Culture

RUDN and Shahid Beheshti University(SBU) chemist proposed an eco-friendly method for the synthesis of pyrrole and pyrazole derivatives with a wide range of applications in medicine: from antidepressants to anticancer. Moreover, the synthesized compounds possess interesting fluorescence features, and the bioactive scaffolds might attract great interest in the fields of clinical diagnostics and biomedical research in the future. The results are published in the Organic & Biomolecular Chemistry.

Heterocyclic compounds expose remarkable chemistry with significant applications in medicinal and organic chemistry, industry, and pharmaceutical. These compounds are widely found in many natural products such as vitamins, hormones, antibiotics, alkaloids, herbicides, pigments, and dyes. Besides, a wide variety of heterocyclic rings is originated from the scaffolds of various drugs and bioactive molecules. Among them, pyrrole and pyrazole are heterocycles with a wide biological activity. They are part of drugs for the treatment of cancer, headaches and depression, relieving inflammation and a number of other diseases. Some of them demonstrate fluorescent properties, and therefore they can be used for clinical diagnosis, for example, cancer. However, the synthesis of compounds with these heterocycles remains non eco-friendly and expensive. It needs high temperatures and hazardous compounds. The RUDN and SBU chemist and his colleagues from Tehran-Iran suggested a safer and cheaper way to create pyrrole and pyrazole derivatives.

"Pyrroles and pyrazoles represent one of the most active classes of compounds, possessing a wide range of biological activities. It includes anti-inflammatory, antidepressant, antitubercular activity, they are also active against microbes, fungi and bacteria. That is not the complete list. Still, it is a powerful challenge to design an ideal synthetic protocol for this type of biologically active compound using environmentally friendly and step-economic methods and less hazardous reagents under mild reaction conditions", Dr. Ahmad Shaabani from RUDN and SBU.

The chemists have obtained compounds of pyrazole and pyrrole derivatives by the "one-pot" method, when all the stages of synthesis take place in a single reactor. Thus, scientists do not need to waste time and reagents on the isolation and purification of intermediate compounds. In total, four types of substances participate in the reaction: aminopyrazole, aldehyde, dimethyl acetylenedicarboxylate, isocyanide. They convert in a domino reaction, when all the steps occur one after the other without additional compounds. The reaction occurs at a low temperature -- 45? -- under ultrasound irradiation in the presence of p-toluenesulfonic acid as a catalyst.

By changing the combinations of the four reactants, the chemists obtained 22 compounds. It turned out that most of them have fluorescent features -- they glow blue under the ultraviolet light. The most intense fluorescence was associated with the presence of bromine derivatives in the cyclic fragments of the obtained substances.

"This eco-friendly, mild condition and atom-economical process generated two C-N and two C-C bonds and formed two five-membered heterocycles connected to each other. We believe that these new classes of fluorescent compounds may be of excellent interest in biomedical applications and clinical diagnostics in the future".

With the start of the United Nations' Decade on Ecosystem Restoration, which runs through 2030, a tremendous amount of money and effort will be put into re-growing forests, making over-exploited farmland productive, and reviving damaged marine environments. This is a good, and vital, initiative. Without quick action to clean up the fallout of humanity's scorched-earth economic systems, goals on hunger, biodiversity and climate will be unattainable.

But in examining restoration projects already underway across the globe, a group of scientists has found that restoration action is at risk of failure if it doesn't make social and political considerations at the center of efforts.

"Biophysical considerations are usually central to restoration efforts," said Marlène Elias, a CGIAR gender researcher at the Alliance of Bioversity International and CIAT. "While there's usually a peripheral nod at other issues, there generally isn't substantial engagement with the social, human and political dimensions of restoration."

The research is part of a special edition of Ecological Restoration titled "Restoration by Whom, for Whom," published in June 2021. The eleven papers include a successful kelp restoration project on Canada's West Coast, centered on the worldviews, ethics, and values of the Haida First Nation, with co-authors from the Haida First Nation. There is a study of a lake restoration project in Bangalore, India, where the lake ecosystem was "successfully" restored but the main beneficiaries were well-heeled urban residents at the exclusion of more vulnerable local communities who used to depend on the lake to fish, water their livestock, and more. Another group of authors reflect on inclusiveness in restoration based on their experience developing a mangrove restoration project with local communities.

Other research included work onfarmer-managed natural regeneration in Ghana, on-farm experiments and payments for ecosystem services in Kenya, a government-led tree planting initiative in Vietnam and the use of an adapted Restoration Opportunities Assessment Methodology in India. The remaining papers provide perspectives on multi-stakeholder engagement and restoration approaches that offer entry points for inclusive restoration.

Authors include scientists from the CGIAR's International Food Policy Research Institute, International Water Management Institute, and World Agroforestry, as well as from universities, Indigenous communities, NGOs, governments, the World Resources Institute, and other organizations from around the globe.

"Restoration projects need to be more inclusive," Elias said. "If you're looking at major goals like restoring millions of square kilometers of land, planting a trillion trees, or rehabilitating marine ecosystems, you're almost certainly not going to have success unless you put people at the center of the work."

A feminist political ecology of restoration

In the collection's introductory paper, Elias and the special issue's co-guest editors, Deepa Joshi and Ruth Meinzen-Dick, delve into "feminist political ecology" (FPE) and what this means in the context of ecological restoration. Meinzen-Dick said that one reason that social and political issues are often left out of restoration projects is because they're "messy." Top-down, one-size-fits all "solutions" tend to fail because land-rights issues, complicated relations among stakeholders, divergent worldviews and value systems, and potentially unequal distributions of benefits and costs are not addressed at the outset. While many oft-disenfranchised groups are left out of restoration plans, rural women face some of the most significant constraints in top-down restoration projects.

"Our aim is to prompt critical reflection that can open new avenues for meaningful engagement with issues of power and justice in restoration, to challenge the assumptions and discourses that (re)produce the status quo, and suggest ways forward for more political, inclusive agendas," Joshi writes.

The FPE approach focuses on three main pillars: gendered power relations, historical awareness and scale integration. The first refers to the inter-relations and inequalities on the basis of gender and other factors of social differentiation that shape rights to resources, decision-making, labor, and more that critically influence natural resource management.

Historical awareness means recognizing that current patterns of resource use and management can't be understood within considering the historical social, economic, political, and ecological contexts within which they are embedded. Scale integration refers to the fact that local resource management strategies are a function of factors (such as institutions) that go far beyond the local scale, such as international agendas, national policies, markets and commodity prices.

