Culture

First patient trial of new drug class shows half of cancers stop growing

Drug works by stopping cancers repairing DNA damage

Early results suggest it is particularly effective alongside chemotherapy

A new precision medicine targeting cancer's ability to repair its DNA has shown promising results in the first clinical trial of the drug class.

The new study, designed to test the drug's safety, found that half of patients given the new drug either alone or with platinum chemotherapy saw their cancer stop growing, and two patients saw their tumours shrink or disappear completely.

Damage to the DNA in cells is the root cause of cancer - but it is also a fundamental weakness in tumours, and cancer cells can be killed by further damaging their DNA or attacking their ability to repair it.

The new phase I trial tested the first in a new family of drugs blocking a key DNA repair protein called ATR. Phase I trials are designed to assess the safety of new treatments, and it's unusual to see a clinical response at this stage.

A team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, led a trial of the benefit of an ATR inhibitor called berzosertib either on its own or with chemotherapy in 40 patients with very advanced tumours, treated in hospitals around the world.

The researchers established the doses at which the drug was safe for use in further clinical trials, and found berzosertib on its own caused only mild side effects.

Surprisingly for a phase I trial, the researchers also found that berzosertib stopped tumours growing in over half of patients given the drug either on its own or with chemotherapy - 20 out of 38 patients whose treatment response could be measured.

The drug's benefit in blocking DNA repair was even more marked in patients also given chemotherapy, which works by causing DNA damage. In these patients, 15 of 21, or 71 per cent saw their disease stabilise - suggesting that chemotherapy boosted sensitivity to berzosertib.

One patient with advanced bowel cancer whose tumour contained faults in key DNA repair genes including CHEK1 and ARID1A responded remarkably well to berzosertib on its own, seeing his tumours disappear and staying cancer free for more than two years.

Another woman with advanced ovarian cancer whose disease had come back after treatment with a drug blocking PARP, another key DNA repair protein, received the combination treatment and saw her tumours shrink.

This patient's response suggests that berzosertib could be explored as a strategy to overcome resistance to the PARP inhibitor family of targeted treatments.

The drug is now moving forward in further trials, and the hope is that it could be developed into a new targeted treatment for patients, and help overcome resistance to other precision medicines such as PARP inhibitors that target DNA repair.

The new results are published in the Journal of Clinical Oncology today (Monday), and the trial was funded by Merck KGaA, Darmstadt, Germany, the manufacturer of the drug.

Drug resistance - as cancers evolve in response to treatment - is one of the biggest challenges facing cancer research and treatment today. The Institute of Cancer Research (ICR), a charity and research institute, will be focusing on how to overcome cancer evolution and drug resistance in its new Centre for Cancer Drug Discovery, for which it still needs to raise the final £2 million.

The ICR discovered how to genetically target the first approved precision medicine attacking cancer's ability to repair DNA, the PARP inhibitor olaparib.

Professor Johann de Bono, Head of Drug Development at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, said:

"Our new clinical trial is the first to test the safety of a brand new family of targeted cancer drugs in people, and it's encouraging to see some clinical responses even in at this early stage. Now, we and others are planning further clinical trials of berzosertib and other drugs blocking the ATR protein.

"In future, this new class of ATR inhibiting drugs could boost the effect of treatments like chemotherapy that target cancer DNA, expand our range of treatment options and overcome resistance to other targeted treatments.

Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:

"Targeting a cancer's ability to repair its DNA is a fundamentally important avenue of cancer research which has delivered some of the most important advances against the disease in recent years.

"It's exciting to see the first clinical trial of a drug targeting a key player in the DNA repair process have such promising results, and I look forward to the results of further studies testing the benefit of this new family of targeted treatments.

"I'm keen to explore the potential for these ATR inhibitors to overcome resistance to other targeted drugs and to form effective treatment combinations. That's exactly the kind of approach we will be taking in our new Centre for Cancer Drug Discovery as we look to block off cancer's escape routes by creating a new generation of anti-evolution treatments."

A group of researchers from the University of Helsinki used novel and powerful methods to disentangle the patterns of parallel evolution of freshwater three-spined sticklebacks at different geographic scales across their distribution range. The group concludes that the conditions under which striking genome-wide patterns of genetic parallelism can occur may in fact be far from common - perhaps even exceptional.

The three-spined stickleback (Gasterosteus aculeatus), a thumb-sized fish distributed across the Northern hemisphere, is a textbook model species in evolutionary biology. With the retreat of ice sheets since the last glacial maximum, ancestral marine populations have repeatedly colonised newly formed freshwater habitats. Across their distribution range, sticklebacks in these novel freshwater environments exhibit remarkable similarities in their morphology, physiology and behaviour, a phenomenon known as "parallel evolution".

"What is really remarkable in our results is that the repeatability of evolution in response to similar selection pressures in different oceans can be so different," says group leader Juha Merilä, Professor at the Faculty of Biological and Environmental Sciences, University of Helsinki.

The genetic underpinnings of such parallel evolution have fascinated scientists for years, and they have discovered that the observed marine-freshwater differentiation is underlain by surprisingly parallel changes also at the genetic level. However, most studies on this topic have been based on either limited geographic sampling or focused only on populations in the Eastern Pacific region.

"As scientists, we are often tempted to provide simple narratives to extremely complex problems. What I liked the most about this project is that we did the exact opposite: we show that the story behind the three-spined stickleback's spectacularly fast adaptation to novel habitats may be more complex than previously thought. I think that deciphering the role of demographic history in shaping evolutionary adaptation is a necessary step in solving the mystery," says co-author Paolo Momigliano, postdoctoral researcher at the Faculty of Biological and Environmental Sciences, University of Helsinki.

Genetic parallelism 10 times higher in the Eastern pacific

With novel and powerful methods, a group of researchers from the University of Helsinki disentangled patterns of parallel evolution of freshwater three-spined sticklebacks at different geographic scales across their distribution range. They found that the extraordinary level of genetic parallelism observed in the Eastern Pacific region is not observed in the rest of the species' range. In fact, they found approximately 10-fold higher levels of genetic parallelism in the Eastern Pacific compared to the rest of the world.

