Scientists at The Institute of Cancer Research, London, found that the drug could reinvigorate the response to chemotherapy in cancers that had become resistant, in both cells grown in the lab and in mice.

The drug, known as BOS172722, works by forcing cancer cells through cell division too quickly — leading to fatal errors in parcelling out DNA.

The first clinical trial of the new treatment is now under way in solid tumours including aggressive triple-negative breast cancers — and the researchers believe it might also be effective against other fast-growing cancers including ovarian cancer.

The new study is published in the journal Molecular Cancer Therapeutics and was funded by The Institute of Cancer Research (ICR) — a charity and research institute — as well as by Cancer Research UK, Breast Cancer Now and Sixth Element Capital LLP.

BOS172722 is an example of one of the new evolution-busting therapies that will be the focus of the ICR’s planned £75 million Centre for Cancer Drug Discovery.

The drug was discovered at the ICR in the Cancer Research UK Cancer Therapeutics Unit. It blocks a molecule called MPS1, which plays a central role in controlling cell division.

MPS1 is involved in organisation of chromosomes during cell division, ensuring they are distributed correctly between daughter cells and making sure that cell division doesn’t go ahead until they have been parcelled out evenly.

By blocking MPS1 using the new drugs, cancer cells speed through cell division with the wrong number of chromosomes and die as a consequence.

The ICR researchers found that cancer cells in dishes treated with the MPS1 inhibitor went through cell division in just 11 minutes, compared with 52 minutes without the drug.

And fast-dividing cells, from triple-negative breast cancers, ovarian and lung cancers, were especially sensitive to the effects of blocking MPS1.

Currently, people with triple-negative breast cancer receive taxane chemotherapies, such as paclitaxel, as their standard care. Paclitaxel also affects the distribution of chromosomes during cell division but blocks the cell from dividing, which causes the cell to die. However, some cells escape becoming resistant to the drug and giving rise to more tumours.

Treatment with paclitaxel in combination with BOS172722 dramatically reduced time in cell division — from 110 minutes with paclitaxel alone to 15 minutes when combined with BOS172722. All cells treated with the combination divided with gross chromosomal abnormalities and died as a result, whereas 40 per cent remained alive with paclitaxel alone.

The MPS1 inhibitor was also effective at lower doses when used in combination with paclitaxel in mice, and was well tolerated by mice at the doses that almost completely eliminated the tumours.

Professor Spiros Linardopoulos, Professor of Cancer Biology and Therapeutics at The Institute of Cancer Research, London, who led the study, said:

“We have discovered a brand new type of cancer treatment that uses cancer’s rapid growth against it, by forcing cells through cell division so quickly that they accumulate fatal errors. The drug works especially well in combination with chemotherapy in triple negative breast cancer cells — the deadliest form of breast cancer for which there are few successful treatments.

“Crucially, the combination is anticipated to be effective in cancer patients that have already become resistant to chemotherapy alone and has the potential to become a much-needed extra treatment option that could extend the lives of patients.

“The phase I trial of this combination is currently well under way and I look forward to the results.”

Professor Rajesh Chopra, Director of Cancer Therapeutics in the new Centre for Cancer Drug Discovery, said:

“Cancer’s ability to evolve and become drug resistant is the cause of the vast majority of deaths from the disease. We plan to counter that ability with the world’s first ‘Darwinian’ drug discovery programme within our Centre for Cancer Drug Discovery, dedicated to creating a new generation of anti-evolution treatments.

“Our new MPS1 inhibitor is a great example of a drug that seeks to outsmart cancer by blocking off a key evolutionary escape route, and in doing so we believe it can breathe new life into a chemotherapy that had ceased to be effective.”

Baroness Delyth Morgan, Chief Executive at Breast Cancer Now, which helped to fund the study, said:

“It’s really promising that combining this newly-discovered drug with a standard chemotherapy could, in future, provide a new way to treat triple negative breast cancer and may even prevent the disease from becoming resistant to treatment.

“With triple negative breast cancer still lacking in targeted treatments, we urgently need to find new options to stop more women dying. This exciting study shows how well these drugs complement each other at a molecular level to destroy cancer cells.

“We now look forward to the results of clinical trials to understand whether this approach may be as effective and safe in humans. In the meantime, anyone with questions about their breast cancer treatment can call our free Helpline on 0808 800 6000 to speak to one of our expert nurses.”

Note

Triple negative breast cancers are so-called because they have different biology to other types of breast cancer, lacking key treatment targets present in those fed by the hormones oestrogen (ER+) or progesterone (PR+), or that are driven by human epidermal growth factor receptor 2 (HER2+).