"We conclude that much needs to change to address the systemic fault lines that create exclusions in restoration policies and practice, and to legitimize the plural voices, values, meanings and situated knowledges of what makes the environment or nature in order to sustainably transform degraded landscapes," they write.

None of this undermines the importance of applied ecological science in restoration initiatives: the understanding of ecosystem function, interactions between diverse species ranging from fungi to trees, and the importance of biodiversity in restoration are all key to successful restoration.

"But the dominance of the natural sciences over the social sciences in the field of restoration results in a framing of restoration as a primarily technical issue, rather than as a socio-ecological issue with multiple, intricately intertwined dimensions," Elias said. "Ecological outcomes cannot be sustained without addressing social inclusion and equity. The point of restoration is not only to enhance ecosystem services, but to ensure the ecological, social, economic, cultural, and other functions that landscapes under restoration provide to improve human wellbeing."

Inaccessible workplaces, normative departmental cultures and 'ableist' academic systems have all contributed to the continued underrepresentation and exclusion of disabled researchers in the Geosciences, according to an article published today (Thursday 8 June) in Nature Geosciences.

The article argues that changes to both working spaces and attitudes are urgently needed if institutions are to attract, safeguard and retain people with disabilities.

Anya Lawrence, a disabled early career researcher in the University of Birmingham's School of Geography, Earth and Environmental Science and author of the piece says:

"Disabled geoscientists like myself face barrier after barrier on a daily basis just to get by in academia. My aim, in writing this article, was to capture some of the shared difficulties that disabled geoscientists experience, particularly struggles that may be less obvious or less apparent at a surficial level, but are significant nonetheless. For example, I think it may come as a surprise to some that traditional workplace cultures like communal coffee breaks can actually be a source of exclusion for those with disabilities. Likewise, 'feeling sorry' and showing pity for disabled colleagues could seem well-meaning but just serves to reinforce negative stereotypes towards disability."

The article makes a series of suggestions about how those with disabilities can be attracted, supported and retained in academic geosciences such as university leaders taking advice from outside agencies with experience in embedding inclusion in the workplace, along with making visible commitments to disability-hiring initiatives.

Anya adds: "I think lots of examples of best practice are already out there in other sectors. It's a case of whether people across the various different levels of the academic hierarchy from those in the highest leadership roles to the academics 'on the ground' and doing the research in Geoscience departments, are committed to creating respectful cultures and welcoming spaces for disabled scholars."

"Although I have encountered many hurdles myself, I am very fortunate in that I have an amazingly supportive supervisor and head of school and also my parents who everyday face the challenge of caring for a disabled child with nothing but great courage and selflessness. I realise that so many disabled researchers just don't have this kind of close support network and are quite isolated and alone in academia."

Another potential initiative outlined in the article is increased collaborative research involving mixed groups of disabled and non-disabled geoscientists.

"Collaborating with other geoscientists without disabilities or with different disabilities to me has been really beneficial not only at a personal level but for the research itself," says Anya. "By working with people who have different opinions, life experiences and areas of expertise from myself I have learnt so much; I have been prompted to try new methods and analytical techniques, publish my findings in outlets I hadn't even heard of and think critically about my research at every stage of the process - all of which wouldn't have been possible had I kept going it alone."

"It's also just nice to feel included and valued- working with people who appreciate my involvement and view disability as being different, not deficient, means the world to me. To this end I would like to thank the editors of Nature Geoscience, especially Dr James Super and Dr Simon Harold for being sensitive and deeply respectful in their communication and, most of all, for inviting someone with lived experience of disability to contribute to the discussion on disability in the geosciences!"

DURHAM, N.C. - Biomedical engineers at Duke University have demonstrated that a class of interwoven composite materials called semi-interpenetrating polymer networks (sIPNs) can be produced by living cells. The approach could make these versatile materials more biologically compatible for biomedical applications such as time-delayed drug delivery systems.

The research appears online on June 8 in the journal Nature Communications.

The concept of sIPNs has been around for more than 100 years and has been used in automotive parts, medical devices, molding compounds and engineering plastics. The general idea is for one or more polymers to assemble around another polymer scaffold in such a way that they become interlocked. Even though the polymers are not chemically bonded, they cannot be pulled apart and form a new material with properties greater than the simple sum of its parts.

Traditional methods for manufacturing sIPNs typically involve producing the constituent parts called monomers and mixing them together in the right chemical conditions to control their assembly into large networks in a process called polymerization.

"When it works, it's a fantastic platform that can incorporate different functionalities into the self-assembled layer for biomedical or environmental applications," said Lingchong You, professor of biomedical engineering at Duke. "But the process is often not as biocompatible as you might want. So we thought why not use living cells to synthesize the second layer to make it as biocompatible as possible?"

In the new paper, Zhuojun Dai, a former postdoc in the You lab who is now an associate professor at the Shenzhen Institute of Synthetic Biology, uses a platform that the lab has been developing for several years called "swarmbots" to do just that.

The swarmbots are living cells that are programmed to produce biological molecules within their walls and then explode once their population reaches a certain density. In this case, they're programmed to produce monomers called elastin-like polypeptides (ELPs) fused to functional features called SpyTag and SpyCatcher. These two molecular structures form a lock-and-key system, allowing the ELPs to self-assemble into a polymer chain when mixed. As they grow, these polymers entangle themselves with the polymeric microcapsules containing the cells to form sIPNs.

Each monomer can contain multiple SpyTags or SpyCatchers and can also be fused to proteins that generate a readout or have specific functions. It's sort of like making a chain-link fence out of many tiny charm bracelets that have room for clasps and charms.

The researchers first program the cells to fill this accessorizable feature with a fluorescent protein to prove that the system can lock them into place. After that successful demonstration, they turn their attention to engineering a useful drug delivery system with their new invention.

"You could replace the fluorescent marker with anything that has a function you want to feature," said You. "We decided to touch on antibiotics because it's one of the other focuses of our lab."

Beta-lactam antibiotics, such as penicillin and its derivatives, are some of the most commonly used antibiotics in the world. They're also often overused and can have negative effects such as destroying the natural microbiome that lives within our guts.

To demonstrate one way in which their new cell-built sIPNs could be useful, the researchers fill the accessorizable spot with beta-lactamase, which can degrade beta-lactam antibiotics. By injecting the newly functionalized sIPNs into mice, the researchers showed the platform could slowly release the otherwise short-lived protective molecule to help the mice's gut microbiomes ward off negative side effects from the antibiotics.

