Publisher Health

An estimated quarter of adults and two-thirds of children have strong fears around needles, according to the U.S. Centers for Disease Control and Prevention. Yet, public health depends on people being willing to receive vaccines, which are often administered by a jab.
Darcy Dunn-Lawless, a doctoral student at the University of Oxford’s Institute of Biomedical Engineering, is investigating the potential of a painless, needle-free vaccine delivery by ultrasound. He will share the recent advancements in this promising technique as part of Acoustics 2023 Sydney, running Dec. 4-8 at the International Convention Centre Sydney. His presentation will take place Dec. 4 at 11:00 a.m. Australian Eastern Daylight Time.
“Our method relies on an acoustic effect called ‘cavitation,’ which is the formation and popping of bubbles in response to a sound wave,” said Dunn-Lawless. “We aim to harness the concentrated bursts of mechanical energy produced by these bubble collapses in three main ways. First, to clear passages through the outer layer of dead skin cells and allow vaccine molecules to pass through. Second, to act as a pump that drives the drug molecules into these passages. Lastly, to open up the membranes surrounding the cells themselves, since some types of vaccine must get inside a cell to function.”
Though initial in vivo tests reported 700 times fewer vaccine molecules were delivered by the cavitation approach compared to conventional injection, the cavitation approach produced a higher immune response. The researchers theorize this could be due to the immune-rich skin the ultrasonic delivery targets in contrast to the muscles that receive the jab. The result is a more efficient vaccine that could help reduce costs and increase efficacy with little risk of side effects.
“In my opinion, the main potential side effect is universal to all physical techniques in medicine: If you apply too much energy to the body, you can damage tissue,” Dunn-Lawless said. “Exposure to excessive cavitation can cause mechanical damage to cells and structures. However, there is good evidence that such damage can be avoided by limiting exposure, so a key part of my research is to try and fully identify where this safety threshold lies for vaccine delivery.”
Dunn-Lawless works as part of a larger team under the supervision of Dr. Mike Gray, Professor Bob Carlisle, and Professor Constantin Coussios within Oxford’s Biomedical Ultrasonics, Biotherapy and Biopharmaceuticals Laboratory (BUBBL). Their cavitation approach may be particularly conducing to DNA vaccines that are currently difficult to deliver. With cavitation able to help crack open the membranes blocking therapeutic access to the cell nucleus, the other advantages of DNA vaccines, like a focused immune response, low infection risk, and shelf stability, can be better utilized.

Self-folding polymers containing gadolinium forming nanosized complexes could be the key to enhanced magnetic resonance imaging and next-generation drug delivery, as demonstrated by scientists at Tokyo Tech. Thanks to their small size, low toxicity, and good tumor accumulation and penetration, these complexes represent a leap forward in contrast agents for cancer diagnosis, as well as neutron capture radiotherapy.
Magnetic resonance imaging (MRI) is a crucial diagnostic tool for cancer, enabling the capturing of detailed images of soft tissues. To visualize tumors more clearly in MRI scans, doctors usually inject patients with contrast agents. These compounds affect the way nearby hydrogen ions respond to the radiofrequency pulses used in MRI. Ideally, contrast agents should selectively accumulate in tumors and increase their contrast in the MRI scan.
However, despite many research efforts, conventional gadolinium (Gd)-chelate contrast agents are reaching their performance limits. Simply put, achieving an optimal dose in the distribution of Gd-chelates within tumors, healthy tissue, and blood has proven challenging without resorting to excessive Gd doses.
Against this backdrop, a collaborative study by a research team from Tokyo Institute of Technology (Tokyo Tech), National Institutes for Quantum Science and Technology (QST) and Innovation Center of Nanomedicine (iCONM), led by Associate Professor Yutaka Miura of Tokyo Tech, successfully developed a novel NCA with exceptional performance thanks to an innovative molecular design. Their findings were published in the Advanced Science on November 29.
The proposed nano-contrast agent (NCA) is based around the use of Gd as a contrast agent in what the researchers called a “self-folding macromolecular drug carrier (SMDC).” They incorporated clinically approved Gd-containing chelates into a polymer chain composed of poly(ethylene glycol) methyl ether acrylate (PEGA) and benzyl acrylate (BZA). Since the polymer contained both hydrophilic and hydrophobic segments, it quickly folded itself into a small capsule-like shape when immersed in water, with the hydrophobic segments at the core and the hydrophilic segments at the outer shell.
