Now, however, researchers at Dana-Farber Cancer Institute and the University of Trento, Italy, have developed a blood test, described in Cancer Discovery, that can reliably detect NEPC and differentiate it from CRPC-adenocarcinoma (CRPC-adeno).

NEPC is currently diagnosed using a biopsy of tumor tissue from a metastatic tumor site. Yet, it isn’t always clear to clinicians when to do a biopsy. Further, biopsies may be unreliable since metastatic tumors are often heterogeneous.

“As prostate cancer treatments get more effective, we expect the emergence of different types of treatment resistance like neuroendocrine prostate cancer that help them evade treatment,” says co-lead author Himisha Beltran, MD, associate professor of medicine, Lank Center for Genitourinary Oncology and the Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute. “We hope this blood test can be used by clinicians to determine if a patient is developing neuroendocrine prostate cancer.”

Approximately 10-15% of patients with metastatic prostate cancer develop NEPC. The transition involves a shift from cancer cells that are dependent on hormones called androgens to cancer cells that no longer even recognize androgens.

“They can stop expressing the androgen receptor,” says Beltran. “They shut down their hormone-driven identity and they turn on a new identity as a way to develop resistance to treatment.”

In previous research, the international team studied tissue samples from biopsies to identify the genetic and epigenetic changes related to this transition. They found that, across the whole genome, specific epigenetic changes, in the form of DNA methylation changes that switch genes on or off, distinguish CRPC-adeno from NEPC.

These epigenetic changes can be detected in blood because the body is constantly shedding fragments of dead cells into the bloodstream. Those cells come from all over the body, including from tumors. The fragments include bits of DNA, called cell free DNA (cfDNA), along with whatever epigenetic tags and structures were attached to them when the cell died.

Beltran collaborated with a computational team at the University of Trento, led by Francesca Demichelis, PhD, co-lead author on the study, to create a blood panel test, called NEMO (NEuroendocrine MOnitoring panel). “The test selectively probes cfDNA in blood plasma for relevant DNA fragments and measures their methylation,” says Demichelis. “Because the number of methylated regions needed to distinguish between normal, CRPC-adeno, and NEPC cells is small, the panel of genes sequenced by the test is minimal and efficient.”

NEMO reports two measures: the tumor fraction, a measure of disease burden based on the ratio of tumor DNA to normal DNA in the blood; and the tumor type, either CRPC-adeno or NEPC. The tumor type is reported as a score on a continuum because a patient’s cancer might be a mix of the two.

“It not only picks up the neuroendocrine phenotype but also can pick up subtypes in the middle, as tumors transition from one subtype to the other,” says Beltran.

Beltran’s team tested NEMO in several preclinical models of prostate cancer and in blood samples from multiple patient cohorts with known prostate cancer subtypes. The NEMO tumor type score identified subtypes with a high level of accuracy.

The team also evaluated NEMO in two clinical trials of patients with aggressive CRPC. The panel’s estimation of tumor fraction was consistent with other accepted measures of disease burden, suggesting that the test could be used to monitor response to treatment by revealing if a tumor is shrinking or not. This is especially valuable because, measures of disease burden, such as prostate-specific antigen levels, become unreliable when a tumor switches its identity to NEPC.

NEMO successfully identified patients with NEPC in the two clinical trials based on pathology reports. It also identified patients who had not been diagnosed with NEPC yet had signs of a transition to NEPC in their pathology reports.

“Now that we have robustly shown the accuracy of this panel test, we’re excited to apply it to clinical questions,” says Beltran. “We’d like to determine if this test can help us predict which patients respond to certain prostate cancer treatments, including precise treatments that target neuroendocrine prostate cancer.”

The information in a NEMO panel may also help clinicians select targeted treatments for patients or help investigators learn more about the disease. Further, adds Beltran, the test’s approach could potentially be applied to other forms of cancer to distinguish subtypes.

Longer term, Beltran and colleagues will take steps toward transitioning NEMO into a clinical test that physicians can order and use in practice.

Funding: The Prostate Cancer Foundation, National Cancer Institute, Fondazione AIRC per la Ricerca sul Cancro ETS, Cancer Research UK, United States Department of Defense, the Doris Duke Foundation, the Safeway Foundation, the V Foundation, and the Institute for Prostate Cancer Research.

Peat is a vast carbon sink: per square metre it is able to store more CO₂ than any other ecosystem in the world. The peatlands of the Netherlands, but also those in places such as Scandinavia and the Baltic states, therefore play an important role in the fight against climate change. However, peat is coming under increasing pressure and is extremely sensitive to the dry summers we are experiencing as a result of climate change. This is what researchers from the Radboud Institute for Biological and Environmental Sciences have concluded.