"I have been studying the worldwide population histories of the species in my PhD. We found their ancestral populations are residing in the Eastern Pacific. We predicted that the region harbours the source of ancestral genetic variations for parallel evolution, and such genetic variation could be lost during colonisation to the rest of the world, for instance in the Atlantic. These predictions were tested by both empirical and simulated data," explains first author Bohao Fang, PhD candidate from the Faculty of Biological and Environmental Sciences, University of Helsinki.

What happens in the Eastern Pacific, stays in the Eastern Pacific

Their simulations showed that this difference in the degree of parallelism likely depends on the loss of standing genetic variation - the raw material upon which selection acts - during the colonisation of the Western Pacific and Atlantic Oceans from the Eastern Pacific Ocean.

This discrepancy could have been further accentuated by periods of strong isolation and secondary contact between marine and freshwater habitats in the Eastern Pacific, consistent with the group's results and the geological history of the area. This secondary contact likely happened after the colonisation of the Atlantic Basin, resulting in much more genetic variation available for local adaptation in the Eastern Pacific - variation that never had the chance to spread to the Atlantic. In other words, the discrepancy in genetic patterns of parallel evolution between the two oceans is a result of the complex demographic history of the species, which involved range expansions and demographic bottlenecks.

"Our less assumption-burdened methods have been a key to quantifying parallel evolution at different geographic scales for the type of data that was available for this study. I thoroughly enjoy developing novel methods to study adaptation and evolution, and the idea that parallel evolution might be exceptional in the Eastern Pacific compared to the rest of the world has intrigued me for a long time. It was a lucky coincidence that I became a part of the Ecological Genetics Research Unit led by Juha Merilä where the samples to finally test this hypothesis became available," concludes Petri Kemppainen, co-first author, method developer, and postdoctoral researcher at the Faculty of Biological and Environmental Sciences, University of Helsinki.

A metal organic framework (MOF)-based water splitting photocatalyst, developed at KAUST, has brought researchers a step closer to generating clean hydrogen fuel using sunlight.

"Using solar energy to efficiently make green fuels is the ultimate goal for many catalysis researchers," says Jorge Gascon, director of the KAUST Catalysis Center, who led the research. However, it remains challenging to find efficient, long-lived, low-cost water-splitting photocatalysts.

In Gascon's team, the aim is to use MOFs to find sustainable photocatalytic water splitting materials. "We work with MOFs because they are like a LEGO construction toy--you have different parts with which you can play and vary to get desired properties," says Nikita Kolobov, a member of Gascon's team.

MOFs consist of metal ions connected by carbon-based organic linkers in a highly regular and repeating two- or three-dimensional array. By varying the metal and the organic component, a diverse family of materials can be made. "This modularity makes MOFs an excellent platform for developing a fundamental understanding of photocatalytic processes," Gascon says. "We can evaluate new concepts in photocatalysis that may be difficult or impossible to develop and evaluate using other classes of materials."

For their latest work, Gascon, Kolobov, Amandine Cadiau and their colleagues created a MOF that used titanium metal ions with H4TBAPy, an organic linker known to absorb energy from a broad spectrum of sunlight. By combining H4TBAPy with titanium, the team aimed to create a material that could efficiently put that energy to use.

The titanium in the light-activated MOF had the ideal energy levels for the hydrogen production part of photocatalytic water splitting, the team showed. "The organic part of the MOF acted as an antenna that collected light and transmitted that energy to the metal node, which activated it to perform catalytic transformations," Kolobov says.

"Although the new MOF's hydrogen evolution reaction activity was modest compared to some inorganic semiconductors, its performance is already among the best titanium-based MOF materials," Kolobov says. "MOFs are still in their infancy when it comes to photocatalytic applications," he adds. "We believe the modular approach toward their construction offers unlimited possibilities for performance improvement, and we are taking the first steps in this direction."

"Every step to better understand how catalysts work under light illumination is important," Gascon says. "Our main objective at this moment is to come up with new MOF structures able to efficiently perform overall water splitting."

The lockdown measures introduced in Italy to deal with COVID-19 have produced a mobility contraction which is not homogeneously distributed across Italian municipalities and regions. An examination of the steep fall on the Italian mobility network during the pandemic reveals some counterintuitive results, calling for further analysis.

Indeed, a counterintuitive and somehow paradoxical result emerges, since the contraction of mobility, in relative terms, has been more intense in the Regions where the diffusion of the virus has been negligible. Moreover, the shrinking of mobility flows has been more intense where the average income per capita is lower and inequality in the distribution of income is higher.

This is one of the key findings of the paper published in the Proceedings of the National Academy of Sciences by the research group (Giovanni Bonaccorsi, Andrea Flori, Francesco Pierri) coordinated by professor Fabio Pammolli at Impact, School of Management, Politecnico di Milano and CADS, joint center of Politecnico di Milano and Human Technopole, in collaboration with the research team of Walter Quattrociocchi (Università di Venezia) and Antonio Scala (CNR).

The study analyzed a large-scale data set of anonymized near-real-time mobility data from the Facebook Data for Good Program, for over 3m Italian citizens. Data was collected before and after the lockdown introduced by the Italian Government.

The researchers observed a sharp reduction in the movements of individuals, with an average reduction in mobility of 70%.

However, even though mobility restrictions were designed and implemented for the whole Italian territory, their distribution across geographical areas reveals substantial differences. In particular, somehow paradoxically, those Regions which have been more affected by the contagion in the North-East of Italy have experienced a reduction of mobility flows that is less pronounced in relative terms. In particular, in municipalities in Lombardy and Veneto, the two regions which have been hit mostly by COVID-19, the contraction in mobility flows has been 5% to 15% lower than the national average. On the contrary, southern and poorer Regions in the South of Italy like Abruzzo and Calabria, which have been scarcely affected by the virus, show a contraction in mobility which has been 16% to 20% higher than the national average.