Using this approach, the researchers could produce SMDC-Gds molecules smaller than 10 nanometers in diameter. Through experiments in mice with colon cancer, they verified that these NCAs not only accumulated better in tumors, but that they were also promptly eliminated from the bloodstream, leading to enhanced MRI performance without toxic effects. “the high accumulation in tumor while quick blood clearance profile of SMDC-Gds allows for the increase in the tumor-to-major organ accumulation ratios as well as minimizing the unnecessary deposition of Gds,” explains Prof. Miura.
Moreover, the team also demonstrated a novel effect that puts SMDC-Gds ahead of existing Gd-chelates. Ideally, the motion of Gd ions should be minimal so that their influence on nearby hydrogen ions is steady and prolonged. In the proposed molecular design, the core/shell structure creates a ‘crowded’ molecular environment that suppresses not only the rotation, but also the segmental and internal motions of Gd ions. The resulting effect is a stronger contrast in MRI images, which will allow for use of alternative elements with safer profiles not only in patients but also environment in future.
It’s worth highlighting that the applications of SMDC-Gds extend beyond MRI. These compounds can be used in neutron capture therapy (NCT), a promising targeted radiotherapy technique in which Gds capture neutrons and release high energy radiations, killing nearby cancer cells. Experiments in mice revealed that NCT following repeated SMDC-Gd injection led to greatly suppressed tumor growth. The team believes the reason for this was the selective accumulation and deep penetration of SMDC-Gds into tumor tissues.
Collectively, the researchers’ collaborative efforts to achieve these findings underscore the potential of SMDCs not only for better MRI diagnostics, but also as effective tools for treating cancer and other diseases. “This study presents further possibilities for exploiting drug delivery using various therapeutic cargos, and we are currently investigating the development of such SMDC systems,” concludes a hopeful Prof. Miura.

Neurodegenerative diseases are characterized by the deposition of clumped proteins in the brain and progressive neuronal cell death. Although the causal link between protein aggregates and neurodegeneration is clear, it is still unclear in what way misfolded proteins trigger cell death. A team headed by Professor Jörg Tatzelt, head of the Department of Biochemistry of Neurodegenerative Diseases at Ruhr University Bochum, Germany, showed that misfolded prion proteins can inactivate the TDP-43 protein. TDP-43 is essential for maintaining protein balance in all cell types, especially in nerve cells. A dysfunction of TDP43 is associated with amyotrophic lateral sclerosis and frontotemporal dementia. 
Protein aggregates and neurodegeneration
The causes of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia and prion diseases can be many and varied. But there is a common denominator, namely protein misfolding and the occurrence of protein deposits in the brain. “Various approaches and models have shown that misfolded proteins play a crucial role in the disease process,” says Jörg Tatzelt. “Still, there’s an ongoing debate about the nature of the harmful protein species and how misfolded proteins selectively damage specific neurons.”
Studies on genes associated with pathologies have revealed two basic mechanisms by which misfolded proteins can lead to neurodegeneration: Firstly, misfolding can cause the protein to acquire toxic activity. Secondly, the misfolding can lead to a loss of the physiological function of the protein, which impairs important physiological processes in the cell.
“The assumption used to be that every neurodegenerative disease was characterized by the misfolding of a specific protein,” explains Jörg Tatzelt. “However, it has since been shown that misfolded proteins that are produced more frequently in one disease can also induce the aggregation of other proteins, a mechanism referred to as cross-seeding.”
The prion protein and TDP-43
TDP-43 (TAR DNA-binding protein 43) is a protein that helps to translate genetic information into specific proteins. It thus helps to maintain the protein balance in nerve cells. The clumping of TDP-43 in the cell is a characteristic feature in the brains of patients suffering from amyotrophic lateral sclerosis or frontotemporal dementia.

Misfolding of the prion protein triggers prion diseases such as Creutzfeldt-Jakob disease. All research findings to date indicate that the misfolded prion protein acquires toxic activity. However, the exact mechanisms by which disease-associated prion proteins trigger the death of nerve cells are only partially understood.