"Nobody has used living cells as a factory to produce monomers in real-time for sIPNs before," said You. "The proof-of-principle demonstration shows that, not only can we fabricate these types of functional materials with live cells, but they can exhibit medically relevant functions."

Humans expect that AI is Benevolent and trustworthy. A new study reveals that at the same time humans are unwilling to cooperate and compromise with machines. They even exploit them.

Picture yourself driving on a narrow road in the near future when suddenly another car emerges from a bend ahead. It is a self-driving car with no passengers inside. Will you push forth and assert your right of way, or give way to let it pass? At present, most of us behave kindly in such situations involving oth-er humans. Will we show that same kindness towards autonomous vehicles?

Using methods from behavioural game theory, an international team of researchers at LMU and the University of London have conducted large-scale online studies to see whether people would behave as cooperatively with artificial intelligence (AI) systems as they do with fellow humans.

Cooperation holds a society together. It often requires us to compromise with others and to accept the risk that they let us down. Traffic is a good example. We lose a bit of time when we let other people pass in front of us and are outraged when others fail to reciprocate our kindness. Will we do the same with machines?

Exploiting the machine without guilt

The study which is published in the journal iScience found that, upon first encounter, people have the same level of trust toward AI as for human: most expect to meet someone who is ready to cooperate.

The difference comes afterwards. People are much less ready to reciprocate with AI, and instead exploit its benevolence to their own benefit. Going back to the traffic example, a human driver would give way to another human but not to a self-driving car.

The study identifies this unwillingness to compromise with machines as a new challenge to the future of human-AI interactions.

"We put people in the shoes of someone who interacts with an artificial agent for the first time, as it could happen on the road," explains Dr. Jurgis Karpus, a behavioural game theorist and a philosopher at LMU Munich and the first author of the study. "We modelled different types of social encounters and found a consistent pattern. People expected artificial agents to be as cooperate as fellow humans. However, they did not return their benevolence as much and exploited the AI more than humans."

With perspectives from game theory, cognitive science, and philosophy, the researchers found that 'al-gorithm exploitation' is a robust phenomenon. They replicated their findings across nine experiments with nearly 2,000 human participants.

Each experiment examines different kinds of social interactions and allows the human to decide whether to compromise and cooperate or act selfishly. Expectations of the other players were also measured. In a well-known game, the Prisoner's Dilemma, people must trust that the other characters will not let them down. They embraced risk with humans and AI alike, but betrayed the trust of the AI much more often, to gain more money.

"Cooperation is sustained by a mutual bet: I trust you will be kind to me, and you trust I will be kind to you. The biggest worry in our field is that people will not trust machines. But we show that they do!" notes Prof. Bahador Bahrami, a social neuroscientist at the LMU, and one of the senior researchers in the study. "They are fine with letting the machine down, though, and that is the big difference. People even do not report much guilt when they do," he adds.

Benevolent AI can backfire

Biased and unethical AI has made many headlines--from the 2020 exams fiasco in the United Kingdom to justice systems--but this new research brings up a novel caution. The industry and legislators strive to ensure that artificial intelligence is benevolent. But benevolence may backfire.

If people think that AI is programmed to be benevolent towards them, they will be less tempted to co-operate. Some of the accidents involving self-driving cars may already show real-life examples: drivers recognize an autonomous vehicle on the road, and expect it to give way. The self-driving vehicle meanwhile expects for normal compromises between drivers to hold.

"Algorithm exploitation has further consequences down the line. If humans are reluctant to let a polite self-driving car join from a side road, should the self-driving car be less polite and more aggressive in order to be useful?" asks Jurgis Karpus.

"Benevolent and trustworthy AI is a buzzword that everyone is excited about. But fixing the AI is not the whole story. If we realize that the robot in front of us will be cooperative no matter what, we will use it to our selfish interest," says Professor Ophelia Deroy, a philosopher and senior author on the study, who also works with Norway's Peace Research Institute Oslo on the ethical implications of inte-grating autonomous robot soldiers along with human soldiers. "Compromises are the oil that make soci-ety work. For each of us, it looks only like a small act of self-interest. For society as a whole, it could have much bigger repercussions. If no one lets autonomous cars join the traffic, they will create their own traffic jams on the side, and not make transport easier".

As COVID-19 restrictions ease nationwide and more people host indoor gatherings, investing in a high efficiency particulate air (HEPA) purifier might not be a bad idea, says a University of Cincinnati College of Medicine researcher.

Several published studies evaluating aerosols and submicron particles similar in size to the SARS-CoV-2 virion have shown that portable HEPA purifiers are able to significantly reduce airborne COVID-19 particles, says Ahmad Sedaghat, MD, PhD, director of the UC Division of Rhinology, Allergy and Anterior Skull Base Surgery.

Sedaghat identified the medical literature showing published studies on the effectiveness of HEPA purifiers. His review is available online in the scholarly journal of the American Academy of Otolaryngology-Head and Neck Surgery Foundation.

Air purifiers could benefit hospitals and physician offices where aerosol-generating procedures occur, but they are also useful for reducing COVID transmission anywhere that large groups of individuals congregate.

"One of the issues with COVID-19, is when physicians perform an aersol-generating medical procedure any asymptomatic COVID-19 positive patient may release SARS-CoV-2 laden aersols into the air," explains Sedaghat. "Guidance from the Centers for Disease Control indicates that we can rely on our HVAC systems to slowly decontaminate the air during an hour timeframe. Studies in the medical literature are showing us that we can use portable air purifiers to do a better and faster job of decominating these airborne particles to keep our patients and staff safe."

"Air purifiers with HEPA filters can be used as very effective means to decontaminate the air above and beyond what many HVAC systems may offer," says Sedaghat who also published studies documenting COVID-19 infection leading to reduced taste and smell in patients and possibly attacking the central nervous system.

"If people are walking around coughing or sneezing because it is allergy season and by chance they happen to be one of these asymptomatic carriers of COVID-19, there is a danger of transmission in individuals not vaccinated," says Sedaghat. "People are catching the disease from asymptomatic carriers."

"The results of this study can be applied to our daily lives outside of a physician's office," says Sedaghat. "If you want to host larger gatherings you should consider putting the air purifiers into your living room to help decontaminate anything that is released into the air. HEPA based air purifiers work the best. HEPA based air purifiers decontaminate these airborne particles much faster and more effectively than non HEPA filters."

"They aren't terribly expensive and you can buy these at any home improvement or department store to help decontaminate air borne coronavirus," says Sedaghat. "This may be more important for controlling the spread of COVID-19 for people who are still not vaccinated."

