Culture

New research coming out of UBC's Okanagan campus may take the current 'gold standard' for heart valves to a new level of reliability.

A team of researchers at UBCO's Heart Valve Performance Lab (HVPL) has developed a way to improve overall blood flow through the valves, so the design of mechanical heart valves will more closely match the real thing.

"Despite more than 40 years of research, we are still chasing the goal of creating mechanical heart valves that perform consistently and seamlessly inside the human body," explains Dr. Hadi Mohammadi, an associate professor at the School of Engineering and lead researcher for the HVPL. "The way blood travels through the body is very unique to a person's physiology, so a 'one-size fits all' valve has always been a real challenge."

Mohammadi, along with doctoral student Arpin Bhullar, has developed an innovative mechanical bileaflet that enables the mechanical heart valve to function just like the real thing. A bileaflet valve--two semicircular leaflets that pivot on hinges--is a mechanical gateway that allows consistent blood-flow and ensures the flow is in one direction.

While developed decades ago and used regularly to improve a patient's blood flow, artificial valves have never been perfect, says Mohammadi. With existing versions of bileaflets, there is a small risk of blood clots or even a backflow of blood.

The design of the bileaflet is crucial for maintaining blood flow in order to eliminate risk to the patient. Mohammadi believes he's found a way to fix the problem, by adding a slight twist to the design.

"Our findings show our apex heart valve maintains consistent flow as a result of its breakthrough design--specifically the valve's curvature which mitigates clotting."

The initial design was confirmed by Dr. Guy Fradet, head of Kelowna General Hospital's cardiothoracic surgery program. Mohammadi says it takes decades for innovations in mechanical heart valves before they are used on humans, but he is confident his novel leaflet-shaped valve is the way of the future.

"The work we're doing has resulted in the design of a valve which may serve as the foundation for the next generation of bileaflet mechanical heart valves," he says. "Our research, with computer simulation and in-vitro studies, helped evaluate the performance of the proposed valve and also compare it to the industry gold standard."

Researchers with the Fatty Acid Research Institute (FARI) and collaborators at Cedars-Sinai Medical Center in Los Angeles and in Orange County, CA, have published the first direct evidence that higher omega-3 blood levels may reduce risk for death from COVID-19 infection. The report was published in the journal Prostaglandins, Leukotrienes and Essential Fatty Acids on January 20, 2021.

There are several papers in the medical literature hypothesizing that omega-3 fatty acids should have beneficial effects in patients with COVID-19 infection, but up until now, there have been no published peer-reviewed studies supporting that hypothesis.

This study included 100 patients admitted to the hospital with COVID-19 for whom admission blood samples had been stored. Clinical outcomes for these patients were obtained and blood was analyzed for the Omega-3 Index (O3I, red blood cell membrane EPA+DHA levels) at OmegaQuant Analytics (Sioux Falls, SD). Fourteen of the patients died.

The 100 patients were grouped into four quartiles according to their O3I, with 25% of the patients in each quartile. There was one death in the top quartile (i.e., 1 death out of 25 patients with O3I>5.7%), with 13 deaths in the remaining patients (i.e., 13 deaths out of 75 patients with O3I

In age-and-sex adjusted regression analyses, those in the highest quartile (O3I >5.7%) were 75% less likely to die compared with those in the lower three quartiles (p=0.07). Stated another way, the relative risk for death was about four times higher in those with a lower O3I (

"While not meeting standard statistical significance thresholds, this pilot study - along with multiple lines of evidence regarding the anti-inflammatory effects of EPA and DHA - strongly suggests that these nutritionally available marine fatty acids may help reduce risk for adverse outcomes in COVID-19 patients. Larger studies are clearly needed to confirm these preliminary findings," said Arash Asher, MD, the lead author on this study.

Agreeing with Dr. Asher, cardiology researcher and co-developer with Dr. Harris of the Omega-3 Index, Clemens von Schacky, MD, (CEO, Omegametrix GmbH, Martinsried, Germany, and not involved with the study) said, "Asher et al have demonstrated that a low Omega-3 Index might be a powerful predictor for death from COVID-19. Although encouraging, their findings clearly need to be replicated."

Omega-3 expert James H. O'Keefe, Jr., MD, (Director of Preventive Cardiology, Saint Luke's Mid America Heart Institute, Kansas City, MO, and also not involved with the study) observed, "An excessive inflammatory response, referred to as a 'cytokine storm,' is a fundamental mediator of severe COVID-19 illness. Omega-3 fatty acids (DHA and EPA) have potent anti-inflammatory activities, and this pilot study provides suggestive evidence that these fatty acids may dampen COVID-19's cytokine storm."