TDP-43 loses its physiological function through PrP-mediated cross-seeding
Using in vitro and cell culture approaches, animal models and brain samples from patients with Creutzfeldt-Jakob disease, the researchers showed that misfolded prion proteins can trigger the clumping and inactivation of TDP-43. The prion proteins interact with TDP-43 in vitro and in cells, thus inducing the formation of TDP aggregates in the cell. As a result, TDP-43-dependent splicing activity in the cell nucleus is significantly reduced, leading to altered protein expression. “Prion protein and TDP-43 are partners in crime in neurodegenerative diseases, so to speak,” says Jörg Tatzelt.
An analysis of brain samples showed that in some Creutzfeld-Jacob patients, TDP-43 aggregates were found alongside the prion protein deposits. This study has revealed a new mechanism of how disease-associated prion proteins can affect physiological signaling pathways through cross-seeding.

Insulin is a hormone that decreases blood glucose levels. The only cells that produce insulin are pancreatic beta cells (β-cells), and a decrease in these cells is a major cause of diabetes. Although therapies aimed at increasing pancreatic β-cells are eagerly awaited, a strategy that can increase β-cells has, thus far, not been developed.
In a promising development, a research group has revealed that stimulating autonomic vagal nerves connected to the pancreas can improve the function and also increase the number of pancreatic β-cells in mice.
The group, which was led by Associate Professor Junta Imai, Assistant Professor Yohei Kawana, and Professor Hideki Katagiri from the Tohoku University Graduate School of Medicine, published their findings in the international scientific journal Nature Biomedical Engineering on November 9, 2023.
“Using optogenetics, we first developed a means to stimulate individually the vagus nerve leading to the pancreas in mice,” says Imai. “This novel method led to a marked elevation in the amount of insulin in the blood when sugar was administered, indicating improved β-cell function.”
Additional stimulation of this nerve over two weeks more than doubled the original number of β-cells. Stimulating the pancreatic vagal nerves activated β-cells in terms of both quality and quantity.
When Imai and his colleagues applied this method to a mouse model of insulin-deficient diabetes, the regeneration of pancreatic β-cells ameliorated diabetes in these mice. This represents the first successful treatment of diabetes in mice by stimulating the vagal nerves connected to the pancreas.
“We hope our achievements lead to the development of new strategies and preventive methods for diabetes,” adds Imai. “We also expect it to advance our understanding of the mechanisms that regulate the function and number of pancreatic β-cells, as well as the causes of diabetes.”
The research in the project was supported by the Japan Science and Technology Agency (JST), [Moonshot R&D] as well as by the Japan Agency for Medical Research and Development (AMED-PRIME).

Pancreatic beta cells (β-cells) reside in a cluster of cells in the pancreas known as the islets of Langerhans. Pancreatic β cells are the only cells that produce insulin — a hormone that decreases blood glucose levels. A decrease in pancreatic β cells is a major cause of diabetes.
Scientists have long known that pancreatic β cells increase during pregnancy and promptly return to their original number following birth. But scientists still do not understand the underlying mechanisms that cause the cells to go back to their original number.
In a significant breakthrough, a research group has discovered that a type of white blood cell called macrophages ‘eat’ (phagocytose) the pancreatic β cells, thereby revealing the process behind their return to previous levels after pregnancy.
The research group, which was led by Associate Professor Junta Imai, Assistant Professor Akira Endo, and Professor Hideki Katagiri from Tohoku University’s Graduate School of Medicine, published the results in the journal Development Cell on September 15, 2023.
Initially, the group examined the number of pancreatic β cells in the islets of Langerhans in a mouse model of pregnancy. They confirmed the cell number was double at the end of the pregnancy when compared to non-pregnant mice, but that it then gradually decreased, returning to the original amount after delivery.
“After we observed the islets of Langerhans before and after delivery, we noticed an increase in macrophages, which protect the body from infections by engulfing bacteria, foreign substances and dead cells, after delivery,” says Imai. “When we applied treatment to inhibit this process, the blood glucose levels became too low (hypoglycemia).”
Additional microscopic observation of the islets of Langerhans after birth revealed β cells to be phagocytosed by macrophages. This mechanism appeared to keep the mother’s blood glucose levels from decreasing excessively after delivery by rapidly reducing pancreatic β cells to their normal pre-pregnancy number.
Next, the group identified the protein responsible for attracting the macrophages into the islets of Langerhans: cytokine CXCL10. Accordingly, the inhibition of CXCL10 function suppressed the decrease in pancreatic β cells after birth.