Air purifiers offer added protection but UC researchers also found that better-fitting facemasks greatly improve protection against COVID-19 as well.

New Orleans, LA - Research conducted at LSU Health New Orleans Neuroscience Center of Excellence reports that Elovanoids, bioactive chemical messengers made from omega-3 very-long-chain polyunsaturated fatty acids discovered by the Bazan lab in 2017, may block the virus that causes COVID-19 from entering cells and protect the air cells (alveoli) of the lung. Their findings are published online in Scientific Reports, available here.

"Because the compounds are protective against damage in the brain and retina of the eye and the COVID-19 virus clearly damages the lung, the experiment tested if the compounds would also protect the lung," notes Nicolas Bazan, MD, PhD, Director of the LSU Health New Orleans Neuroscience Center and senior author of the paper.

The research team tested Elovanoids (ELVs) on infected lung tissue from a 78-year-old man in petri dish cultures. They found that ELVs not only reduced the ability of the SARS-CoV-2 spike protein to bind to receptors and enter cells, but they also triggered the production of protective, anti-inflammatory proteins that counteract lung damage.

The scientists report that ELVs decreased the production of ACE2. ACE2 is a protein on the surface of many cell types. ACE2 receptors act like locks on cells, and the SARS-CoV-2 spike proteins act like keys that open the locks letting the virus enter cells to multiply rapidly. They also demonstrated for the first time that alveolar cells are endowed with pathways for the biosynthesis of ELVs.

"Since SARS-CoV-2 affects nasal mucosa, the GI tract, the eye, and the nervous system, uncovering the protective potential of ELVs expands the scope of our observations beyond the lung," adds Dr. Bazan. "Our results provide a foundation for interventions to modify disease risk, progression, and protection of the lung from COVID-19 or other pathologies (including some types of pneumonia)."

Fraud is going uninvestigated by police who are "hiding behind the veil" of the Action Fraud national crime reporting agency.

In his paper published this week in Policing, Professor Mark Button, director of the Centre for Counter Fraud Studies at the University of Portsmouth argues that, Action Fraud, which has been widely derided, has become a useful veil from which the police can hide their inadequate response.

Figures from Action Fraud, the arm of the police responsible for recording scams and fraud, show that between 2019 and 2020, over 800,000 people reported being a victim of fraud, with £2.3bn finding its way into criminal hands. However, Professor Button calculated just 0.6 per cent of police officers are dedicated to investigating fraud.

The research focused on reviews and investigations carried out over the past 20 years and found that these have consistently highlighted the low priority given to the investigation of financial crimes in England and Wales. In 2018 the House of Commons home affairs committee said that "the proportion of fraud cases being investigated is shockingly low".

Professor Button says: "Action Fraud is in reality a call centre provided by a private company under contract to the City of London Police.

"The staffs it employs are largely low-skilled and paid at around the minimum wage. It has no capacity to investigate. However, even in the area it does have responsibility for there is an evidence of areas in need of improvement."

"Considering fraud and computer misuse crime amounts to a third to half of all crime against individuals this is a huge mismatch".

Professor Button suggests radical change is required to address the investigative gap through either a move towards regional investigation of economic crime or a national solution, through a National Economic Crime Agency.

Economic crime is the most common type of crime and costs society billions of pounds. In the current policing structures economic crime will always be the 'Cinderella' crime falling behind other policing priorities and lacking the resources required for agencies to effectively tackle it. Much of economic crime requires specialist knowledge.

The paper aims to start a debate around the future structures of policing for economic crime centred around a national body or regional forces rather than the traditional local forces.

For two decades, the number of Americans who die each year from drug overdoses has steadily risen, from less than 20,000 in 1999 to more than 80,000 in 2020. By studying patterns of these drug-related fatalities, researchers at University of California San Diego School of Medicine, San Diego State University (SDSU), and international collaborators have designed and validated a prediction model to signal counties at risk of future overdose death outbreaks. The goal of the open-source tool is to predict and prevent deaths through early deployment of public health resources.

Findings were published June 9, 2021 by Lancet Public Health.

"A big challenge for public health experts is figuring out which parts of the country are at greatest risk of future overdose outbreaks. If we can predict where such outbreaks may happen, then we will be empowered to intervene and stop deaths from occurring," said senior author Annick Borquez, PhD, an epidemiologist and assistant professor in the Division of Infectious Disease and Global Public Health at UC San Diego School of Medicine.

The opioid epidemic has been described as an overlapping triple wave of fatal overdoses due to prescription opioids, heroin and highly potent synthetic opioids, including fentanyl. The investigators used this third wave to investigate whether a tool could be developed to predict and prevent deaths.

"This study provides a novel, rigorously validated tool to inform policy planning in the context of overdose epidemics driven by emerging drugs and sets a new standard for the development of a data-driven response to drug use epidemics," said first author Charlie Marks, MPH, graduate research assistant, SDSU-UC San Diego joint doctoral program in Interdisciplinary Research in Substance Abuse.

Using CDC data from 2013 (when the fentanyl epidemic began) up to 2018 (the most recent data available at the time), the research team designed and trained a retrospective statistical model to find patterns in the relationship between county characteristics and overdose deaths, then used the data to predict fatality rates in the next year. The predictions were then compared with actual overdose death rates in each county.

"We found that our approach brought substantial improvement to predicting counties with high fatal overdose rates compared to a simple benchmark that relied on past year rates alone. We also found that increased overdoses in a neighboring county are very predictive of future overdoses in a given county, indicating that the overdose epidemic spreads geographically," said Marks.

The team developed the OD Predict Explorer web tool, a publicly available interface where results of the time-limited model are presented and available for research purposes. Users can click on a map and compare what the model predicted from 2013 to 2018 versus what was observed and determine whether the tool actually identified the counties with the highest overdose across the country, including those experiencing new spikes.

"Many of the counties with the most deaths were concentrated in the Midwest and Northeast, where the fentanyl epidemic has hit hardest, but an increasing number of states in the West are affected as well. There's this idea that this epidemic has been focused in rural areas where the prescription opioid epidemic started, but the reality is overdose deaths have been increasing in cities too. For example, San Francisco and San Diego have seen steep increases in fentanyl overdose deaths in the past year," Borquez added.

Borquez and Marks note that that all predictive models are limited by the data sets used to inform them and said more timely and available information related to deaths, drug markets and seizures and prescription data at both county and state levels, is urgently needed.

"While our approach can be effective, it also requires that fatal overdose data from all the counties in the U.S. be accessible and available for the current year, which unfortunately is not yet standard practice," said Borquez. "Our model will only be useful in predicting and preventing deaths if there is no lag in getting data from local and national agencies."

