UT Southwestern Medical Center researchers have developed a method to map protein changes that occur in different subtypes of breast cancer cells in response to DNA damage from a new class of chemotherapy drugs.
The research could someday lead to a test to predict an individual patient’s response to a particular drug in the class of cancer therapies called PARP1 inhibitors, they said.
“Using patented technology we developed at UT Southwestern, we identified very different PARP1 signatures in various breast cancer subtypes,” said Dr. Yonghao Yu, Associate Professor of Biochemistry and corresponding author of the study.
The signatures, which he compared to bar codes at the grocery store, reveal how proteins from breast cancer subtypes are modified differently by the enzyme PARP1, which stands for poly (ADP-ribose) polymerase 1. This enzyme is critical to the cancer cell’s DNA repair response to chemotherapy that damages DNA, the cell’s genetic material, he added.
PARP1 is the major target for PARP1 inhibitor drugs, the first three of which were recently approved by the Food and Drug Administration to treat ovarian cancer. PARP1 inhibitors are being evaluated against other types of cancer in clinical studies at UT Southwestern and at dozens of other medical centres around the world, said Dr. Yu, a Virginia Murchison Linthicum Scholar in Medical Research. The drugs target cancer cells by blocking the function of PARP1 and crippling DNA repair. Although DNA damage is recognized as a potent activator of the PARP1 response, the cell-signalling cascades that follow PARP1 activation are poorly understood in other contexts, he said.
“I stress that this research is still in its early stages,” he said. “We think these results could have profound clinical implications. Our ultimate goal is to develop a signature, or fingerprint, for the changes in cellular proteins in response to the enzyme PARP1. A test based on a PARP1 signature could someday help doctors predict a particular patient’s response to a specific PARP1 inhibitor,” he said.
That would be a step toward the era of personalized medicine, he added.
At any given time, human cells contain about 12,000 proteins that work through signalling pathways to carry out the work of the cell, such as metabolism and the cell’s response to stress. The highly sensitive mass spectrometry system developed by Dr. Yu and his colleagues and first described in a 2013 article can pick out 200 or so modified, or tagged, proteins that form the PARP1 response signature. He compared his system to a shopper buying a watermelon at a grocery store where a bar code scanner is used to identify the particular type of melon being purchased.
In reference to the cancerous and noncancerous cells studied here, the chemical tag (or bar code) takes the form of a cluster of atoms that have a distinctive weight that can be measured with a sensitive mass spectrometer. Because chemical tags are part of the cancer cell’s efforts to set off signalling pathways to repair DNA, a better understanding of those pathways could result in new treatment targets, Dr. Yu explained.
The UT Southwestern researchers found significant differences between the signatures of noncancerous breast tissue cells that contained working copies of the tumour-suppressing BRCA1 and BRCA2 genes and breast cancer cells that lacked working BRCA1 and BRCA2 genes. Mutations in those two genes are thought to account for an estimated 10 percent of all breast cancer cases, they said.
“A major hypothesis within the field is that tumours that lack working BRCA genes tend to be more sensitive to PARP1 inhibitors because they are more dependent on PARP1 for DNA damage repair compared to noncancerous cells,” Dr. Yu said.
UT Southwestern Medical Centerhttps://tinyurl.com/y9wgpnn7