In “Potentially Preventable Intensive Care Unit Admissions in the United States, 2006 — 2015,” lead author Gary E. Weissman, MD, MSHP, a researcher at the Palliative and Advanced Illness Research Center at the University of Pennsylvania in Philadelphia, and co-authors analyzed more than 16 million ICU admissions and estimated that between one in six and one in seven such admissions might have been avoided.

“This study was motivated by my experiences caring for patients in the medical ICU who required maximal life support because, a few weeks or months before, they couldn’t afford basic preventive medical services,” Dr. Weissman said.

The researchers analyzed three large data sources from 2006-15: Medicare Fee-for-Service, a Medicare Advantage plan and a large private national insurer. Altogether, the data sources represented nearly two-thirds of U.S. adults age 65 and older and about 13 percent of the entire U.S. population. During this time period, there were nearly 100 million hospital admissions, of which 16.7 percent included an ICU admission.

The authors acknowledge in the article that there is no “gold standard” definition of a preventable ICU admission. For their analysis, they identified two patient groups whose care could potentially be handled better outside the ICU: those with an “ambulatory care sensitive condition” and those with a “life-limiting malignancy” who are nearing the end of their life.

Those in the first group have a chronic or medical condition such as high blood pressure, urinary tract infection or uncontrolled diabetes that with timely outpatient care can prevent the patient from being hospitalized.

Those in the second group are patients with cancer who are likely to die within a year and for whom palliative care may be appropriate. Although the authors only looked at life-limiting malignancy, they noted that ICU admissions may be preventable for other serious illnesses, including chronic lung disease, heart failure and neurodegenerative disorders.

The study also found:

• Over the 10-year time period, ICU hospitalizations for ambulatory care sensitive conditions have been slowly decreasing while the proportion of those in the ICU with a life-limiting malignancy has been increasing.
• There were wide regional differences in ICU admissions and an almost eight-fold difference among states in the rates of ICU admissions.
• The rate of ICU admissions in different geographic areas among these two patient groups appears to be explained partly by the number of ICU beds available.

The authors said these findings may suggest a strategy for the expected increase in ICU services as the U.S. population ages. “A substantial portion of ICU admissions in the U.S. may be prevented,” they wrote. “Investing in outpatient, preventive and palliative services should therefore be viewed as an important complementary, if not alternative, strategy to increasing the critical care workforce in seeking to provide the best care for the nation’s sickest patients.”

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A key resource to advance research in quantum information science would be a source that could efficiently and reliably produce single photons. However, because quantum processes are inherently random, creating a photon source that produces single photons on demand presents a challenge at every step.

Now University of Illinois Physics Professor Paul Kwiat and his former postdoctoral researcher Fumihiro Kaneda (now an assistant professor at Frontier Research Institute for Interdisciplinary Sciences at Tohoku University) have built what Kwiat believes is “the world’s most efficient single-photon source.” And they are still improving it. With planned upgrades, the apparatus could generate upwards of 30 photons at unprecedented efficiencies. Sources of that caliber are precisely what’s needed for optical quantum information applications.

The researchers’ current findings were published online in Science Advances on October 4, 2019.

Kwiat explains, “A photon is the smallest unit of light: Einstein’s introduction of this concept in 1905 marked the dawn of quantum mechanics. Today, the photon is a proposed resource in quantum computation and communication — its unique properties make it an excellent candidate to serve as a quantum bit, or qubit.”

“Photons move quickly — perfect for long-distance transmission of quantum states — and exhibit quantum phenomena at the ordinary temperature of our everyday life,” adds Kaneda. “Other promising candidates for qubits, such as trapped ions and superconducting currents, are only stable in isolated and extremely cold conditions. So the development of on-demand single-photon sources is critical to realizing quantum networks and might enable small room-temperature quantum processors.”

To date, the maximum generation efficiency of useful heralded single photons has been quite low.

Why? Quantum optics researchers often use a nonlinear optical effect called spontaneous parametric down-conversion (SPDC) to produce photon pairs. In a designed crystal, within a laser pulse containing billions of photons, a single high-energy photon can be split into a pair of low-energy photons. It’s critical to produce a photon pair: one of the two gets detected — which destroys it — to “herald” the existence of the other, the single-photon output of the photon source.

But making that quantum conversion from one into two photons happen is against all odds.

“SPDC is a quantum process, and it’s uncertain whether the source will produce nothing, or one pair, or two pairs,” Kwiat notes. “The probability of producing exactly one pair of single photons is at most 25 percent.”