To get some insights into these findings, the research team led by Professor Pammolli reconstructed the economic and social features of the affected Italian municipalities, i.e., income per capita, fiscal capacity, deprivation, urban density, and inequality in the distribution of income.

The sudden stop triggered by the COVID-19 outbreak has been treated analogously to a large-scale, extreme, natural disaster. Through a quantile regression technique, the researchers have found that those municipalities which have been mostly affected by the lockdown are the ones where income per capita is lower and inequality is higher. Municipalities where income per capita is below the national average (€18.175) have experienced a contraction in mobility which, on average, is 10% higher than the national average reduction.

The study sheds light on some unanticipated consequences of lockdown interventions, revealing how mobility disruption could have induced an increase in socio-economic segregation, damaging mostly the poor and the fragile.

As one of the first epicenters of this disease, China has announced the most efficient prevention measures to slow down the spread of the COVID-19 lockdown by restricting the movement of populations nationwide after the Chinese New Year 2020, which caused tremendous economic losses and also a substantial reduction in emission of air pollutant from vehicles and factories. Surprisingly, despite such large decreases in primary pollution, air quality in China was not as clean as expected. Heavy multi-day haze pollution still covered the northern and eastern China for several times, raising questions about the well-established relationship between human activities and air quality and even China's efforts on air pollution control that have been extensively implemented in the past few years.

Focusing on this air pollution issue concerned by the public and policymakers, the study, published in the journal National Science Review (18th June), reveals that a sharp emission reduction in transportation caused more secondary formation of particle by enhanced atmospheric oxidizing capacity in the eastern China, which offset the effort of primary emission reduction.

This study integrated multiple observational datasets, including ambient air quality monitoring network, chemical composition measurements, and satellite retrievals, together with up-to-date emission estimation and dozens of numerical simulation experiments, to comprehensively analyze the non-linear response of air pollution to emission reduction during the COVID-19 lockdown.

Dynamic economic and industrial statistics in the first two months of 2020 were collected to estimate emission reduction due to COVID-19 lockdown. The thermal power generation in January to February was 8.9% lower than that in 2019, while cement production in the first two month was 29.5% lower than that in 2019. Comparatively, on-road transportation has fallen off a cliff during the lockdown, with a decline in national traffic volume of 70%.

Such a large drop of anthropogenic emission led to substantially decreased primary pollution in the atmosphere, particularly nitric oxide (NOx) emitted from vehicles. The nonlinear response of ozone, one important atmospheric oxidant, to NOx increased the atmospheric oxidizing capacity and subsequently accelerated the chemical production of secondary particle. Under unfavorable meteorological conditions, faster oxidation offset the emission reduction and thus gave rise to still-severe haze pollution in the eastern China. Findings also reveal that a synchronous control of volatile organic compounds (VOCs) can serve as an effective way to overcome deteriorating haze pollution with NOx reduction.

The study shows direct and consistent "observational" and modeling evidences on the non-linear relationship of emission reduction and secondary haze pollution in the real world. The unique natural experiment of dramatic emission reduction during China's COVID-19 lockdown indicated that the arbitrary reductions in NOx and other air pollutant emissions led to substantial increases in ozone, which in turn increased atmospheric oxidizing capacity and enhanced formation of secondary particles. In China, winter haze and summer ozone pollution are the two major air quality challenges, but with different and separated control policies. Emissions regulation imposed since 2013 have successfully reduced haze pollution in eastern China, while the study suggests that the benefit of proposed further reductions in primary emissions might be offset by enhanced secondary formation of particle. A non-linear tipping-point of NOx chemistry may bring about more challenge to China's haze mitigation than anticipated. Only with coordinated and collaborative control on various primary emissions can China achieve long-term haze mitigation.

An innovative use of focused ultrasound being pioneered at the University of Virginia School of Medicine is showing promise against glioblastoma, the deadliest brain tumor, and could prove useful against other difficult-to-treat cancers.

The technique hits cancer cells with a drug that sensitizes them to sound waves, then blasts them with focused ultrasound. The sound waves create tiny bubbles inside the cancer cells, causing them to die.

The work is early, with researchers testing the concept on cell samples in lab dishes. But their results suggest the technique has "substantial potential for treatment of malignant brain tumors and other challenging oncology indications," such as lung cancer, breast cancer and melanoma, the researchers report in a new scientific paper. They predict the technique will be particularly useful in treating cancers in sensitive parts of the body that are difficult to access.

"Sonodynamic therapy with focused ultrasound offers a new therapeutic approach to treating patients with malignant brain tumors," said UVA Health neurosurgeon Jason Sheehan, MD, PhD. "This approach combines two approved options, [the drug] 5-ALA and focused ultrasound, to produce a powerful tumoricidal effect on several different types of glioblastomas."

Aggressive Glioblastoma

Glioblastomas are the most common malignant brain tumors in adults. They are inevitably fatal, typically within 12 to 18 months of diagnosis. The shortage of effective treatments for this aggressive cancer means new approaches are needed desperately.

To evaluate the potential of their new focused ultrasound technique, the UVA researchers looked at its effects on both rat and human cell samples. They examined the benefits of the "sonosensitizing" drug, 5-ALA, and focused ultrasound individually and in combination, and they found that the pairing was far more effective than either alone. The drug reduced the number of viable cancer cells by 5%, while focused ultrasound reduced it by 16%. Together, the reduction was 47%.

"Focused ultrasound has the potential to improve outcomes for patients with complex brain tumors and other neurosurgical pathologies," Sheehan said. "We may be at the tip of the iceberg in terms of intracranial indications for focused ultrasound."

Busting Cancer With Bubbles

Many applications of focused ultrasound rely on the technology's ability to create tiny points of heat inside the body to burn away harmful cells, or to damage cells enough to provoke an immune response. Sheehan's approach is notable in that it takes another tack, destroying cancer cells without generating heat.