"Further model refinement and securing access to restricted data through broad collaborations will be next steps to improve model performance. Imagine if we could develop predictive tools for substance use epidemics, similar to what was developed to predict COVID-19 infections and deaths."

Borquez predicted it would be one to two years before the tool is sufficiently refined to make real-time predictions at a national level based on available data, but that a promising avenue in the short term will involve applying it in states that share recent overdose death information.

"We urgently need methods to predict where these overdoses and other outbreaks may occur. Outbreaks such as hepatitis and HIV are also connected to drug use, and can be prevented too," said Borquez. "Investing in drug use surveillance and harm-reduction infrastructure doesn't solve one problem, it solves multiple problems at once."

Medulloblastoma is a rare but devastating childhood brain cancer. This cancer can spread through the spinal fluid and be deposited elsewhere in the brain or spine. Radiation therapy to the whole brain and spine followed by an extra radiation dose to the back of the brain prevents this spread and has been the standard of care. However, the radiation used to treat such tumors takes a toll on the brain, damaging cognitive function, especially in younger patients whose brains are just beginning to develop.

A national study led by Washington University School of Medicine in St. Louis and St. Jude Children's Research Hospital suggests that children with what is called "average risk medulloblastoma" can receive a radiation "boost" to a smaller volume of the brain at the end of a six-week course of radiation treatment and still maintain the same disease control as those receiving radiation to a larger area. But the researchers also found that the dose of the preventive radiation treatments given to the whole brain and spine over the six-week regimen cannot be reduced without reducing survival. Further, the researchers showed that patients' cancers responded differently to therapy depending on the biology of the tumors, setting the stage for future clinical trials of more targeted treatments.

Children with average risk medulloblastoma have five-year survival rates of 75% to 90%. In contrast, children with what's called "high risk medulloblastoma" have five-year survival rates of 50% to 75%. Other factors -- such as a child's age and whether the tumor has spread -- help determine the risk category. For this study, the researchers focused on patients with average risk medulloblastoma.

The findings appears online June 10 in the Journal of Clinical Oncology.

"Medulloblastoma is a devastating disease," said first and corresponding author Jeff M. Michalski, MD, the Carlos A. Perez Distinguished Professor of Radiation Oncology at Washington University. "It is a malignant brain tumor that develops in the cerebellum, the back lower part of the brain that is important for coordinating movement, speech and balance. The radiation treatment for this tumor also can be challenging, especially in younger children whose brains are actively developing in these areas. There's a balance between effectively treating the tumor without damaging children's abilities to move, think and learn."

Children with average risk medulloblastoma typically undergo surgery to remove as much of the tumor as possible. They also receive chemotherapy and radiation therapy to prevent the spread of the tumor to other parts of the brain and spine through the cerebrospinal fluid.

"We wanted to investigate whether we could safely reduce the amount of radiation these patients receive -- sparing normal parts of the brain and lessening the side effects for children with this type of brain cancer -- while also maintaining effective treatment," said Michalski, also vice chair and director of clinical programs in the Department of Radiation Oncology. "We found that reducing the dose of radiation received over the six-week course of treatment had a negative impact on survival. But we also found that we could safely reduce the size of the volume of the brain that receives a radiation boost at the end of the treatment regimen. We hope such measures can help reduce the side effects of this treatment, especially in younger patients."

Collaborating with children's hospitals across the U.S. and internationally, the researchers evaluated 464 patients treated for average risk medulloblastoma that was diagnosed between ages 3 and 21. Younger patients, ages 3 to 7 -- a key time for brain development -- were randomly assigned to receive either standard dose (23.4 gray) or low dose (18 gray) radiation to the head and spine region in each of 30 treatments given over six weeks. Older patients all received the standard dose, since their brain development is less vulnerable to radiation. In addition, all patients were randomly assigned to receive two different sizes of a radiation "boost" at the end of the six weeks of therapy. For the boost, all patients received a cumulative radiation dose of 54 gray to either the entire region of the brain called the posterior fossa, which includes the cerebellum, or to a smaller region of the brain that includes the original outline of the tumor plus an additional margin of up to about two centimeters beyond the original tumor boundary.

"The patients who received the smaller boost did just as well as those who received the whole posterior fossa boost," said Michalski, who treats patients at Siteman Kids at Washington University School of Medicine and St. Louis Children's Hospital. "Many doctors have already adopted this smaller boost volume, but now we have high-quality evidence that this is indeed safe and effective."

For patients receiving the smaller boost volume, 82.5% survived five years with no worsening of the cancer. And for those receiving the larger boost volume to the entire posterior fossa, 80.5% survived five years with no worsening of the disease. These numbers were not statistically different. In a subset of tumors with mutations in a gene called SHH, patients actually showed improved survival with the smaller boost volume.

But for the younger children, the lower dose of radiation over six weeks did not result in similar survival numbers. Of those receiving the standard dose of craniospinal radiation, about 83% survived five years with no worsening of the cancer. Of those receiving the lower dose, about 71% survived five years with no worsening of the cancer. That difference in survival was statistically significant.

"We saw higher rates of recurrence and tumor spreading in the younger patients receiving the lower dose of craniospinal radiation," Michalski said. "In general, it's not safe to lower the dose of radiation in children with medulloblastoma even if we know the lower dose might spare their cognitive function. However, a specific subgroup of patients -- those with mutations in a gene called WNT -- did well on the lower dose, so we're now doing studies just with these specific patients to see if we can safely lower the radiation dose for them."

The tumors were categorized into four molecular subgroups based on their gene expression and predicted biology. The first group's tumors have mutations in WNT signaling pathways; the second have mutations in the SHH gene; and the third and fourth groups' tumors each have different and more complex patterns of gene mutations. The researchers found differences in tumors' responses to treatment based on tumor biology that can guide the design of future clinical trials.

"We've made great strides over the last 15 years in appreciating the molecular diversity of medulloblastoma," said senior author Paul Northcott, PhD, of St. Jude Children's Research Hospital. "We performed whole-exome sequencing and DNA methylation profiling to assign patients to molecular subgroups. This was a critical step in contextualizing this trial based on the latest biology and showed us some important differences in how children respond to therapy that would otherwise not have been clear. Results from this study will play a vital role in designing the next generation of clinical trials for children with medulloblastoma."