“We hope our results will contribute to clarifying the means by which normal blood glucose levels are maintained as well as the development of methods to prevent and treat diabetes,” adds Imai.
The research was supported by the Japan Science and Technology Agency (JST) [Moonshot R&D] as well as by the Japan Agency for Medical Research and Development (AMED-PRIME).

Hispanic/Latina women with a history of hypertensive disorders of pregnancy (HDP) — conditions marked by high blood pressure during pregnancy — are more likely to have abnormalities in their heart structure and function decades later when compared with women without a history of HDP, according to a National Institutes of Health-supported study. The findings, published in the journal Hypertension, also suggest that while having high blood pressure later in life can contribute to these abnormalities, HDP play the greater role, significantly raising a woman’s risk of developing cardiovascular disease.
“The changes in cardiac structure and function that this study uncovers are known predictors of cardiovascular events such as heart failure and even death,” said Jasmina Varagic, Ph.D., program officer in the Vascular Biology and Hypertension branch at the National Heart, Lung, and Blood Institute (NHLBI), part of NIH. “These findings emphasize the importance of recognizing HDP as an important risk factor for these future problems, especially in this understudied population of women.”
The rates of HDP, which include preeclampsia, eclampsia, and gestational hypertension, more than doubled between 2007-2019 in the U.S., with Hispanic/Latina women having the highest rate of over 60 cases per 1000 live births. Previous studies have shown that among women who have HDP, up to 20% will continue to have high blood pressure six months after giving birth and will also have up to a 10-fold lifetime risk of chronic hypertension. But researchers were unclear just how HDP was driving the high risk of cardiovascular disease many of these women later developed.
“Prior to our study the question was: Do abnormalities in the structure and function of the heart develop because of the HDP itself, or because many of the women who have HDP then go on to develop chronic high blood pressure?” asked Odayme Quesada, M.D., medical director for The Christ Hospital Women’s Heart Center, and lead author on the study. “Our study helps to answer this question.”
For the study, the researchers used participants in the NHLBI-funded Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a multi-center community-based cohort of Hispanic/Latino adults. The cohort included 5,168 women who had at least one prior pregnancy and whose average age was 58.7 years — well past childbearing age — at the time of the study.
The participants underwent ultrasound scans to look for alterations in the structure and function of the heart, focusing on the left ventricle, considered the workhorse of the heart that pumps blood into the body. Researchers looked for alterations in the thickness and shape of the ventricle, and how well the heart squeezes and relaxes. The researchers found that prior HDP was associated with alterations in how the heart contracts and relaxes, increased thickness of the heart wall, and higher rates of abnormal geometry in the left ventricle. These abnormalities, particularly in the geometry of the left ventricle, are known to predict future cardiovascular events, including heart failure, ischemic heart disease, and sudden cardiac death.
The researchers also discovered that having hypertension later in life only accounted for part of the changes seen in heart structure and function. For example, they found that hypertension experienced by the women at the time of the study explained only 14% of the risk of having abnormal geometry of the left ventricle, while the rest was explained by having HDP at the time of their pregnancies.
“This underscores the importance of early surveillance for heart abnormalities in women whose pregnancy is complicated by HDP, and also the importance of managing high blood pressure to prevent later life cardiovascular disease,” said Varagic. She added that factors beyond blood pressure that link HDP to later life heart abnormalities need further investigation.

In Korea, occupational hazards are on the rise, particularly in the construction sector. According to a report on the ‘Occupational Safety Accident Status’ by Korea’s Ministry of Employment and Labor, the industry accounted for the highest number of accidents and fatalities among all sectors in 2021. To address this rise, the Korea Occupational Safety and Health Agency has been providing virtual reality (VR)-based construction safety content to daily workers as part of their educational training initiatives.
Nevertheless, current VR-based training methods grapple with two limitations. Firstly, VR-based construction safety training is essentially a passive exercise, with learners following one-way instructions that fail to adapt to their judgments and decisions. Secondly, there is an absence of an objective evaluation process during VR-based safety training. To address these challenges, researchers have introduced immersive VR-based construction safety content to promote active worker engagement and have conducted post-written tests. However, these post-written tests have limitations in terms of immediacy and objectivity. Furthermore, among the individual characteristics that can affect learning performance, including personal, academic, social, and cognitive aspects, cognitive characteristics may undergo changes during VR-based safety training.