To test out the new technique, the researchers had to develop custom equipment so they could perform the focused ultrasound research on the cell samples. They did this from scratch, using a 3D printer and software at the Charlottesville-based Focused Ultrasound Foundation, a longtime supporter of focused ultrasound research at UVA and elsewhere.

The researchers say the new platform will advance focused ultrasound research in the future. Using it, scientists can quickly screen cell types and sonosensitizing drugs like the one used in UVA's study. It will also be a benefit in pre-clinical and clinical testing in people, they say.

Pioneering Focused Ultrasound

While the sonosensitizing research is in its earliest phases, Sheehan is launching a separate glioblastoma clinical trial in people using a different focused ultrasound approach. That study will evaluate the technology's potential to open the brain's protective barrier briefly so that doctors can deliver treatments to the tumor that they normally can't.

Sheehan's research is part of a broad effort at UVA to explore the potential of focused ultrasound to treat various types of diseases. For example, UVA researchers are examining the technology's ability to treat breast cancer and epilepsy.

Pioneering research by UVA neurosurgeon Jeff Elias, MD, already paved the way for the federal Food and Drug Administration to approve focused ultrasound to treat essential tremor, a common movement disorder, and tremor caused by Parkinson's disease. Focused ultrasound treatment for those conditions is now available to appropriate patients. Learn more about focused ultrasound at UVA.

Glioblastoma Results Published

Sheehan and his colleagues have published their initial glioblastoma results in the Journal of Neuro-Oncology. The research team consisted of Kimball Sheehan, Darrah Sheehan, Mohanad Sulaiman, Frederic Padilla, David Moore, Sheehan and Zhiyuan Xu. Padilla and Moore are employed by the Focused Ultrasound Foundation.

By softening a cell's nucleus so that it can squeeze its way through dense connective tissues, a group of researchers believe they've demonstrated a new way to help the body efficiently repair injuries. The team of researchers from the University of Pennsylvania tested this theory by using a medication to inhibit enzymes in the nucleus of knee's meniscus cells, which allowed the cells to move through environments that were previously impenetrable. This study was published in Science Advances.

The study focuses on cells in the meniscus, which is a thin layer of dense connective tissue in the human knee. However, the approach could prove effective beyond that specific area.

"In this case, we studied how meniscus cell nuclei can be softened to promote their migration through meniscus tissues. We have also shown similar enhancement of cell migration in other types of connective tissues, such as tendons or the cartilage covering the ends of bones," said the study's first author, Su Chin Heo, PhD, an assistant professor of research of Orthopaedic Surgery, who works within the McKay Orthopaedic Research Lab.

The paper's corresponding author, Robert L Mauck, PhD, the Mary Black Ralston Professor of Orthopaedic Surgery and director of the McKay Lab, noted that "this finding may pave the way for new therapeutics to improve endogenous repair of a number of dense connective tissues that have poor natural healing capacity and are prone to failure."

After an injury, the body requires cells to move into the afflicted area and deposit new tissues so that the tissue can be repaired, like a truck delivering cement to a construction site. Allowing cells to move more freely into these areas could make healing quicker and/or more efficient. However, the team believed that stiff nuclei were the limiting factor, especially when it came to dense tissue such as the meniscus in the knee. Moving through this type of tissue could rupture or otherwise damage a repair cell's nucleus as it tried to squeeze through the tight spaces between cells. As such, damage to tissue like the meniscus could heal poorly, if at all, and result in frequent reinjury.

To remedy that, the team of researchers applied an inhibitor drug to cells called trichostatin A (TCA) that makes the proteins within their nuclei soften up, allowing for the nucleus as a whole to become more malleable. In the truck analogy, this would be like switching from a rigid truck trailer to one with a canvas cover so that it could access a job site at the end of a road with low-hanging trees. The cover could bend as it made its way through the branches but not get hung up or damaged like a boxy, metal trailer would.

In the study, the teams saw that isolated meniscus cells that had been treated with TCA were able to move through areas that were once thought to be impassible to reach defects in tissue. This is important becomes some of the repair methods used for injuries involve fibrous scaffolding, which can also be dense and impenetrable. These areas, too, could be infiltrated with the repair cells whose nuclei were softened, the study showed.

Moving forward, the researchers are preparing to conduct trials of this technique in meniscus tears in large animals. There is also a possibility that this work has applicability beyond just musculoskeletal injuries.

"This isn't something we've tested yet, but this approach could potentially be used to enhance the wound healing process of other types of tissues, such as in the skin," Mauck said.

In this articale, we have described a new practical cyclocondensation synthesis for a series of [1,2,4]triazolo[4,3-c]pyrido[3,2-e] pyrimidine and pyrido[2',3':4,5] pyrimido[6,1-c][1,2,4] triazine from 2-amino-3-cyano-4.6-diarylpyridines. Also polyheterocyclic compounds containing [1,2,4]triazolo and [1,2,3,4]tetrazolo moieties were also synthesized through the reactions of 3-hydrazino-8,10-diaryl [1,2,4]triazolo[4,3-c]pyrido[3,2-e]pyrimidine with both formic acid and the formation of diazonuim salt respectively . Newly synthesized heterocycles structures were confirmed using elemental analysis, IR, 1H-NMR, 13C-NMR and mass spectral data. DFT and computational studies were carried out on five of the synthesized poly heterocyclic compounds to show their structural and geometrical parameters involved in the study. Molecular docking using Tankyrase I enzyme as a target showed how the studied heterocyclic compounds act as a ligand interacting most of active sites on Tankyrase I with a type of interactions specified for H-bonding and VDW. We investigated that the five studied ligands act as inhibitors for different active sites along the target. The molecular docking study also revealed that the compound 6c was the most effective compounds in inhibiting Tankyrase I enzyme (2rf5), this result can help strongly in inhibition of carcinogenic cells and cancer treatment.

Humans can effortlessly recognize and react to natural sounds and are especially tuned to speech. There have been several studies aimed to localize and understand the speech-specific parts of the brain, but as the same brain areas are mostly active for all sounds, it has remained unclear whether or not the brain has unique processes for speech processing, and how it performs these processes. One of the main challenges has been to describe how the brain matches highly variable acoustic signals to linguistic representations when there is no one-to-one correspondence between the two, e.g. how the brain identifies the same words spoken by very different speakers and dialects as the same.

