Posts Tagged ‘technology’

Showcase of latest advances in medical imaging for revolutionary proton therapy cancer treatment

The University of Lincoln’s Professor Nigel Allinson MBE will deliver the keynote talk at the tenth International Conference on Position Sensitive Detectors. The conference, which takes place from 7th to 12th September 2014, features the latest developments in this field from leading researchers around the world.

Professor Allinson leads the pioneering PRaVDA (Proton Radiotherapy Verification and Dosimetry Applications) project. He and his multinational team are developing one of the most complex medical instruments ever imagined to improve the delivery of proton beam therapy in the treatment of cancer.

Proton beam therapy is a type of particle therapy that uses a beam of protons to irradiate diseased tissue. Proton beam therapy has the ability to deliver high doses of radiation directly to a tumour site with very little radiation being absorbed into healthy tissue.

PRaVDA, funded by a £1.6 million grant from the Wellcome Trust, will provide a unique instrument capable of producing real-time 3D images — a proton CT — of a patient, drawing data from the same protons used in the treatment itself.

The patent-pending technology, which uses detectors at the heart of the Large Hadron Collider at CERN alongside world-first radiation-hard CMOS imagers, will reduce dose uncertainties from several centimetres to just a few millimetres.

This promises to make proton therapy an option for thousands more cancer patients by reducing the risks of healthy tissue being damaged during treatment, particularly in vulnerable parts of the body such as the brain, eye and spinal cord.

Professor Allinson, who will also be talking about his research to prospective students at the University of Lincoln open day on Saturday, 20th September, said: “PRaVDA will ensure more difficult tumours will become treatable and more patients overall will be able to receive this revolutionary treatment.”

Other members of the PRaVDA team will also present their work at the conference, describing in more detail the high-speed tracking technology that can record the paths of individual protons as they enter and leave a patient. The team will also outline how they make and test the new detectors in PRaVDA to ensure they are resistant to the high levels of radiation present in proton therapy.

The researchers have just taken delivery of some of the technology which will lie at the heart of the system: two state-of-the-art custom integrated circuits (chips) which will underpin PRaVDA’s imaging capabilities.

One device is a radiation-hard CMOS imager, measuring 10cm x 6.5cm, and producing more than 1,500 images per second. The camera chip in a mainstream smartphone is a CMOS imager but PRaVDA’s chip is over 300 times larger and operates 50 times faster — the fastest large-area CMOS imager ever made. The completed PRaVDA instrument will contain 48 of these imagers, giving a total imaging area of nearly two-and-a-half square metres.

The second device is the read-out chip for the very high-speed strip detectors that track the passage of individual protons as they enter and exit a patient. This chip, called Rhea, converts the electric charge created by a passing proton into a digital signal with additional logic to provide accurate timing (to one hundredth of one millionth of a second) while preventing erroneous signals being recorded.

The strip detectors were designed at the University of Liverpool by the same team that developed detectors for the Large Hadron Collider at CERN, which led to the discovery of the Higgs Boson in 2013. Nearly 200 Rheas are used in the complete PRaVDA system.

PRaVDA’s industrial partner, ISDI LTD, designed both devices. Their testing was undertaken by the project’s second industrial partner, aSpect Systems GmbH, in Dresden, Germany.

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Novel gene predicts both breast cancer relapse, response to chemotherapy

Despite advancements in cancer treatment, breast cancer remains the most common cancer among Singapore women. Thirty percent of early breast cancer patients in the world experience relapse due to metastasis, or the spread of cancer cells to other organs in the body. Some patients also do not respond well to chemotherapy. The inability to forecast relapses or the effectiveness of chemotherapy has led to a pressing need to identify predictive markers, which doctors can use to tailor appropriate treatment for each breast cancer patient at an early stage.

In a study published recently in the Journal of Clinical Investigation, a top-tier journal for discoveries in basic and clinical biomedical research, the team of scientists jointly led by Dr Vinay Tergaonkar, Principal Investigator at IMCB and Dr Alan Prem Kumar, Principal Associate at CSI Singapore and Assistant Professor at the Department of Pharmacology, NUS Yong Loo Lin School of Medicine, uncovered a gene, DP103, which is activated in metastatic breast cancer. DP103 acts as a master regulator, which expresses two sets of unfavourable proteins — one leads to metastasis and the other causes patients to be unresponsive to chemotherapy. Consequently, doctors can predict the probability of metastasis by examining the levels of DP103 in breast cancer patients. The same gene could also be used to predict whether a patient would respond to chemotherapy.