The FARI research team is currently seeking funding to expand upon these preliminary observations. Individuals and organizations that want to support this research are encouraged to visit FARI's donations page.

DALLAS, Jan. 25, 2021 — Psychological health can positively or negatively impact a person’s health and risk factors for heart disease and stroke, according to “Psychological Health, Well-Being, and the Mind-Heart-Body Connection,” a new American Heart Association Scientific Statement, published today in the Association’s flagship journal Circulation. The statement evaluates the relationship between psychological health and heart health, summarizing ways to help improve psychological health for people with and at risk for heart disease.

“A person’s mind, heart and body are all interconnected and interdependent in what can be termed ‘the mind-heart-body-connection,’” said Glenn N. Levine, M.D., FAHA, master clinician and professor of medicine at Baylor College of Medicine, chief of the cardiology section at the Michael E. DeBakey VA Medical Center, both in Houston, and chair of the writing committee for the Scientific Statement. “Research has clearly demonstrated that negative psychological factors, personality traits and mental health disorders can negatively impact cardiovascular health. On the other hand, studies have found positive psychological attributes are associated with lower risk of cardiovascular disease and mortality.”

Negative psychological health conditions include depression, chronic stress, anxiety, anger, pessimism and dissatisfaction with one’s current life. These conditions are associated with potentially harmful biological responses, such as:

irregularities of heart rate and rhythm;
increased digestive complaints;
increased blood pressure;
inflammation; and
reduced blood flow to the heart.

Negative psychological health is also associated with health behaviors that are linked to an increased risk for heart disease and stroke, such as smoking, lower levels of physical activity, unhealthy diet, being overweight and not taking medications as prescribed.

Due to evidence that connects negative psychological health to heart disease, the statement suggests regular mental health screening for people with or at risk for cardiovascular disease. The authors note that psychological therapy and mind-body programs can lead to better cardiovascular health. Programs that improve psychological health include cognitive behavioral therapy, psychotherapy, collaborative care management approaches, stress reduction therapy and meditation.

The Statement highlights research showing that both the cumulative effect of daily stressors and exposure to traumatic events can also increase the risk of heart disease and stroke. Patients’ self-report of general stress as well as work-related stress have been associated with an up to 40% increased risk of developing or dying from heart disease.

“Most studies of psychological health are observational, with many involving self-reporting from patients, which presents challenges to establishing specific cause and effect relationships,” said Levine. “However, a preponderance of such studies is highly suggestive and allows one to make reasonable conclusions about an association between negative psychological health and cardiovascular risk.”

On the other hand, studies have found positive psychological health associated with a lower risk of cardiovascular disease and death. Positive psychological health characteristics include happiness, optimism, gratitude, sense of purpose, life satisfaction and mindfulness. “The data is consistent, suggesting that positive psychological traits play a part in better cardiovascular health,” said Levine.

People with positive psychological health were also more likely to have health factors linked to a lower risk of developing cardiovascular disease:

lower blood pressure;
better glucose control;
less inflammation; and
lower cholesterol.

Positive psychological health is also associated with beneficial health behaviors such as smoking cessation, increased physical activity, heart-healthy eating, increased medication adherence and regular check-ups and health screenings.

Also, said Levine, social factors may further influence cardiovascular health. People with better mental health tend to have positive social relationships, support and connections, which can facilitate healthier adaptation to life’s challenges.

Levine adds, “Wellness is more than simply the absence of disease. It is an active process directed toward a healthier, happier and more fulfilling life, and we must strive to reduce negative aspects of psychological health and promote an overall positive and healthy state of being. In patients with or at risk for heart disease, health care professionals need to address the mental wellness of the patient in tandem with the physical conditions affecting the body, such as blood pressure, cholesterol levels, chest pain, etc.”

This Scientific Statement was prepared by the volunteer writing group on behalf of the American Heart Association’s Council on Clinical Cardiology; the Council on Arteriosclerosis, Thrombosis and Vascular Biology; the Council on Cardiovascular and Stroke Nursing; and the Council on Lifestyle and Metabolic Health.

DALLAS, Jan. 25, 2021 — The continued global burden of stroke and how it disproportionately affects women are highlighted in new science published online today in the February issue of Stroke, a journal of the American Stroke Association, a division of the American Heart Association. Stroke editors selected nine manuscripts focused on stroke disparities in women in this collaboration with Go Red for Women®, the Association’s global movement to end heart disease and stroke in women.