‘In our lab, under controlled conditions, we first ensured that large blocks of peat were well moistened over a long period of time’, explains lead author Bjorn Robroek. ‘We then slowly dried the peat out. One half was exposed to mild drought, with the water level roughly five centimetres lower than the peat itself. The other half was subjected to extreme drought conditions; in this case the water was twenty centimetres below the peat. This is comparable to a period of three weeks without rain — something that has also become increasingly common in the Netherlands in recent years.’

These experiments revealed that peat exposed to mild drought still absorbs a reasonable amount of carbon. Robroek: ‘Under extreme drought conditions, however, the peat can hardly take on any more carbon. In the event of an extended period of drought it even releases the carbon again.’

Biodiversity

Drought not only affects peatlands, of course. Dry summers have made other ecosystems more fragile too. However, in the case of grasslands, for example, we now have methods to combat problems caused by drought. Increasing the biodiversity in this kind of ecosystem (by incorporating a greater number of different plants), as in the case of the Future Dikes project, keeps the ecosystem healthy and resilient.

Nevertheless, according to Robroek, when it comes to peatlands, improving biodiversity in this way is of little use in terms of tackling drought. ‘The different mosses that we tested in our peat experiments do little to nothing to combat drought. That does not mean that biodiversity is not important for peat: it helps with carbon storage, for example. But in the battle against drought a different approach is needed.’

Politics

There are little things that consumers can do to protect peat. ‘Buy peat-free potting substrate and compost, for example’, cautions Robroek. ‘In the end, however, this is mainly a problem that will have to be solved at political level. In the past the buffer zones alongside rivers often consisted of peatland, but today much of this is grassland intended for agricultural use. These areas are constantly mowed and ploughed and therefore hardly retain any water. As a result, water from these floodplains drains more quickly into the rivers, causing flooding.’

‘Switching over to natural management methods costs time and money, but will have huge benefits in the future. Peatlands, even lowland peat areas, will then retain considerably more water and therefore offer much better protection. You could compare this to a sponge that gradually releases water back to the landscape. In such places peat is also the most effective option when it comes to storing carbon.’

“The simulator has a huge benefit as a research tool for those who study different heart valve conditions and interventions,” says senior author and biomedical engineer Ellen Roche of the Massachusetts Institute of Technology. “It can serve as a surgical training platform for clinicians, medical students, and trainees, allow device engineers to study their new designs, and even help patients better understand their own disease and potential treatments.”

Before new interventions reach humans, they undergo rigorous testing in heart simulators and animal subjects. However, current heart simulators don’t completely capture the complexity of a heart and have a short shelf-life of two to four hours. Animal studies are expensive and time consuming, and the findings may not always translate to humans. The biorobotic heart can bridge these gaps as a less expensive method with a shelf life of months.

The researchers focused on mitral regurgitation, a disorder in which the valve between the left heart chambers doesn’t close properly — resulting in a leaky heart valve where blood can flow backwards. This condition, affecting about 24.2 million people worldwide, can cause shortness of breath, swelling in the limbs, and heart failure. Given the intricacy of the valve’s structure, surgeries to correct the disorder are highly complex, highlighting a need for effective technology and precise surgical techniques.

To better understand the mitral valve in healthy and diseased states, the team built a biorobotic heart based on a pig heart. The researchers replaced the heart muscle in the left chamber with a silicone-made soft robotic pump system actuated by air. When inflated, the system twists and squeezes the heart like real heart muscle, pumping artificial blood through a mock circulation system and simulating the beat of a biological heart.

When the team damaged the mitral valve in the biorobotic heart, it showed characteristics of a leaky heart valve. The team then had cardiac surgeons correct the damage with three different techniques: anchoring the flailing valve leaflet tissue with artificial chords, replacing the valve with a prosthetic valve, and implanting a device to help valve leaflet closing.

All three procedures were successful, bringing the pressure, flow, and heart function to normal. The system also enabled the research team to collect real-time data during surgery and is compatible with current imaging technologies used in the clinics. Because the artificial blood used in the system is clear, it also allows direct visualization of the procedure. The findings demonstrated the device as a new heart model.

“It was really interesting for the surgeons to see every step,” says Roche. “When you’re working with patients, you can’t visualize the process because there’s blood in the heart.” She foresees their heart model as a realistic environment for cardiac surgery training and practice.

Next, the team aims to optimize the current biorobotic heart system by shortening the production time and lengthening the shelf life even more. Instead of using a pig heart, they’re also exploring 3D printing technology to recreate a synthetic human heart for the system.

“Our biorobotic heart may help improve the device design cycle, allow rapid iterations, get things approved by regulatory bodies, and launch them into the market quickly,” says Roche. “Expediting and improving these processes will ultimately benefit patients.”