For this latest study, the researchers, led by Professor Riitta Salmelin, decoded and reconstructed spoken words from millisecond-scale brain recordings in 16 healthy Finnish volunteers. They adopted the novel approach of using the natural acoustic variability of a large variety of sounds (words spoken by different speakers, environmental sounds from many categories) and mapping them to magnetoencephalography (MEG) data using physiologically-inspired machine-learning models. These types of models, with time-resolved and time-averaged representations of the sounds, have been used in brain research before. The novel, scalable formulation by co-lead author Ali Faisal allowed for applying such models to whole-brain recordings, and this study is the first to compare the same models for speech and other sounds.

Aalto researcher and lead author Anni Nora says, 'We discovered that time-locking of the cortical activation to the unfolding speech input is crucial for the encoding of speech. When we hear a word, e.g. "cat", our brain has to follow it very accurately in time to be able to understand its meaning'.

As a contrast, time-locking was not highlighted in cortical processing of non-speech environmental sounds that conveyed the same meanings as the spoken words, such as music or laughter. Instead, time-averaged analysis is sufficient to reach their meanings. 'This means that the same representations (how a cat looks like, what it does, how it feels etc.) are accessed by the brain also when you hear a cat meowing, but the sound itself is analyzed as a whole, without need for similar time-locking of brain activation', Nora explains.

Time-locked encoding was also observed for meaningless new words. However, even responses to human-made non-speech sounds such as laughing didn't show improved decoding with the dynamic time-locked mechanism and were better reconstructed using a time-averaged model, suggesting that time-locked encoding is special for sounds identified as speech.

Results indicate that brain responses follow speech with especially high temporal fidelity

The current results suggest that, in humans, a special time-locked encoding mechanism might have evolved for speech. Based on other studies, this processing mechanism seems to be tuned to the native language with extensive exposure to the language environment during early development.

The present finding of time-locked encoding, especially for speech, deepens the understanding of the computations required for mapping between acoustic and linguistic representations (from sounds to words). The current findings raise the question of what specific aspects within sounds are crucial for cueing the brain into using this special mode of encoding. To investigate this further, the researchers aim next to use real-life like auditory environments such as overlapping environmental sounds and speech.
'Future studies should also determine whether similar time-locking might be observed with specialization in processing other sounds through experience, e.g. for instrumental sounds in musicians', Nora says

Future work could investigate the contribution of different properties within speech acoustics and the possible effect of an experimental task to boost the use of time-locked or time-averaged mode in sound processing. These machine learning models could also be very useful when applied to clinical groups, such as investigating individuals with impaired speech processing.

Philadelphia, June 22, 2020 - Dairy producers are feeding dairy calves more milk before weaning, as research has demonstrated that greater milk consumption provides short- and long-term benefits for calves. Encouraging solid feed consumption by calves on high-milk diets, however, can be challenging. Researchers have concluded that gradual weaning solves this problem more effectively than abrupt weaning, but more research is needed to optimize the process. In a recent article appearing in the Journal of Dairy Science, scientists from the University of Guelph studied gradual weaning of 60 calves divided into four groups using two weaning programs and two feed placement locations.

It is unknown whether a step-wise reduction in milk consumption during gradual weaning is better than a more continuous reduction. "It was predicted that small, frequent reductions in milk would be a more natural weaning process and cause less stress," said lead investigator Trevor DeVries, PhD, Department of Animal Biosciences, University of Guelph, Guelph, ON, Canada. "Therefore, reducing milk by larger quantities in a step-wise weaning program may be more noticeable to the calf and result in more behavioral indicators of stress, such as increased activity and vocalizations." Improving weaning transition, optimizing solid feed intake to prepare for a solid diet, increasing weight gain, and reducing stress are all important considerations.

The University of Guelph study compared continuous reduction of milk during weaning with step-wise reduction, as well as varying the location of the solid feed. Solid feed was placed next to the calves' milk source or on the opposite side of the pen, next to their water source. Because cows associate locations with the quality of food located there, the researchers hypothesized that placing the solid feed near the highly desirable milk would encourage solid feed intake.

Contrary to expectations, both weaning programs resulted in similar solid feed consumption, weight gain, and behavioral indicators of stress. As hypothesized, however, calves fed solid feed near their milk supply consumed more solid feed, milk, and water prior to weaning, resulting in 10 percent higher average daily weight gain during that time period. These calves also had greater feed efficiency in the second week of weaning and showed fewer stress-related behaviors once weaning concluded. This work highlighted that further research is needed on weaning strategies, water placement, and how these apply in group housing situations.

As China upgrades pangolins to the highest protected status level, an alternative approach to using long standing forensic methods is helping wildlife crime investigators disrupt poachers and animal traffickers in an effort to bring them to justice.

A team of scientists and experienced investigators from the University of Portsmouth have joined the battle to stop the pangolin becoming extinct, by adapting forensic fingerprinting techniques that lift finger-marks from the scales of these endangered animals.

Up to 2.7 million pangolins are poached every year (African Wildlife Foundation, 2019) making these unusual animals the most illegally trafficked mammals in the world. Also known as a 'scaly anteater, it has recently been linked to the spread of COVID-19 due to being on sale in wildlife markets in China. Pangolin meat is considered a delicacy in China and Vietnam, while its scales are used in traditional Asian medicine* and traditional African bush medicine.

The University has created an International Wildlife Crime cross-discipline working group with the Zoological Society London and the Wildlife Conservation Society and through international collaboration with wildlife crime officers, they have produced a solution that works.

A study, published in the Forensic Science International Journal, sets out the success of a two- year project, led by the University in collaboration with crime officers in Benign, Kenya, Cameroon and India.