To address this, a team of researchers led by Associate Professor Choongwan Koo from the Division of Architecture & Urban Division at Incheon National University, Korea, has now proposed a groundbreaking machine learning approach for forecasting personal learning performance in VR-based construction safety training that uses real-time biometric responses. Their paper was made available online on October 7, 2023, and will be published in Volume 156 of the journal Automation in Construction in December 2023.
“While traditional methods of evaluating learning outcomes that use post-written tests may lack objectivity, real-time biometric responses, collected from eye-tracking and electroencephalogram (EEG) sensors, can be used to promptly and objectively evaluate personal learning performances during VR-based safety training,” explains Dr. Koo.
The study involved 30 construction workers undergoing VR-based construction safety training. Real-time biometric responses, collected from eye-tracking and EEG to monitor brain activity, were gathered during the training to assess the psychological responses of the participants. Combining this data with pre-training surveys and post-training written tests, the researchers developed machine-learning-based forecasting models to evaluate the overall personal learning performance of the participants during VR-based safety training.
The team developed two models — a full forecast model (FM) that uses both demographic factors and biometric responses as independent variables and a simplified forecast model (SM) which solely relies on the identified principal features as independent variables to reduce complexity. While the FM exhibited higher accuracy in predicting personal learning performance than traditional models, it also displayed a high level of overfitting. In contrast, the SM demonstrated higher prediction accuracy than the FM due to a smaller number of variables, significantly reducing overfitting. The team thus concluded that the SM was best suited for practical use.
Explaining these results, Dr. Koo emphasizes, “This approach can have a significant impact on improving personal learning performance during VR-based construction safety training, preventing safety incidents, and fostering a safe working environment.” Further, the team also emphasizes the need for future research to consider various accident types and hazard factors in VR-based safety training.
In conclusion, this study marks a significant stride in enhancing personalized safety in construction environments and improving the evaluation of learning performance!

IIASA researchers have introduced an innovative methodology for reconstructing data on fertility and education, particularly in developing countries with inconsistent or unreliable data sets.
Decision makers need consistent and reliable data to evaluate the impact of women’s education on fertility, particularly during periods of educational expansion and fertility transition (in other words, the decline of fertility from high levels), which is common in populations across the world today. This is especially important in developing countries where demographic issues are intricately connected to a range of other challenges, such as economic disparities, healthcare access, education gaps, environmental and climate change impacts, and political instability. However, getting hold of accurate and consistent data on fertility rates based on education and age is a challenge in many regions.
To help address the problem, Afua Durowaa-Boateng from the Vienna Institute of Demography (Austrian Academy of Sciences) together with IIASA researchers Anne Goujon and Dilek Yildiz, developed a modeling framework that can be used to reconstruct existing data to assess the role of education in fertility decline, providing historical evidence that can inform future population projections. Their work has been published in the journal Demographic Research.
“Our reconstructed data can help facilitate the assessment of the role of education in fertility decline and make up for the lack of available time series data. Furthermore, the estimates and historical evidence that our model provides can be used to inform the future when they are used in population projections,” Durowaa-Boateng explains.
The results affirm existing literature that women with a higher level of education tend to have lower fertility rates and also tend to have children at a later age. However, during an initial period, the fertility of educated women may be higher than that of women without education, as shown by the case of most countries in sub-Saharan Africa at the onset of the fertility decline in the 1980s. As education levels increase, the gap in fertility rates between individuals with different educational backgrounds increases, and then decreases as shown in the case of many Latin American countries which started their fertility transition in the 1970s and by 2020 show a reduced gap.
The study’s findings suggest that as more women become educated and reduce fertility, those with lower education levels tend to follow suit within their communities. This research is valuable for policymakers and organizations in low-income countries, providing insights into the spillover effects of education on fertility behavior.
“While the findings of our analysis are key for policymaking, the main immediate users will probably be scholars who can use the consistent time series data in their own models. Our research also opens avenues for more applications to reconstruct imperfect and incomplete education specific demographic data on fertility in other world regions such as South Asia,” says Yildiz.
“The fact that more researchers will be able to assess the role of education in fertility decline during the demographic transition, and the importance of changes in the age schedule in fertility depending on education, can be fed into population projections depending on different scenarios of education development as implemented at IIASA under the Shared Socioeconomic Pathways projections. The spillover effect of education on fertility behavior is important for policymakers and international organizations working in other low-income countries,” adds Goujon, who is the IIASA Population and Just Societies Program Director.