Increasing evidence shows that physical activity and exercise training may delay or prevent the onset of Alzheimer's disease (AD). In aging humans, aerobic exercise training increases gray and white matter volume, enhances blood flow, and improves memory function. The ability to measure the effects of exercise on systemic biomarkers associated with risk for AD and relating them to key metabolomic alterations may further prevention, monitoring, and treatment efforts. However, systemic biomarkers that can measure exercise effects on brain function and that link to relevant metabolic responses are lacking.

To address this issue, Henriette van Praag, Ph.D., from Florida Atlantic University's Schmidt College of Medicine and Brain Institute and Ozioma Okonkwo, Ph.D., Wisconsin Alzheimer's Disease Research Center and Department of Medicine at the University of Wisconsin-Madison and their collaborators, tested the hypotheses that three specific biomarkers, which are implicated in learning and memory, would increase in older adults following exercise training and correlate with cognition and metabolomics markers of brain health. They examined myokine Cathepsin B (CTSB), brain derived neurotrophic factor (BDNF), and klotho, as well as metabolomics, which have become increasingly utilized to understand biochemical pathways that may be affected by AD.

Researchers performed a metabolomics analysis in blood samples of 23 asymptomatic late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50 percent female) who participated in the "aeRobic Exercise And Cognitive Health (REACH) Pilot Study" (NCT02384993) at the University of Wisconsin. The participants were divided into two groups: usual physical activity (UPA) and enhanced physical activity (EPA). The EPA group underwent 26 weeks of supervised treadmill training. Blood samples for both groups were taken at baseline and after 26 weeks.

Results of the study, published in the journal Frontiers in Endocrinology, showed that plasma CTSB levels were increased following this 26-week structured aerobic exercise training in older adults at risk for AD. Verbal learning and memory correlated positively with change in CTSB but was not related to BDNF or klotho. The present correlation between CTSB and verbal learning and memory suggests that CTSB may be useful as a marker for cognitive changes relevant to hippocampal function after exercise in a population at risk for dementia.

Plasma BDNF levels decreased in conjunction with metabolomic changes, including reductions in ceramides, sphingo- and phospholipids, as well as changes in gut microbiome metabolites and redox homeostasis. Indeed, multiple lipid metabolites relevant to AD were modified by exercise in a manner that may be neuroprotective. Serum klotho was unchanged but was associated with cardiorespiratory fitness.

"Our findings position CTSB, BDNF, and klotho as exercise biomarkers for evaluating the effect of lifestyle interventions on brain function," said van Praag, corresponding author, an associate professor of biomedical science, FAU's Schmidt College of Medicine, and a member of the FAU Brain Institute and the FAU Institute for Human Health & Disease Intervention (I-HEALTH). "Human studies often utilize expensive and low throughput brain imaging analyses that are not practical for large population-wide studies. Systemic biomarkers that can measure the effect of exercise interventions on Alzheimer's-related outcomes quickly and at low-cost could be used to inform disease progression and to develop novel therapeutic targets."

CTSB, a lysosomal enzyme, is secreted from muscle into circulation after exercise and is associated with memory function and adult hippocampal neurogenesis. Older adults with cognitive impairment have lower serum and brain CTSB levels. BDNF is a protein that is upregulated in the rodent hippocampus and cortex by running and is important for adult neurogenesis, synaptic plasticity, and memory function. Klotho is a circulating protein that can enhance cognition and synaptic function and is associated with resilience to neurodegenerative disease, possibly by supporting brain structures responsible for memory and learning.

"The positive association between CTSB and cognition, and the substantial modulation of lipid metabolites implicated in dementia, support the beneficial effects of exercise training on brain function and brain health in asymptomatic individuals at risk for Alzheimer's disease," said van Praag.

Scientists say naked mole rats - a rodent native to West Africa - may hold the key to new treatments for degenerative diseases such as cancer and dementia.

The reclusive animals have a lifespan far in excess of other rodents - for example, mice and rats live about two years, whereas naked mole rats can live for 40 or 50 years.

Researchers at the University of Bradford say the animals have a unique DNA repair mechanism that enables them to prevent cancers and other degenerative conditions, including dementia.

Cancer resistant

Professor Sherif El-Khamisy, Director of the Institute of Cancer Therapeutics at the University, said: "Naked mole rats are fascinating creatures, not least because they are so long lived compared to other rodents of the same size. They also do not suffer from - what we call in humans - age associated disorders, such as cancer, dementia and neurological decline.

"What we're trying to do is to understand what makes them so resistant and then to try to harness that knowledge to come up with new treatments for cancer and conditions like dementia in people.

"This is not about extending life but extending the quality of life."

DNA mutations

Prof El-Khamisy, from the University's Faculty of Life Sciences, is the lead author of a paper, DNA Homeostasis and Senescence: Lessons from the Naked Mole Rat, recently published in the International Journal of Molecular Sciences.

It states: "As we age, our bodies accrue damage in the form of DNA mutations. These mutations lead to the generation of sub-optimal proteins, resulting in inadequate cellular homeostasis and senescence*. The build-up of senescent cells negatively affects the local cellular micro-environment and drives ageing associated disease, including neurodegeneration.

"Which processes show an increased burden as naked mole rats age may identify novel biological targets to mitigate our own degeneration."

Prof El-Khamisy added: "This is a new area of research, so there are still lots of things we don't know. For example, Alzheimer's and dementia are caused by protein aggregations in the brain and this has been a puzzle to scientists for many years. There are questions around how those proteins form and also how the body deals with them. Clearly, naked mole rats are much better than us at dealing with them.

"If we can work out how they do this, we could look to adopt similar systems in humans or to use these markers as a predictive tool to be able to say 'this person is more likely to develop dementia or cancer as they age', and then take appropriate steps."

Naked mole rats fact file

Naked mole rats are mostly hairless, wrinkly rodents that grow to between three and 13 inches.

They live for 40 or 50 years and are immune to cancer and some types of pain, such as that from biting insects and spicy plants.

In the wild, they live in hierarchical colonies (with a queen, soldiers and workers) sometimes numbering up to 300, creating a warren of underground tunnels and rooms the size of several football pitches.

They live most of their lives in caves or underground, yet despite their lack of exposure to the sun, they have a strong circadian rhythm.

A pup naked mole rat weighs less than a penny.

* In biology, homeostasis is the state of steady internal, physical, and chemical conditions maintained by living systems; whereas senescence is the condition or process of deterioration with age.

People often think about human behavior in terms of what is happening in the present--reading a newspaper, driving a car, or catching a football. But other dimensions of behavior extend over weeks, months, and years.