“Stroke continues to be a leading cause of death and disability worldwide, with women being more adversely affected by the global burden of stroke,” said Stroke Editor-In-Chief Ralph L. Sacco, M.D., M.S., FAHA, a past president of the American Heart Association. “As our population ages, the number of stroke survivors will continue to rise, especially among women. We must include more women in stroke research so we can enhance the critical evidence necessary to provide the appropriate stroke treatments needed to save and improve lives.”

Worldwide, stroke is the second leading cause of death. More than 101 million people have a stroke each year, and more than 6.6 million people die of a stroke, annually. About 1 in 4 stroke survivors will experience another stroke within five years.

“The papers highlighted in this issue feature international research and perspective from more than half a dozen countries,” said Sacco, chair of the department of neurology, the Olemberg Family Chair in Neurological Disorders and executive director of the Evelyn F. McKnight Brain Institute at the University of Miami Leonard Miller School of Medicine, in Miami, Florida. “This collective work from some of the most renowned scientists in the field offers important insight, recommendations and guidance for addressing this critical topic.”

Two of the studies addressed concerns about the lack of women in stroke clinical trials, thus limiting information to ensure appropriate stroke treatment for women, which has long been an issue for scientists.

Why Are Women Less Represented in Intracerebral Hemorrhage Trials? - Tatiana Greige et al.  Researchers examined the different reasons men and women were excluded from a major trial about treatment for hemorrhagic, or bleeding, strokes.

The intracerebral hemorrhage DEFeroxamine (iDEF) trial was a prospective, multicenter, randomized, placebo-controlled, double-blind, phase 2 trial that evaluated the use of deferoxamine mesylate versus placebo (saline) infusions in patients with hemorrhagic strokes at 40 hospitals in Canada and the U.S. While iDEF included 293 participants, only 38.2% of participants were women. The major reason for this disparity was the exclusion of participants over the age of 80 — 22.4% of women were not included in the trial for this reason versus 12.61% of men.

The under-enrollment of women in stroke clinical trials: What are the causes and what should be done about it? - Cheryl Carcel; Matthew Reeves

Addressing the age barrier to stroke research is one of several recommendations offered in a commentary of presentations made at the European Stroke Organization-World Stroke Organization 2020 virtual conference. The authors noted that discrepancies in the enrollment of women in stroke clinical trials raises concerns about the generalizability of trial results, as well as the potential for reduced access and use of new therapies in women. Their recommendations for addressing this include:

More research, both quantitative and qualitative, should be undertaken to identify the causes and barriers to enrolling women in stroke clinical trials, particularly to understand how the attitudes and beliefs of women towards research and health in general may be impacting their participation in studies.
Stroke trials should avoid using an upper age limit as an exclusion criterion (e.g., >80 years) since this has been shown to have a disproportionate effect on the number of women enrolled in trials.
Researchers should make greater efforts to collect appropriate data from trial screening logs to better identify specific factors that could help in understanding why women may be under-enrolled in stroke trials.
The number of trial investigators and research staff who are women should be increased and has the potential to create environments in which more women are enrolled in stroke clinical trials.

Below are highlights of some of the other manuscripts in this issue, which can be accessed in full here.

Sex, age, and socioeconomic differences in non-fatal stroke incidence and subsequent major adverse outcomes - Ralph K. Akyea et al.

Researchers for this large cohort study used data from the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) to assess stroke incidence in the general population of the United Kingdom from 1998-2019. During this time, 82,774 people survived a stroke, of which 44,614 (53.9%) were women. Men in the study experienced stroke at a younger age compared to women (71.4 vs 76.9 years, respectively). Men ages 30-74 years had higher stroke incidence rates compared to women; however, among those ages 75 and older, the incidence rates were much higher in women.

The rate of stroke incidence among people ranked in the lowest ranking of socioeconomic status was 10% higher than the rate in the highest socioeconomic status rank. Those rankings were based on such factors as income; employment; education, skills and training; health and disability; crime; barriers to housing and services; and living environment.

The researchers also examined a subset of 68,877 stroke survivors who had not had previous complications. Of those:

47,500 eventually had a major adverse cardiovascular event, 25,731 were women (68.8% of all the female survivors);
33,831 had another stroke (more than 52% were women);
20,335 died of any cause (more than 59% were women); and
9,174 died of cardiovascular complications (more than 61% were women).

The researchers noted their findings show a higher burden of major adverse outcomes (such as a cardiovascular event, stroke or death) observed in women when compared to men after first non-fatal stroke is largely accounted for by age and socioeconomic status.

Advances in Stroke: Stroke in Women - Moira K. Kapral et al.