The new method uses gelatine lifters with a low-adhesive gelatine layer on one side, which are used universally by forensic practitioners for lifting footwear marks, finger-marks and trace materials off various objects in criminal investigations. Until now, it is believed they have never been used in wildlife crime.

The initial study proved the suitability of gelatine lifting for visualising finger-marks on pangolin scales. The gelatine lifter is easily applied to the scale, removed and scanned using a specialist scanning system. The finger-marks were then graded for the presence of ridge detail and 74 per cent of the gelatine lifts examined produced clear finger-mark detail.

Since this first trial (in 2018), the fingerprinting technique has been developed further. Training workshops and events in Africa and Asia have enabled wildlife officers to share experiences and develop the practice in their own environment, working together with researchers to hone the methods most suitable to their practice. This has resulted in law enforcement agencies being better placed to identify poachers and traffickers and then bring them to justice.

Dr Brian Chappell, Senior lecturer in Criminal Investigation at the University of Portsmouth, said: "We found that wildlife crime officers across Africa and Asia have extensive expertise and knowledge in relation to the wildlife, the crimes committed and the behaviour of the traffickers, but they had little experience of forensic methods and practice. There was a lack of suitable resources and forensic evidence was not used to its full potential. Complex technologies and intricate scientific methods were not suitable to the working environment of the wildlife enforcement officers, therefore easy to use, inexpensive methods were required."

The research team of forensic experts, with assistance from DEFRA and the UK Border Force, worked with the wildlife crime enforcement officers to get a detailed understanding of their challenging working conditions and the harsh environments. to develop concepts that worked for them.

Dr Paul Smith, Director of the Forensic Innovation Centre at the University of Portsmouth, said: "The low-tack adhesive gelatine lifters have been used in crime scene and forensic practice for over 100 years, but we adapted bespoke packs and lifted evidence successfully off pangolin scales. This technique was easy to use, effective and suitable for practice.

"It equips the wildlife crime rangers and has the potential to be a deterrent to would-be traffickers, and a usable tool to help save the Pangolin."

PORTLAND, OR - Black patients are better represented in taxpayer-funded clinical trials testing new cancer treatments compared to trials run by pharmaceutical companies - although black patients are not fully represented in cancer clinical trials, regardless of sponsor.

These are results of a study conducted by SWOG Cancer Research Network, a member of the National Cancer Institute's (NCI) National Clinical Trials Network (NCTN), the oldest and largest publicly-funded cancer trial network in the United States. For more than 60 years, SWOG and other NCTN groups have run thousands of trials that enroll about 20,000 patients each year. The results are published in JNCI Cancer Spectrum, and will be presented as a poster in the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting II held June 22-24.

Formerly known as the NCI Clinical Trials Cooperative Group Program, the NCTN is comprised of more than 2,200 cancer centers, academic medical centers, and community hospitals across the U.S. and around the world. The network plays an integral role in establishing the standard of care for cancer patients by testing new treatments, from chemotherapy, radiation, and surgical interventions to the new wave of immunotherapies and personalized drugs based on patients' unique genetic profiles. A companion network, the NCI Community Oncology Research Program (NCORP), runs prevention and cancer care delivery trials, and includes community and rural hospitals in its network, including sites with significant minority and underserved patient populations. About 25 percent of all NCORP trial volunteers are racial and ethnic minorities. Both NCTN and NCORP trials are designed by doctors, paid for with public funds from the National Institutes of Health (NIH) through the NCI, and powered by patient volunteers.

Joseph Unger, PhD, a SWOG biostatistician and health services researcher based at Fred Hutchinson Cancer Research Center, specializes in cancer disparities research with a focus on the impacts of insurance status, race and ethnicity, and income on health outcomes. For this study, Unger compared black enrollment in NCI-sponsored trials and industry-sponsored trials.

"It's a critical question," Unger said. "Trials are an important way - sometimes the only way - for cancer patients to receive potentially breakthrough drugs. Everyone can get cancer, so everyone should have the same access to investigational cancer treatments. In addition, it's very important from a scientific standpoint to evaluate new treatments in patients who reflect the demographics of the general cancer population."

To conduct the study, Unger and his team used three databases. One was the SWOG trials database, used as a proxy to estimate the rate of participation among NCI trials. In addition, Unger's colleagues - led by Kanwal P.S. Raghav, MD, of MD Anderson Cancer Center and Jonathan M. Loree, MD of BC Cancer - created a database of pharmaceutical company sponsored trials that supported new drug applications and included data on trial participation by race. Finally, the team used data from the NCI's Surveillance, Epidemiology and End Results (SEER) program, as well as data compiled by the U.S. Census Bureau, to estimate the expected rate of black participation in the cancers they studied.

Unger and his team analyzed data from a total of 358 trials - 85 industry trials and 273 SWOG trials - that enrolled 93,825 patients being treated for 15 different cancer types. Enrollments spanned the years 2003-2018. The findings: In those 15 cancers, the rate of black enrollment in industry trials was 3 percent, compared to 9 percent in SWOG trials and 12 percent in the corresponding U.S. cancer population, according to the team's estimates.

"This study confirmed that black cancer patients are severely underrepresented in pharmaceutical company sponsored trials, with fewer than one in four of the expected number enrolled," Unger said. "Black representation in industry trials was also far below that of NCTN trials, with only one black patient enrolled for every three enrolled in NCTN trials."

These results can inform policy. The U.S. Food and Drug Administration, in partnership with AACR, is examining ways to improve representation of black patients in FDA registration trials. Registration trials are specially designed studies conducted with the expectation that the data they produce will be used to apply to the FDA for new drug approval, or to expand the uses of a currently approved cancer drug. Unger serves on this FDA and AACR task force.

"NCI sponsored trials have a broader mandate," Unger said. "They reach beyond just the major cancer centers to serve patients in a more diverse community-based clinical setting. This could serve as a model for pharma trials aiming to increase representativeness of all patients."

Unger's study was funded by the National Institutes of Health through National Cancer Institute grant award CA189974 and CA189873 and in part by The Hope Foundation for Cancer Research and the Michael Smith Health Professional Investigator program.