The researchers hope that their data and model, which is freely available on an accompanying website that also presents the data graphically, will be used by scholars and policymakers to address demographic challenges around the world, and particularly in Africa. There are plans to expand the website with additional research on population in Africa in the near future.

The BASHIR™ Endovascular Catheter (THROMBOLEX, Inc.), recently approved by the U.S. Food and Drug Administration (FDA), is paving the way to more effective and safe treatment for acute pulmonary embolism. Already shown to be effective for reducing blockages in lung arteries, new research at the Lewis Katz School of Medicine at Temple University shows that the BASHIR™ catheter also reduces blockages in the smaller segmental pulmonary artery branches. These branches are ultimately responsible for oxygenating the blood in the lungs.
The new study, which was part of the National Institutes of Health-sponsored multicenter RESCUE clinical trial, further showed a correlation between decreased numbers of blockages in the small lung arteries and functional recovery of the right ventricle of the heart, which pumps blood into the main pulmonary artery of the lungs. Compared to other devices, the BASHIR™ catheter also had significantly lower bleeding rates, a key advance in acute pulmonary embolism treatment. The findings are described in JACC: Advances.
“Blockages in these smaller, distal pulmonary arteries have never previously been explored in patients treated for acute pulmonary embolism,” explained Riyaz Bashir, MD, FACC, Professor of Medicine, Director of Vascular and Endovascular Medicine in the Section of Cardiology, Department of Medicine at the Lewis Katz School of Medicine and Temple University Hospital, co-inventor of the BASHIR™ Endovascular Catheter, and first author on the new report.
The BASHIR™ catheter is a small tube-like device that consists of a helical basket with six mini-infusion catheters at its farthest end. When the infusion basket is expanded within a clot in a large blood vessel, new channels open, enabling blood to flow through the clot. Blood that flows through carries the body’s clot-dissolving chemicals into the channels, accelerating clot breakdown. Researchers at THROMBOLEX™ Inc. were involved in developing and commercializing this platform technology.
The occlusion of small lung arteries is the major reason for the reduction in blood flow in patients with acute pulmonary embolism. “The more occlusions a patient has, the lower their survival,” Dr. Bashir said. “Among the treatment goals is relieving obstructions in both large and small arteries.”
Patients who survive may, over more extended periods, be at high risk of developing chronic thromboembolic pulmonary hypertension (CTEPH), which is a life-threatening condition caused by increased blood pressure in the lungs.
In the new study, Dr. Bashir and colleagues observed reductions in occlusions in segmental and proximal branches of the pulmonary artery 48 hours following treatment with the BASHIR™ catheter. The blockages decreased even in those arteries that were distant from where the infusion basket was located, enabling improved blood flow and healing of the right ventricle.

“We suspect that the improvements in blood flow are due to both the expansion of the basket and the flow of the body’s clot dissolving molecules into the clot, which cause the blockage to shrink,” Dr. Bashir said. “As the volume of blood flow improved, right ventricular function also improved, which could translate to better survival.”
In future work, Dr. Bashir and colleagues plan to investigate mechanisms behind the observed reductions in arterial blockage. More extensive trials are also needed to understand better the impact of treatment with the BASHIR™ catheter on patient survival and incidence of CTEPH.
Other researchers who contributed to the new study were Gregory Piazza, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston; Brian Firth, Thrombolex Inc, New Britain, Pennsylvania; Kenneth Ouriel, NAMSA (SYNTACTX), New York; Akhilesh Sista, Division of Interventional Radiology, Department of Radiology, Cornell University School of Medicine, New York; Parth Rali, Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University; Anthony Comerota, Inova Heart and Vascular Institute, Inova Alexandria Hospital, Alexandria, Virginia; Vladimir Lakhter, Division of Cardiovascular Diseases, Lewis Katz School of Medicine, Temple University; Ayman Iskander, Division of Cardiology, St Joseph’s Hospital, Syracuse; Malcolm Foster, Department of Cardiology, East Tennessee Heart, Turkey Creek, Knoxville; Ripal Gandhi, Division of Interventional Radiology, Miami Cardiac and Vascular Institute, Miami, Florida; Amir Darki, Department of Cardiology, Loyola University Medical Center, Maywood, Illinois; Robert Lookstein, Department of Radiology, Mount Sinai Hospital, New York; and Kenneth Rosenfield, Department of Cardiology, Massachusetts General Hospital, Boston.