Examples include a child learning how to read; an athlete recovering from a concussion; or a person turning 50 and wondering where all the time has gone. These are not changes that people perceive on a day-to-day basis. They just suddenly realize they're older, healed, or have a new development skill.

"The field of neuroscience looks at the brain in multiple ways," says Franco Pestilli, a neuroscientist at The University of Texas at Austin (UT Austin). "For example, we're interested in how neurons compute and allow us to quickly react--it's a fast response requiring visual attention and motor control. Understanding the brain needs big data to capture all dimensions of human behavior."

As an expert in vision science, neuroinformatics, brain imaging, computational neuroscience, and data science, Pestilli's research has advanced the understanding of human cognition and brain networks over the last 15 years.

Pestilli likes to compare the brain to the Internet, a powerful set of computers connected by cables simultaneously keeping many windows open and programs running. If the computer is healthy but the cables are not, long range communication between computers in different parts of the brain begins to fail. This in turn creates problems for our long-term behavior.

Pestilli and team are also interested in how biological computations change over longer time periods--such as how does our brain change as we lose our vision?

"We've shown that if you change the input into the eye, it can change the brain's white matter, which is equivalent to the brain's cabling system--just like computers are connected with cables, our brain has millions of cables connecting millions of tiny computers called neurons."

This research was published in Nature Scientific Reports in March 2021.

Brainlife.io--The Platform Scientists Need to Do the Science They Want

New cloud technologies are becoming necessary to help researchers collaborate, process, visualize, and manage large amounts of data at unprecedented scales.

A key aspect of Pestilli's work started in 2017 when he received a grant from the BRAIN Initiative through the National Science Foundation (NSF) to launch Brainlife.io. At that time, he was an associate professor in Psychological and Brain Sciences with Indiana University.

The Brainlife.io computing platform provides a full suite of web services to support reproducible research on the cloud. More than 1,600 scientists from around the world have accessed the platform thus far. BrainLife.io allows them to upload, manage, track, analyze, share, and visualize the results of their data.

Currently, the platform serves different communities of scientists from psychology to medical science to neuroscience, and includes more than 600 data processing tools. Brainlife.io integrates different expertise and development mechanisms for making code and publishing it on the cloud--while tracking every detail that happens to the data.

"We've processed more than 300,000 datasets thus far--and we're serving many new users as the number of scientists accessing our platform has exploded during the pandemic," Pestilli said. "A lot of new people came to Brainlife.io because they lost access to their physical facilities."

The platform relies on supercomputing infrastructure to run simulations on high performance computing (HPC) hardware. "National systems like Jetstream (Indiana University/TACC), Stampede2 (TACC), and Bridges-2 (Pittsburgh Supercomputing Center) are fundamental to what we do. We've received a lot of support the Extreme Science and Engineering Discovery Environment (XSEDE) funded by NSF."

BrainLife.io is also funded via collaborative awards from the National Institutes of Health (NIH) and the Department of Defense.

Aina Puce is a professor in Psychological and Brain Science at Indiana University. She is a self-proclaimed neophyte with regard to Brainlife.io, yet she is a world expert in neuroimaging, and the principal investigator of an NIH grant that supports the development of neurophysiological data management and analyses on the platform.

"I jumped in at the deep end to help Franco and his team expand the functionality of the platform to neurophysiological data," Puce said.

"Brainlife.io is allowing us to start to perform cutting-edge analyses, integrating neurophysiological data and MRI-based data. Studies include research explicitly linking brain structure to brain function, such as how information gets transported from region to region, and how blood flow and brain electrical activity change when performing particular tasks."

Soon, a suite of new tools will be available on Brainlife.io for users to integrate EEG (electroencephalography), MEG (magnetoencephalography), and MRI (magnetic resonance imaging) data, which is "unique and will be tremendously helpful for both science and society," she said.

Puce and team are currently exploring brain activity by recording electrical output, both non-invasively from the scalp and invasively from the inside of the head. They are also detecting magnetic fields produced while a person is at rest and while they are performing tasks such as reading social messages from others.

"This is what we are bringing to Brainlife.io for the first time," Puce said.

Data Drives Discovery

The field of neuroscience is moving from small data sets to large data sets. Larger data sets mean that scientists can extract more statistically powerful insights from the information they collect.

From 1,000 subjects to 10,000 subjects to 500,000 subjects -- the data sets keep growing.

For example, the Adolescent Brain Cognitive Development Study is one of the largest, long-term studies of brain development and child health in the United States. The study is collecting data from over 10,000 adolescent brains to understand biological and behavioral development from adolescence into young adulthood. In another part of the world, the UK Biobank contains in-depth health information from more than 500,000 participants who donated their genetic and clinical data for the good of science; 100,000 of these participants donated brain scans.

"As each new project scales up," Pestilli said, "the size of the data set also scales up, and as a result, the needs for storage and computing change. We're building datasets of a size and impact that only supercomputers can effectively cope. With the recent advent of machine-learning and artificial intelligent methods, and their potential to help humans understand the brain, we need to change our paradigm for data management, analysis, and storage."

Pestilli says that neuroscience research can't survive unless a cohesive ecosystem is built that will integrate the needs of the scientists with hardware and software needs given the tremendous amount of data and the next-generation questions to be explored.

He says that many of the tools developed so far are not easily integrated into a typical work flow or ready to use.

"To make an impact in neuroscience and connect the discipline to the most cutting-edge technologies such as machine learning and artificial intelligence, the community needs a cohesive infrastructure for cloud computing and data science to bring all these tremendous tools, libraries, data archives, and standards closer to the researchers who are working for the good of society," he said.

Fortunately, Pestilli found a like-minded collaborator who shares this vision in Dan Stanzione, the executive director of the Texas Advanced Computing Center (TACC) and a nationally recognized leader in HPC.

Together, they plan to create a national infrastructure that provides a registry for permanent data and analyses records. Researchers will be able to find data and more transparently see the root of how the analysis was conducted. The infrastructure will facilitate what the NSF) requires in data proposals, and what researchers want, which is scientific impact and reproducibility.

In addition, this means that access to data, analysis methods, and computational resources will move toward a more equitable model, providing opportunities for many more students, educators, and researchers than ever before.

"This prospect made me very excited about joining The University of Texas at Austin," Pestilli said. He re-located to Austin in August 2020, right in middle of the COVID-19 pandemic. Being at UT Austin means collaborating with TACC--a key reason why he accepted a professorship in the Department of Psychology.

"I'm confident that we can get it done--this vision is a crucial part of my efforts here."