Unger's research team included Dawn Hershman, MD, of Columbia University; Raymond U. Osarogiagbon MD, of Baptist Cancer Center; Anirudh Gothwal, of Baylor University; Seerat Anand MBBS, of MD Anderson Cancer Center; Arvind Dasari MD, of MD Anderson Cancer Center; Michael Overman MD, of MD Anderson Cancer Center; Jonathan M. Loree MD, of BC Cancer; and Kanwal Raghav, MD, of MD Anderson Cancer Center.

SWOG Cancer Research Network is part of the National Cancer Institute's National Clinical Trials Network and the NCI Community Oncology Research Program, and is part of the oldest and largest publicly-funded cancer research network in the nation. SWOG has nearly 12,000 members in 47 states and six foreign countries who design and conduct clinical trials to improve the lives of people with cancer. SWOG trials have led to the approval of 14 cancer drugs, changed more than 100 standards of cancer care, and saved more than 3 million years of human life. Learn more at swog.org.

In a first-of-its-kind study, researchers have determined that genetics may play a role in how wounds heal. Caleb Phillips, an assistant professor at Texas Tech University and director of the Phillips Laboratory in the Department of Biological Sciences, and doctoral student Craig Tipton led the study, "Patient genetics is linked to chronic wound microbiome composition and healing," published Thursday (June 18) in the open-access, peer-reviewed medical journal PLOS Pathogens.

Phillips, who also serves as Curator of Genetic Resources at the Natural Science Research Laboratory's (NSRL) Robert J. Baker Genetic Resources Collection, said the study determined that certain genes are associated with the number of bacteria and abundance of common pathogens in wounds. The collection of microbes, known as a "microbiome," can determine how a wound heals and how long that process takes. The research also showed that the more diversity within a wound microbiome, the less time it took to heal.

Patients visiting Lubbock's Southwest Regional Wound Care Center (SWRWCC) for the care of a lower-extremity infected wound consented to participation in the study and provided samples from their wound(s) and from a cheek swab. The study used microbiome profiling, genome fingerprinting, wet lab validation, imaging and model development to analyze the samples and data, and included researchers from Texas Tech, the Texas Tech University Health Science Center (TTUHSC), the SWRWCC and the University of North Texas Health Science Center at Fort Worth (UNTHSC).

"We showed that there are identifiable locations in people's genome where, depending on their genotype, they tend to get infections by specific bacteria," Phillips said. "The different genomic locations identified tend to be related in terms of the types of genes they are close to and may regulate. A working hypothesis emerging from the research is that genetic differences influencing genes encoding the way our cells interact with the environment and each other are important for infection differences."

Though there is still work to be done before the research directly benefits patients, Tipton said the study is an important and promising step in that direction.

"Personalized medicine is a current hot topic in modern healthcare, where the goal is to identify inherent differences within individuals that may cause them to be impacted differently by disease and finding treatments that are well-suited and tailored to the individual and may contribute to better patient outcomes," Tipton said. "Our project furthers two equally-interesting avenues of research with potential translation to the clinic. In one, it is our goal to develop robust genomic predictive models that could help physicians to determine a patient's risk for chronic wound infection, particularly to specific bacteria.

"In the second, this work helps to inform how genetic variation in patients can influence microbiome-host interactions and wound infection pathogenesis. By further studying infection pathogenesis and how these complex microbial communities interact, it may be possible to improve existing therapies or to develop new therapeutic strategies altogether."

Phillips said he looks forward to continuing his research at Texas Tech. His lab is developing a follow-up study that he hopes will collect enough information to create accurate predictive models. They also are working on a study exploring how a person's location in the U.S. shapes differences in chronic wound microbiomes.

"Texas Tech provides good support for research and is continually working for growth," Phillips said. "My research, like that of most others, has been generally enhanced by the academic freedom provided at the university. The Natural Science Research Laboratory is a premier Natural History Collection, and the samples archived at the Genetic Resources Collection have allowed me to design studies such as this one that would otherwise not have been possible. The hard work and creativity of doctoral student Craig Tipton were essential to the success of this project, as was collaboration with the laboratories of Nicole Phillips at UNTHSC and Kendra P. Rumbaugh at TTUHSC, Professor Todd Little in the Texas Tech College of Education, the SWRWCC and the NSRL."

Sturgeon, a long-lived, bottom-dwelling fish, are often described as "living fossils," owing to the fact that their form has remained relatively constant, despite hundreds of millions of years of evolution.

In a new study in the Zoological Journal of the Linnean Society, researchers led by Jack Stack, a 2019 University of Pennsylvania graduate, and paleobiologist Lauren Sallan of Penn's School of Arts & Sciences, closely examine the ancient fish species Tanyrhinichthys mcallisteri, which lived around 300 million years ago in an estuary environment in what is today New Mexico. Although they find the fish to be highly similar to sturgeons in its features, including its protruding snout, they show that these characteristics evolved in a distinct evolutionary path from those species that gave rise to modern sturgeons.

The find indicates that, although ancient, the features that enabled Tanyrhinichthys to thrive in its environment arose multiple times in different fish lineages, a burst of innovation that was not previously fully appreciated for fish in this time period.

"Sturgeon are considered a 'primitive' species, but what we're showing is that the sturgeon lifestyle is something that's been selected for in certain conditions and has evolved over and over again," says Sallan, senior author on the work.

"Fish are very good at finding solutions to ecological problems," says Stack, first author on the study, who worked on the research as a Penn undergraduate and is now a graduate student at Michigan State University. "This shows the degree of both innovation and convergence that's possible in fishes. Once their numbers got up large enough, they started producing brand new morphologies that we now see have evolved numerous times through the history of fishes, under similar ecological conditions. "

The first fossil of Tanyrhinichthys was found in 1984 in a fossil-rich area called the Kinney Brick Quarry, about a half hour east of Albuquerque. The first paleontologist to describe the species was Michael Gottfried, a Michigan State faculty member who now serves as Stack's advisor for his master's degree.

