is developed, it could still catch more than 90 percent of colorectal cancers, and it would eliminate the need to retrieve and test individual tumour samples, thus saving time, effort and money,’ Gibbs said.

www.ludwigcancerresearch.org/news/new-screening-test-using-blood-biomarkers-may-identify-risk-colon-cancer-recurrence-early