Dr. Bashir is a co-founder and has an equity interest in Thrombolex, Inc., a medical device company developing interventional catheter-based therapies for the rapid and effective treatment of acute venous thromboembolic disorders. Temple University also holds financial interests in the BASHIR™ Endovascular Catheter and other Thrombolex products pursuant to the license granted to Thrombolex for the University’s interest in patents co-invented by Dr. Riyaz Bashir. As a result of these interests, Temple University could ultimately potentially benefit financially from the outcome of this research. These interests have been reviewed and approved by Temple University in accordance with its Institutional Conflict of Interest policy.

Mathematics, histopathology and genomics converge to confirm that the most aggressive clear cell renal cell carcinomas display low levels of intratumour heterogeneity, i.e. they contain fewer distinct cell types. The study, conducted by the UPV/EHU Ikerbasque Research Professor Annick Laruelle, supports the hypothesis that it would be advisable to apply therapeutic strategies to maintain high levels of cellular heterogeneity within the tumour in order to slow down the evolution of the cancer and improve survival.
Mathematical approaches are gaining traction in modern oncology as they provide fresh knowledge about the evolution of cancer and new opportunities for therapeutic improvement. So data obtained from mathematical analyses endorse many of the histological findings and genomic results. Game theory, for example, helps to understand the “social” interactions that occur between cancer cells. This novel perspective allows the scientific and clinical community to understand the hidden events driving the disease. In actual fact, considering a tumour as a collectivity of individuals governed by rules previously defined in ecology opens up new therapeutic possibilities for patients.
Within the framework of game theory, the hawk-dove game is a mathematical tool developed to analyse cooperation and competition in biology. When applied to cancer cell collectivities, it explains the possible behaviours of tumour cells when competing for an external resource. “It is a decision theory in which the outcome does not depend on one’s own decision alone, but also on the decision of the other actors,” explained Ikerbasque Research Professor Annick Laruelle, an expert in game theory in the UPV/EHU’s Department of Economic Analysis. “In the game, cells may act aggressively, like a hawk, or passively, like a dove, to acquire a resource.”
Professor Laruelle has used this game to analyse bilateral cell interactions in highly aggressive clear cell renal cell carcinoma in two different scenarios: one involving low tumour heterogeneity, when only two tumour cell types compete for a resource; and the other, high tumour heterogeneity, when such competition occurs between three tumour cell types. Clear cell renal cell carcinoma is so named because the tumour cells appear clear, like bubbles, under the microscope. This type of carcinoma has been taken as a representative case for the study, as it is a widely studied paradigm of intratumour heterogeneity (which refers to the coexistence of different subpopulations of cells within the same tumour).
Fresh theoretical approach for new therapeutic strategies
Laruelle has thus shown how some of the fundamentals of intratumour heterogeneity, corroborated from the standpoint of histopathology and genomics, are supported by mathematics using the hawk-dove game. The work, carried out in collaboration with researchers from Biocruces, the San Giovanni Bosco Hospital in Turin (Italy) and the Pontificia Universidade Catolica do Rio de Janeiro has been published in the journal Trends in Cancer by the Ikerbasque Research Professor.
The group of researchers believe that “this convergence of findings obtained from very different disciplines reinforces the key role of translational research in modern medicine and gives intratumour heterogeneity a key position in the approach to new therapeutic strategies” and they conjecture that “intratumour heterogeneity behaves by following similar pathways in many other tumours.”
This may have important practical implications for the clinical management of malignant tumours. The constant arrival of new molecules enriches cancer treatment opportunities in the era of precision oncology. However, the researchers say that “it is one thing to discover a new molecule and quite another to find the best strategy for using it. So far, the proposed approach is based on administering the maximum tolerable dose to the patient. However, this strategy forces the tumour cells to develop resistance as early as possible, thus transforming the original tumour into a neoplasm of low intratumour heterogeneity comprising only resistant cells.” So, a therapy specifically aimed at preserving high intratumour heterogeneity may make sense according to this theoretical approach, as it may slow cancer growth and thus lead to longer survivals. This perspective is currently gaining interest in oncology.