This paper highlights recent advances in the understanding of sex differences in the benefits of endovascular therapy, outcomes after stroke and the potential to prevent stroke in women with a history of hypertensive disorders of pregnancy. This perspective paper includes data analysis from several clinical trials. The researchers found:

The relatively new treatment of mechanical removal of a blood clot, known as endovascular therapy (EVT), was associated with similar functional independence in women and men. Additionally, women had a nearly two-year gain in disability-adjusted life years after EVT compared to men, and women and men had similar 90-day mortality, functional independence, safety outcomes and successful restoration of blood flow to the brain. The researchers noted that while many clinical trials of EVT tended to exclude older women with pre-stroke disability and comorbid conditions, the results of their analysis point to this treatment being equally beneficial for men and women.
The authors identified numerous instances of women having worse stroke outcomes than men – and women had higher rates of death, disability and quality of life, much of which can be attributed to age, stroke severity, pre-stroke function capacity and depression. They suggest targets for interventions could include efforts to reduce stroke severity (e.g., through management of stroke risk factors), address mood disorders (e.g., through routine screening and treatment) and optimize functional status and quality of life (e.g., through rehabilitation).
Another analysis found women are less likely than men (67.8% vs. 76.8%) to be diagnosed with stroke or cerebrovascular event, and there is less investigation into the causes of stroke among women. The authors noted these results are consistent with previous research, and the lack of cause identification and the management of vascular risk factors could have dangerous consequences.
The researchers also analyzed findings from the California Teachers Study that found the risk of stroke before age 60 was modified by aspirin use in women with hypertensive disorders of pregnancy. Women who did not use aspirin had an increased risk of stroke, while those on aspirin therapy did not. The authors noted the fact that aspirin can prevent preeclampsia when taken during pregnancy suggests an interesting link for aspirin use, hypertensive disorders of pregnancy and ischemic stroke risk beyond child-bearing years. These findings are also consistent with prior studies that have identified hypertensive disorders of pregnancy as a risk factor for subsequent stroke, and the authors suggest that aspirin could be a target for future controlled trials for stroke prevention.

The other studies in this special issue include:

The female stroke - sex differences in acute treatment and early outcomes of acute ischemic stroke – Anna Bonkhoff et al.
Absence of consistent sex differences in outcomes from symptomatic carotid endarterectomy and stenting trials – Virginia Howard et al.
Influence of pregnancy on hemorrhage risk in women with cerebral and spinal cavernous malformations – Nycole Joseph et al.
Sex-related differences in clinical features, neuroimaging  and long-term prognosis after transient ischemic attack – Francisco Purroy et al.
Stroke incidence by sex across the lifespan – Manav Vyas et al.

Authors’ disclosures and funding sources for all studies in the special issue are listed in the individual manuscripts.

“We are pleased to publish this important research to enhance our understanding of the unique differences in the diagnosis, treatment and prevention of stroke in women,” Sacco said. “Our essential goal is to prevent stroke, reduce disability and ultimately save lives; education and awareness are critical first steps.”

To raise awareness about how participation in research could further scientific understanding of cardiovascular health, the American Heart Association and Verily, Alphabet’s life sciences and healthcare arm, have launched Research Goes Red. Research Goes Red aims to empower women to contribute to health research. Learn more at www.goredforwomen.org/en/get-involved/research/research-goes-red

Even before public announcements of the first cases of COVID-19 in Europe were made, at the end of January 2020, signals that something strange was happening were already circulating on social media. A new study of researchers at IMT School for Advanced Studies Lucca, published in Scientific Reports, has identified tracks of increasing concern about pneumonia cases on posts published on Twitter in seven countries, between the end of 2019 and the beginning of 2020. The analysis of the posts shows that the "whistleblowing" came precisely from the geographical regions where the primary outbreaks later developed.

To conduct the research, the authors first created a unique database with all the messages posted on Twitter containing the keyword "pneumonia" in the seven most spoken languages of the European Union - English, German, French, Italian, Spanish, Polish, and Dutch - from December 2014 until 1 March 2020. The word "pneumonia" was chosen because the disease is the most severe condition induced by the SARS-CoV-2, and also because the 2020 flu season was milder than the previous ones, so there was no reason to think it to be responsible for all the mentions and worries. The researchers then made a number of adjustments and corrections to the posts in the database to avoid overestimating the number of tweets mentioning pneumonia between December 2019 and January 2020, that is to say in the weeks between the World Health Organization (WHO) announcement that the first "cases of pneumonia of unknown etiology" had been identified - on 31 December 2019 - and the official recognition of COVID19 as a serious transmissible disease, on 21 January 2020. In particular, all the tweets and retweets containing links to news about the emerging virus were eliminated from the database to exclude from the count the mass media coverage of the emerging pandemic.