Physics Professor Fumihiro Kaneda of the Frontier Research Institute for Interdisciplinary Sciences at Tohoku University. Kaneda is a former postdoctoral researcher in the Kwiat group at the Department of Physics, University of Illinois at Urbana-Champaign.

Kwiat and Kaneda solved this low-efficiency problem in SPDC using a technique called time multiplexing. For each run, the SPDC source is pulsed 40 times in equal intervals, producing 40 “time bins,” each possibly containing a pair of photons (although that would rarely be the case). Each time a photon pair is produced, one photon of the pair triggers an optical switch, which routes the sister photon into temporary storage in an optical delay line — a closed loop created with mirrors. By knowing when the photon entered the loop (when the trigger photon was detected), the researchers know exactly how many cycles to hold the photon before they switch it out. In this way, no matter which of the 40 pulses produced the pair, the stored photon can always be released at the same time. Once all 40 pulses have occurred, any stored photons are released together, as though they came from the same time bin.

Kwiat comments, “Mapping a bunch of different possibilities, all the different time bins, to one — it greatly improves the likelihood that you’re able to see something.”

Pulsing the source 40 times essentially guarantees that at least one photon pair is produced for each run.

What’s more, the delay line that the photons are stored in has a loss rate of only 1.2 percent per cycle; because the source is being pulsed so many times, having a low loss rate is crucial. Otherwise, photons produced in the first few pulses could easily be lost.

When the photons are finally released, they are coupled into a single-mode optical fiber at a high efficiency. This is the state that the photons need to be in to be useful in quantum information applications.

Kwiat points out, the efficiency increase from generating photons in this manner is significant. If, for example, an application called for a 12-photon source, one could line up six independent SPDC sources and wait for an event when each of them simultaneously produced a single pair.

“The world’s best competing experiment at the moment using these multiple photon states had to wait something like two minutes until they got a single such event,” Kwiat notes. “They’re pulsing at 80-million times a second — they’re trying very, very often — but it’s only about once every two minutes that they get this event where each source produces exactly one photon pair.

“We can calculate based on our rate the likelihood that we’d be able to produce something like that. We’re actually driving quite a bit slower, so we’re only making the attempt every 2 microseconds — they’re trying it 160 times as often — but because our efficiency is so much higher using multiplexing, we’d actually be able to produce something like 4,000 12-photon events per second.”

In other words, Kwiat and Kaneda’s production rate is about 500,000 times faster.

However, as Kwiat notes, a few problems remain to be solved. One issue stems from the random nature of the down-conversion process: there’s a chance that instead of a single photon pair, multiple photon pairs could be produced. Furthermore, because the down-conversion process used in this experiment was relatively inefficient, the source was “driven” at a higher rate, increasing the probability that such unwanted multiple pairs would be generated.

Even accounting for potential multi-photon events, the efficiency level of this experiment was a world record.

So what’s next, and how will the Kwiat team address these rare unwanted multiphoton events?

Colin Lualdi, a current graduate student working in Kwiat’s research group, is working on upgrading the source with photon-number-resolving detectors that would discard multiphoton events before the delay line is triggered to store them. This improvement would eliminate the issue of multiphoton events altogether.

Another area of ongoing research for Kwiat’s team will improve the efficiency of individual parts of the single-photon-source apparatus. Lualdi believes future improvements will push the rate of single-photon production far beyond the current experiment.

“The eventual goal is to be able to prepare single pure quantum states that we can use to encode and process information in ways that surpass classical approaches,” Lualdi explains. “That’s why it’s so imperative that these sources produce single photons. If the source unexpectedly generates two photons instead of one, then we don’t have the basic building block that we need.”

And in order to be able to perform any kind of meaningful quantum information processing with these photonic qubits, a large supply is needed.

As Kwiat puts it, “The field is moving beyond experiments with just one or two photons. People are now trying to do experiments on 10 to 12 photons, and eventually we’d like to have 50 to 100 photons.”

Kwiat extrapolates that the improvements being made on this work could pave the way toward the capacity to generate over 30 photons at high efficiencies. Kwiat and Kaneda’s results have moved us one step closer to making optical quantum information processing a reality.

Their new study, published in Progress in Biophysics and Molecular Biology on September 13, 2019, provides a foundation for quantitatively determining how differences in viewing angles affect the resulting 3D structures of proteins, and could help other researchers determine the best setup for experiments to improve the imaging technique called cryo-EM.

“This provides a quantitative understanding for why variations in viewing angles affect the quality of resulting 3D structures of proteins, and where we could do better to improve the data,” says Dmitry Lyumkis, a Salk assistant professor of genetics and coauthor of the new work. “These kinds of theoretical frameworks are important to understanding precisely how information is attenuated due to imperfections associated with the imaging experiment, which will lead us to eventually get better structures out of cryo-EM data.”