Nodules — a type of abnormality detected by ultrasound — are extremely common in the thyroid gland. Up to two-thirds of adults have nodules in this gland, and most are benign or only cause a slow-growing cancer that is no threat to life.
A minority are aggressive cancer that requires treatment, leaving physicians and patients with a problem — which nodules need to be biopsied for malignancy tests, which nodules show a small risk and merit observation without a biopsy, and which need no follow-up at all?
“If you have a cancer that is not going to harm you, and you are not aware of it, is it useful to do a fine-needle aspiration?” said Franklin Tessler, M.D., C.M, a professor in the University of Alabama at Birmingham Department of Radiology. “People are asking, what are we doing? Are we using scarce resources wisely?”
Thyroid cancers are greatly over-diagnosed in the United States. About three-quarters of thyroid cancers in women and nearly one-half in men would not — if the nodules had been left alone and not biopsied with a needle — resulted in symptoms or death.
Tessler and a national committee of experts have now published American College of Radiology guidelines for an ultrasoundbased risk stratification system to identify nodules that warrant biopsy or sonographic follow-up. The guidelines, they write, are “designed to identify most clinically significant malignancies while reducing the number of biopsies performed on benign nodules.”
“This potentially will have a big public health effect,” said Tessler, who is also the Radiology executive vice chair and medical director, vice chair for Radiology Informatics, and division director of Diagnostic Radiology.
Their Thyroid Imaging, Reporting and Data System, or TI-RADS, is modelled after the American College of Radiology’s BI-RADS, a widely accepted risk stratification system for breast lesions.
The experts sought guidelines that are 1) founded on ultrasound features defined in their previously published lexicon; 2) easy to apply across a wide gamut of ultrasound practices; 3) able to classify all thyroid nodules; and 4) evidence-based, to the greatest extent possible, with the aid of underlying data on 3,800 nodules and more than 100,000 cancers.
Their new guidelines follow many attempts over the past 15 years to create guidelines for whether to do a fine-needle aspiration biopsy. Most are based on details of the appearance and size of nodules that are visualized with high-resolution ultrasound. But “the plethora, complexity and lack of congruence of these systems has limited their adoption by the ultrasound community and inspired our effort to publish a classification system under the auspices of the American College of Radiology,” Tessler and colleagues write.
The American College of Radiology TIRADS has five different categories for nodule appearance — composition, echogenicity, shape, margin and echogenic foci. The shape category has two choices — widerthan- tall vs. taller-than-wide. The other four categories have four choices each, such as “hypoechoic” under the category echogenicity or “lobulated or irregular” under margin. Each choice as a point value, ranging from 0 to 3 points.
“Wider-thantall,” for example, is 0 points, and “tallerthan- wide” is 3 points. As the authors explain, “Points are given for all the ultrasound features in a nodule, with more suspicious features being awarded additional points. … When assessing a nodule, the reader selects one feature from each of the first four categories and all the features that apply from the final category and sums the points. The point total determines the nodule’s ACR TI-RADS level, which ranges from TR1, benign, to TR5, high suspicion of malignancy.”
If the sum is 0 points, the nodule is TR1 and the guidelines recommend no fineneedle aspiration or follow-up. If the sum is 2 points, the nodule is TR2, or “not suspicious,” and the guidelines recommend no fine-needle aspiration or follow-up.
A sum of 3 points is TR3, or “mildly suspicious.” For these nodules, the guidelines recommend fine-needle aspiration if the nodule is 2.5 centimeters or greater, or about 1 inch or more, and they recommend follow-ups with subsequent ultrasounds if it is 1.5 centimeters or greater.
TR4 nodules, or “moderately suspicious,” are 4 to 6 points, and TR5 nodules, or “highly suspicious,” are 7 points or more. For TR4 nodules, the guidelines recommend fine-needle aspiration if the nodule is 1.5 centimeters or greater and followups if it is 1 centimeter or greater. For TR5 nodules, the guidelines recommend fine-needle aspiration if the nodule is 1 centimeter or greater and follow-ups if it is 0.5 centimeters or greater.
The guidelines recommend limiting fineneedle aspiration to two nodules per patient because biopsy of three or more nodules is poorly tolerated by patients, and the third biopsy increases cost with little added benefit and some additional risk. The guidelines also suggest appropriate timing for follow-up sonograms.