Researchers at Michigan Medicine found a subset of middle-aged men with cerebral palsy are up to 5.6 times more likely to suffer fractures than men without the disorder.

"We are not really sure why this happens," said Edward A. Hurvitz, M.D., professor and chair of the Michigan Medicine Department of Physical Therapy and Rehabilitation. "It may be related to structural differences that occur during adolescent growth, or to greater bone mineral loss at earlier age for people with cerebral palsy compared to peers."

For a study published in BONE, the team examined the timing and site of bone fractures for around 10 million people with and without cerebral palsy using public and private insurance claims from 2016. They found people with the disability have fragile bones that present high fracture risk, but at different times across the lifespan compared to the general population.

"Knowing that critical periods of bone health are different for people with cerebral palsy is vital for clinicians so they aren't missing windows to augment bone strength," said Daniel Whitney, Ph.D., the study lead and assistant professor of physical medicine and rehabilitation at Michigan Medicine.

A period of critical bone health is when a person's bones are rapidly changing. In developmental years, they grow larger and stronger. They lose bone mineral density over time and may become weaker - for women, that can happen during menopause. Physicians often use these critical periods as reference points for fracture prevention efforts and post-fracture health care management.

The team examined fracture risk across the lifespan to see if the critical periods of bone health from the general population align with the timing of fracture vulnerability for people with cerebral palsy.

The result? Well, it's complicated.

In addition to the revelation about the surprisingly elevated fracture risk in middle aged-men, researchers found that adolescence and young adult years are a particularly vulnerable time for fractures for people with cerebral palsy, but in different ways for females and males.

Finding that both age and sex influence fracture risk at different times across the lifespan, the team developed new sex-specific critical periods of bone health for this population.

While this study positions clinical care to better align with the timing of the skeletal needs for people with cerebral palsy, it also raises a number of questions, Whitney said.

"Why do middle-aged men with cerebral palsy exhibit such a drastic increase in fracture risk?" he said. "Do women with cerebral palsy experience a similar timing or effect by the menopause transition on bone health? What is going on with the bone biology and structure early in life that sets the stage for their premature and profound bone fragility?"

It is well known that people with cerebral palsy have a higher risk of fractures, but this new study will change the way we think about fracture prevention, especially for adults, Hurvitz said.

"When we consider the high risk of chronic disease and early mortality associated with fractures that we have discovered in our previous work, fracture prevention for this population is a critical aspect of their care," he said.

The claims data used for the study doesn't reveal the severity of cerebral palsy patient's condition, which, researchers noted, would have added to their understanding of bone fragility.

This study will allow physicians to be more proactive with fracture prevention, and the next step is understanding exactly why bone health presents differently with these patients compared to the general population, Whitney said.

"When we only have a screwdriver, every problem will look like a screw," he said. "This study provides novel insight into the magnitude and unique timing of bone fragility across the lifespan for individuals with cerebral palsy, and it expands our toolkit to identify new ways to address a long-standing problem."

JUNE 10, 2021, NEW YORK - A Ludwig Cancer Research study adds to growing evidence that immune cells known as macrophages inhabiting the body cavities that house our vital organs can aid tumor growth by distracting the immune system's cancer-killing CD8+ T cells.

Reported in the current issue of Cancer Cell and led by Ludwig investigators Taha Merghoub and Jedd Wolchok at Memorial Sloan Kettering (MSK) and Charles Rudin of MSK, the study shows that cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), a molecule that they surprisingly found on the surface of highly activated, cytotoxic and proliferative CD8+ T-cells.

"We believe T-cells that infiltrate the peritoneal cavity can be distracted by the interaction with Tim-4-expressing macrophages," explained study first author Andrew Chow, an assistant attending physician at the Ludwig Collaborative Laboratory at MSK.

The researchers also show that blocking Tim-4 in mouse models of cancer can prevent this distractive interaction and enhance the effectiveness of immunotherapies.

"I think in patients who have these serous cavity macrophages expressing high levels of Tim-4, blocking Tim-4 will make immune based therapies more effective," Merghoub, co-director of the Ludwig Collaborative Laboratory at MSK, said.

Just as people living in different cities might have distinct customs or accents, the macrophages in our bodies can adopt specialized functions and respond to disease differently depending on which tissue they inhabit. Scientists are increasingly interested in such localized responses because macrophage activities can influence recovery from illness or injury and responses to therapy.

Merghoub, Wolchok, Rudin, Chow and colleagues began exploring the role of macrophages in tumor immunosuppression after noticing that cancer patients with lesions in their pleural and peritoneal cavities--which house the lungs and organs of the gastrointestinal tract, respectively--were substantially less responsive to immune checkpoint blockade therapy, which stimulates a CD8+ T cell attack on tumors.

"That told us there was something immunosuppressive in these cavities, so we went hunting for what that could be," Chow said.

Previous studies have shown that other immunosuppressed sites in the body, such as the liver and bone, harbor macrophages expressing high levels of Tim-4. Others have shown that macrophages living in the pleural and peritoneal cavities of mice also exhibit a strong Tim-4 signal.

The researchers therefore suspected that cavity-resident macrophages might impair the anti-tumor activity of CD8+ T cells through the actions of Tim-4.

These suspicions were partly vindicated when the researchers analyzed the cavity macrophages of human lung cancer patients and found that while Tim-4 levels varied between individuals, those with higher levels of the receptor tended to have a reduced presence of CD8+ T cells that had features of responding to the tumor.

Based on these observations, the researchers explored whether blocking Tim-4 would enhance the efficacy of PD-1 blockade therapies in a pre-clinical mouse model of colon and lung cancer in the peritoneal cavity.

"We showed that you get the best tumor protection when you block both molecules," Chow said.

While blocking Tim-4 alone didn't reduce the number of tumors or improve survival in the mice, it did enhance the tumor protection afforded by PD-1 blockade and boost the numbers of CD8+ T cells in the peritoneal cavity. The researchers also showed that Tim-4 blockade reduces immunosuppression in adoptive T-cell therapy, in which tumor-targeting T-cells are isolated and selectively grown in a lab before they're reinfused into the patient.

"Together, these results suggest that Tim-4 blockade is a strategy to improve immunotherapy, regardless of whether you're trying to boost your immune response through immune checkpoint blockade therapy or via adoptive T-cell therapy," said Chow.

For Merghoub, the new findings demonstrate the need to better understand the diversity of immune landscapes in and around tumors. "In the same way we profile tumor genomes to guide the use of small molecule inhibitors for targeted therapies, we need to profile the immune landscapes of tumors and personalize immune-based therapies on the basis of such studies," he said.