“Doctors are unable to tell if a breast cancer patient will respond to chemotherapy until six months after the treatment has been prescribed. It is very worrisome as the ones who are not responsive to chemotherapy usually also suffer relapses due to metastasis. This DP103 gene that we found explains the link and will facilitate doctors in selecting suitable treatments for different cases of breast cancer,” said Dr Tergaonkar.

In addition, the study revealed that reducing the levels of DP103 could contain the cancer, shrink the tumour and make patients more amenable to chemotherapy. All the findings in the study have been validated with samples of breast cancer patients from Singapore, Canada, China and the USA.

“DP103 is a novel biomarker that could help doctors select appropriate treatments for breast cancer patients at an early stage. It is also a therapeutic target which could be explored further to develop drugs that suppress breast cancer growth, as well as metastasis,” said Dr Kumar, who first discovered DP103’s oncogene potential to drive breast cancer metastasis. He is also the Principal Inventor to a patent application on this discovery and is currently looking into ways to regulate DP103 levels in a variety of cancer types at CSI Singapore.

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New analysis reveals tumor weaknesses in epigenetics

Analyzing these modifications can provide important clues to the type of tumor a patient has, and how it will respond to different drugs. For example, patients with glioblastoma, a type of brain tumor, respond well to a certain class of drugs known as alkylating agents if the DNA-repair gene MGMT is silenced by epigenetic modification.

A team of MIT chemical engineers has now developed a fast, reliable method to detect this type of modification, known as methylation, which could offer a new way to choose the best treatment for individual patients.

“It’s pretty difficult to analyze these modifications, which is a need that we’re working on addressing. We’re trying to make this analysis easier and cheaper, particularly in patient samples,” says Hadley Sikes, the Joseph R. Mares Assistant Professor of Chemical Engineering and the senior author of a paper describing the technique in the journal Analyst.

The paper’s lead author is Brandon Heimer, an MIT graduate student in chemical engineering.

Beyond the Genome

After sequencing the human genome, scientists turned to the epigenome — the chemical modifications, including methylation, that alter a gene’s function without changing its DNA sequence.

In some cancers, the MGMT gene is turned off when methyl groups attach to specific locations in the DNA sequence — namely, cytosine bases that are adjacent to guanine bases. When this happens, proteins bind the methylated bases and effectively silence the gene by blocking it from being copied into RNA.

“This very small chemical modification triggers a sequence of events where that gene is no longer expressed,” Sikes says.

Current methods for detecting cytosine methylation work well for large-scale research studies, but are hard to adapt to patient samples, Sikes says. Most techniques require a chemical step called bisulfite conversion: The DNA sample is exposed to bisulfite, which converts unmethylated cytosine to a different base. Sequencing the DNA reveals whether any methylated cytosine was present.

However, this method doesn’t work well with patient samples because you need to know precisely how much methylated DNA is in a sample to calculate how long to expose it to bisulfite, Sikes says.

“When you have limited amounts of samples that are less well defined, it’s a lot harder to run the reaction for the right amount of time. You want to get all of the unmethylated cytosine groups converted, but you can’t run it too long, because then your DNA gets degraded,” she says.

Rapid Detection

Sikes’ new approach avoids bisulfite conversion completely. Instead, it relies on a protein called a methyl binding domain (MBD) protein, which is part of cells’ natural machinery for controlling DNA transcription. This protein recognizes methylated DNA and binds to it, helping a cell to determine if the DNA should be transcribed.

The other key component of Sikes’ system is a biochip — a glass slide coated with hundreds of DNA probes that are complementary to sequences from the gene being studied. When a DNA sample is exposed to this chip, any strands that match the target sequences are trapped on the biochip. The researchers then treat the slide with the MBD protein probe. If the probe binds to a trapped DNA molecule, it means that sequence is methylated.

The binding between the DNA and the MBD protein can be detected either by linking the protein to a fluorescent dye or designing it to carry a photosensitive molecule that forms hydrogels when exposed to light.

The MIT team is now adapting the device to detect methylation of other cancer-linked genes by changing the DNA sequences of the biochip probes. They also hope to create better versions of the MBD protein and to engineer the device to require less DNA. With the current version, doctors would need to do a surgical biopsy to get enough tissue, but the researchers would like to modify it so the test could be done with just a needle biopsy.

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