University of Alabama http://tinyurl.com/y7q9gbse

Researchers at MIT and Brigham and Women’s Hospital have built a flexible sensor that can be rolled up and swallowed. Upon ingestion, the sensor adheres to the stomach wall or intestinal lining, where it can measure the rhythmic contractions of the digestive tract.
Such sensors could help doctors to diagnose gastrointestinal disorders that slow down the passage of food through the digestive tract. They could also be used to detect food pressing on the stomach, helping doctors to monitor food intake by patients being treated for obesity.
The flexible devices are based on piezoelectric materials, which generate a current and voltage when they are mechanically deformed. They also incorporate polymers with elasticity similar to that of human skin, so that they can conform to the skin and stretch when the skin stretches.
In a study the researchers demonstrated that the sensor remains active in the stomachs of pigs for up to two days. The flexibility of the device could offer improved safety over more rigid ingestible devices, the researchers say.
“Having flexibility has the potential to impart significantly improved safety, simply because it makes it easier to transit through the GI tract,” says Giovanni Traverso, a research affiliate at MIT’s Koch Institute for Integrative Cancer Research, a gastroenterologist and biomedical engineer at Brigham and Women’s Hospital, and one of the senior authors of the paper.
Canan Dagdeviren, an assistant professor in MIT’s Media Lab and the director of the Conformable Decoders research group, is the paper’s lead author and one of the corresponding authors. Robert Langer, the David H. Koch Institute Professor and a member of the Koch Institute, is also an author of the paper.
Traverso and colleagues have previously developed ingestible devices that can be used to monitor vital signs or deliver drugs to the digestive tract. With the goal of developing a more flexible sensor that might offer improved safety, Traverso teamed up with Dagdeviren, who previously developed flexible electronic devices such as a wearable blood pressure sensor and flexible mechanical energy harvesters.
To make the new sensor, Dagdeviren first fabricates electronic circuits on a silicon wafer. The circuits contain two electrodes: a gold electrode placed atop a piezoelectric material called PZT, and a platinum electrode on the underside of the PZT. Once the circuit is fabricated, it can be removed from the silicon wafer and printed onto a flexible polymer called polyimide.
The ingestible sensor that the researchers designed for this study is 2 by 2.5 centimeters and can be rolled up and placed in a capsule that dissolves after being swallowed.
In tests in pigs, the sensors successfully adhered to the stomach lining after being delivered endoscopically. Through external cables, the sensors transmitted information about how much voltage the piezoelectrical sensor generated, from which the researchers could calculate how much the stomach wall was moving, as well as distinguish when food or liquid were ingested.
“For the first time, we showed that a flexible, piezoelectric device can stay in the stomach up to two days without any electrical or mechanical degradation,” Dagdeviren says.
This type of sensor could make it easier to diagnose digestive disorders that impair motility of the digestive tract, which can result in difficulty swallowing, nausea, gas, or constipation.
Doctors could also use it to help measure the food intake of patients being treated for obesity. “Having a window into what an individual is actually ingesting at home is helpful, because sometimes it’s difficult for patients to really benchmark themselves and know how much is being consumed,” Traverso says.
In future versions of the device, the researchers plan to harvest some of the energy generated by the piezoelectric material to power other features, including additional sensors and wireless transmitters. Such devices would not require a battery, further improving their potential safety.

MIT
news.mit.edu/2017/flexible-sensors-can-detect-movement-gi-tract-1010

Heart tissue can be imaged in real-time during keyhole procedures using a new optical ultrasound needle developed by researchers at UCL and Queen Mary University of London (QMUL).
The revolutionary technology has been successfully used for minimally invasive heart surgery in pigs, giving an unprecedented, high-resolution view of soft tissues up to 2.5 cm in front of the instrument, inside the body.
Doctors currently rely on external ultrasound probes combined with pre-operative imaging scans to visualise soft tissue and organs during keyhole procedures as the miniature surgical instruments used do not support internal ultrasound imaging.
For the study the team of surgeons, engineers, physicists and material chemists designed and built the optical ultrasound technology to fit into existing single-use medical devices, such as a needle.
“The optical ultrasound needle is perfect for procedures where there is a small tissue target that is hard to see during keyhole surgery using current methods and missing it could have disastrous consequences,” said Dr Malcolm Finlay, study co-lead and consultant cardiologist at QMUL and Barts Heart Centre.
“We now have real-time imaging that allows us to differentiate between tissues at a remarkable depth, helping to guide the highest risk moments of these procedures. This will reduce the chances of complications occurring during routine but skilled procedures such as ablation procedures in the heart. The technology has been designed to be completely compatible with MRI and other current methods, so it could also be used during brain or foetal surgery, or with guiding epidural needles.”
The team developed the all-optical ultrasound imaging technology for use in a clinical setting over four years. They made sure it was sensitive enough to image centimetre-scale depths of tissues when moving; it fitted into the existing clinical workflow and worked inside the body.
“This is the first demonstration of all-optical ultrasound imaging in a clinically realistic environment. Using inexpensive optical fibres, we have been able to achieve high resolution imaging using needle tips under 1 mm. We now hope to replicate this success across a number of other clinical applications where minimally invasive surgical techniques are being used,” explained study co-lead, Dr Adrien Desjardins (Wellcome EPSRC Centre for Interventional and Surgical Sciences at UCL).
The technology uses a miniature optical fibre encased within a customised clinical needle to deliver a brief pulse of light which generates ultrasonic pulses. Reflections of these ultrasonic pulses from tissue are detected by a sensor on a second optical fibre, giving real-time ultrasound imaging to guide surgery.
One of the key innovations was the development of a black flexible material that included a mesh of carbon nanotubes enclosed within clinical grade silicone precisely applied to an optical fibre. The carbon nanotubes absorb pulsed laser light, and this absorption leads to an ultrasound wave via the photoacoustic effect.
A second innovation was the development of highly sensitive optical fibre sensors based on polymer optical microresonators for detecting the ultrasound waves. This work was undertaken in a related UCL study led by Dr James Guggenheim.
University College London
www.ucl.ac.uk/news/news-articles/1217/011217-ultrasound-imaging-needle-surgery