In cryo-EM, or cryogenic electron microscopy, proteins are rapidly frozen in their natural form before being bombarded with electrons. By detecting how the electrons scatter when they hit the sample, researchers can determine the molecular structure of the protein or protein complex. Compared to other imaging methods, it’s easier for scientists to prepare proteins for cryo-EM, and the technique can potentially address a broader set of questions in structural biology. However, a long-standing problem in cryo-EM is that proteins tend to stick to the top or bottom of the sample grid that they’re prepared on. These select orientations mean that researchers can’t always see a protein’s structure from every angle. Tilting the sample, Lyumkis and his colleagues found in 2017, helped solve this problem.

“We knew that qualitatively, tilting improved the data in some cases,” says Lyumkis. “What we didn’t know was exactly the extent to which the structures can be affected by variations in the viewing angle.”

Recently, Philip Baldwin, a senior staff researcher at Salk and the paper’s coauthor, was examining a set of cryo-EM data collected at different viewing angles when he noticed that such variations affected the overall resolution of the resulting protein structure. After some calculations, he realized that the association between the viewing angle and resolution was generalizable to all cryo-EM experiments.

The new formula lets researchers calculate, for any protein at any tilt angle, a number called the sampling compensation factor, or SCF. The closer the SCF value is to 1, the more complete the protein’s structure. If the SCF is 0.5 instead of 1, either the data is incomplete, or researchers must collect data for twice as long to get the same structural resolution. By calculating SCF values ahead of an experiment, scientists can optimize their tilt angle and data collection time.

The new quantitative formulations also helped Lyumkis and Baldwin compute just how incomplete some cryo-EM datasets are. Previously, they might have had to eyeball a set of data and guess whether it was a good or bad approximation of a protein’s structure. Now, the SCF can tell them that numerically.

“It’s very handy,” says Baldwin. “Basically, this formula tells you if you have very bad regions of the protein from which you didn’t collect data.”

Lyumkis and Baldwin hope that using the formula to assess cryo-EM results — which involves a simple calculation or piece of code — will become standard and help guide experiments and new approaches to cryo-EM. This would lead to faster discoveries in basic biological sciences and in drug development.

The work reflects a growing trend at both the Salk Institute and elsewhere toward integrating computational approaches into biology research.

Lyumkis and Baldwin were supported by grants from the National Institutes of Health.

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Typical measurements include the hue (what we typically think of as the “color”), saturation (the intensity of the color, a function of how much gray is mixed in with it, also called “chroma”) and brightness (how much white or black is mixed in with the color). The differences among individuals may be subtle and require precise measurement. The ultimate goal for behavioral ecology studies is usually to examine the relationship between behavior and the colors as other fish see them. However, anesthetics may themselves alter coloration, influencing the very traits the researchers are trying to study.

Males of the livebearing tropical fish Girardinus metallicus are very aggressive when competing for mates. These males have yellow bodies, and males whose yellow is brighter and more saturated are more aggressive. A paper published in The Journal of Fish Biology shows that the commonly used fish anesthetics clove oil and tricaine methanesulfonate (MS222) affect color measurements obtained from digital images.

The researchers photographed the fish individually in a water-filled chamber without anesthetics, anesthetized with clove oil, and anesthetized with MS22 (in randomized order) and measured the hue, saturation and brightness of multiple body regions from digital images measured using computer software. They demonstrated that the anesthetics altered the hue (though it was always within the yellow range), increased the saturation and decreased the brightness of multiple body regions.

The alteration was likely due to rapid “physiological” color change, caused by the movement of structures called melanosomes inside melanin pigment-producing cells. When melanosomes disperse, the area appears dark, and when melanosomes aggregate, the area appears light. The anesthetics may have caused dispersion of melanosomes and consequent darkening of the yellow body regions.

The results that the authors report could be important for multiple disciplines, including behavioral studies with the goals of linking coloration to behavioral variation and comparing groups of fishes to understand the impacts of coloration on evolutionary fitness, studies aimed at understanding the physiological impacts of investment into color traits, and aquaculture studies attempting to characterize the quality of stocks based on coloration traits.

The authors suggest caution when using anesthetics to immobilize fish for certain color measurements. Instead, they advocate a method already employed by some researchers: photographing these types of fish in a small, water-filled chamber under controlled light conditions and with color standards to minimize movement while obtaining results more indicative of the color likely to be seen by other fish in the wild.

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