"The specimen looks like someone found a fish and just pulled on the front of its skull," Stack says. Many modern fish species, from the swordfish to the sailfish, have protuberant snouts that extend out in front of them, often aiding in their ability to lunge at prey. But this characteristic is much rarer in ancient fishes. In the 1980s when Gottfried described the initial specimen, he posited that the fish resembled a pike, an ambush predator with a longer snout.

During the last decade, however, several more specimens of Tanyrhinichthys have been found in the same quarry. "Those finds were an impetus for this project, now that we had better information on this enigmatic and strange fish," Stack says.

At the time that Tanyrhinichthys roamed the waters, Earth's continents were joined in the massive supercontinent called Pangea, surrounded by a single large ocean. But it was an ice age as well, with ice at both poles. Just before this period, the fossil record showed that ray-finned fishes, which now dominate the oceans, were exploding in diversity. Yet 300 million years ago, "it was like someone hit the pause button," Sallan says. "There's an expectation that there would be more diversity, but not much has been found, likely owing to the fact that there just hasn't been enough work on this time period, especially in the United States, and particularly in the Western United States."

Aiming to fill in some of these gaps by further characterizing Tanyrhinichthys, Stack, Sallan, and colleagues closely examined the specimens in detail and studied other species that dated to this time period. "This sounds really simple, but it's obviously difficult in execution," Stack notes, as fossils are compressed flat when they are preserved. The researchers inferred a three-dimensional anatomy using the forms of modern fishes to guide them.

What they noticed cast doubt on the conception of Tanyrhinichthys as resembling a pike. While a pike has an elongated snout with its jaws at the end of it, allowing it to rush its prey head-on, Tanyrhinichthys has an elongated snout with its jaws at the bottom.

"The whole form of this fish is similar to other bottom dwellers," Stack says. Sallan also noticed canal-like structures on its snout concentrated in the top of its head, suggestive of the locations where sensory organs would attach. "These would have detected vibrations to allow the fish to consume its prey," says Sallan.

The researchers noted that many of the species that dwelled in similar environments possessed longer snouts, which Sallan called "like an antenna for your face."

"This also makes sense because it was an estuary environment," Sallan says, "with large rivers feeding into it, churning up the water, and making it murky. Rather than using your eyesight, you have to use these other sensory organs to detect prey."

Despite this, other features of the different ancient fishes' morphology were so different from Tanyrhinichthys that they do not appear to have shared a lineage with one another, nor do modern sturgeon descend from Tanyrhinichthys. Instead the long snouts appear to be an example of convergent evolution, or many different lineages all arriving at the same innovation to adapt well to their environment.

"Our work, and paleontology in general, shows that the diversity of life forms that are apparent today has roots that extend back into the past," says Stack.

In an article published in Nature Ecology & Evolution today (22 June), the leaders of a new global initiative explain how research during this devastating health crisis can inspire innovative strategies for sharing space on this increasingly crowded planet, with benefits for both wildlife and humans.

Many countries around the world went into lockdown to control the spread of Covid-19. Brought about by the most tragic circumstances, this period of unusually reduced human mobility, which the article's authors coined "anthropause", can provide invaluable insights into human-wildlife interactions.

There have been countless posts on social media over the past few months reporting unusual wildlife encounters. Anecdotal observations, especially from metropolitan areas, suggest that nature has responded to lockdown. There not only seem to be more animals than usual, but there are also some surprising visitors: pumas have been spotted prowling the streets of downtown Santiago, Chile, and dolphins recently showed up in untypically calm waters in the harbour of Trieste, Italy.

For other species, the pandemic may have created new challenges. For example, some urban-dwelling animals, like gulls, rats or monkeys, may struggle to make ends meet without access to human food. In more remote areas, reduced human presence may potentially put endangered species, such as rhinos or raptors, at increased risk of poaching or persecution.

The authors emphasise that society's priority must be to tackle the immense human tragedy and hardship caused by Covid-19. But, they argue that we cannot afford to miss the opportunity to chart, for the first time on a truly global scale, the extent to which modern human mobility affects wildlife.

To address this challenge, researchers recently formed the "COVID-19 Bio-Logging Initiative". This international consortium will investigate animals' movements, behaviour and stress levels, before, during and after Covid-19 lockdown, using data collected with nifty animal-attached electronic devices called "bio-loggers".

The article's lead author, Professor Christian Rutz, a biologist at the University of St Andrews, UK, and President of the International Bio-Logging Society, explains: "All over the world, field biologists have fitted animals with miniature tracking devices. These bio-loggers provide a goldmine of information on animal movement and behaviour, which we can now tap to improve our understanding of human-wildlife interactions, with benefits for all."

The team will integrate results from a wide variety of animals, including fish, birds and mammals, in an attempt to build a global picture of lockdown effects.

Dr Francesca Cagnacci, Senior Researcher at the Edmund Mach Foundation in Trento, Italy, and Principal Investigator of the Euromammals research network, says: "The international research community responded quickly to our recent call for collaboration, offering over 200 datasets for analysis. We are very grateful for this support."

So, what do the scientists hope to learn? Dr Matthias-Claudio Loretto, a Marie Sk?odowska-Curie Fellow at the Max Planck Institute of Animal Behavior in Radolfzell, Germany, explains that it will be possible to address previously intractable questions: "We will be able to investigate if the movements of animals in modern landscapes are predominantly affected by built structures, or by the presence of humans. That is a big deal."

These insights will in turn inspire innovative proposals for improving human-wildlife coexistence, according to Professor Martin Wikelski, Director of the Max Planck Institute of Animal Behavior in Radolfzell, Germany. "Nobody is asking for humans to stay in permanent lockdown. But we may discover that relatively minor changes to our lifestyles and transport networks can potentially have significant benefits for both ecosystems and humans."

Coordinated global wildlife research during this period of crisis will provide unforeseen opportunities for humans to forge a mutually beneficial coexistence with other species, and to rediscover how important a healthy environment is for our own well-being.