The analysis of the authors shows an increase in tweets mentioning the keyword "pneumonia" in most of the European countries included in the study as early as January 2020, such as to indicate an ongoing concern and public interest in pneumonia cases. In Italy, for example, where the first lock-down measures to contain COVID-19 infections were introduced on 22 February 2020, the increase rate in mentions of pneumonia during the first few weeks of 2020 differs substantially from the rate observed in the same weeks in 2019. That is to say that potentially hidden infection hotspots were identified several weeks before the announcement of the first local source of a COVID-19 infection (20 February, Codogno, Italy). France exhibited a similar pattern, whereas Spain, Poland, and the UK witnessed a delay of 2 weeks.

The authors also geo-localized over 13,000 pneumonia-related tweets in this same period, and discovered that they came exactly from the regions where the first cases of infections were later reported, such as the Lombardia region in Italy, Madrid, Spain, and Île de France.

Following the same procedure used for the keyword "pneumonia", the researchers also produced a new dataset containing the keyword "dry cough", one of the other symptoms later associated with the COVID-19 syndrome. Even then, they observed the same pattern, namely an abnormal and statistically significant increase in the number of mentions of the word during the weeks leading up to the surge of infections in February 2020.

"Our study adds on to the existing evidence that social media can be a useful tool of epidemiological surveillance. They can help intercept the first signs of a new disease, before it proliferates undetected, and also track its spread" says Massimo Riccaboni, full professor of Economics at the IMT School, who coordinated the research.

This is especially true in a situation like the current pandemic, when lapses in identifying early-warning signals left many national governments blind to the unprecedented scale of the looming public health emergency. In a successive phase of the pandemic, monitoring social media could help public health authorities mitigate the risks of contagion resurgence, for example by adopting stricter measures of social distancing where the infections appear to be increasing, or vice versa relaxing them in other regions. These tools could also pave the way to an integrated epidemiological surveillance system globally managed by international health organizations.

PULLMAN, Wash. - Man's best friend might actually belong to a woman.

In a cross-cultural analysis, Washington State University researchers found several factors may have played a role in building the mutually beneficial relationship between humans and dogs, including temperature, hunting and surprisingly - gender.

"We found that dogs' relationships with women might have had a greater impact on the dog-human bond than relationships with men," said Jaime Chambers, a WSU anthropology Ph.D. student and first author on the paper published in the Journal of Ethnobiology. "Humans were more likely to regard dogs as a type of person if the dogs had a special relationship with women. They were more likely to be included in family life, treated as subjects of affection and generally, people had greater regard for them."

While dogs are the oldest, most widespread domesticated animal, very few anthropologic studies have directly focused on the human relationship with canines. Yet when the WSU researchers searched the extensive collection of ethnographic documents in the Human Relations Area Files database, they found thousands of mentions of dogs.

Ultimately, they located data from more than 844 ethnographers writing on 144 traditional, subsistence-level societies from all over the globe. Looking at these cultures can provide insight into how the dog-human relationship developed, Chambers said.

"Our modern society is like a blip in the timeline of human history," she said. "The truth is that human-dog relationships have not looked like they do in Western industrialized societies for most of human history, and looking at traditional societies can offer a wider vision."

The researchers noted specific instances that showed dogs' utility, or usefulness, to humans, and humans' utility to dogs as well as the "personhood" of dogs--when canines were treated like people, such as being given names, allowed to sleep in the same beds or mourned when they died.

A pattern emerged that showed when women were more involved with dogs, the humans' utility to dogs went up, as did the dogs' personhood.

Another prevalent trend involved the environment: the warmer the overall climate, the less useful dogs tended to be to humans.

"Relative to humans, dogs are really not particularly energy efficient," said Robert Quinlan, WSU anthropology professor and corresponding author on the paper. "Their body temperature is higher than humans, and just a bit of exercise can make them overheat on a hot day. We saw this trend that they had less utility to humans in warmer environments."

Quinlan noted there were some exceptions to this with a few dog-loving cultures in the tropics, but it was a fairly consistent trend.

Hunting also seemed to strengthen the dog-human connection. In cultures that hunted with dogs, they were more valued by their human partners: they were higher in the measures of dogs' utility to humans and in personhood. Those values declined, however, when food production increased whether it was growing crops or keeping livestock. This finding seemed to go against the commonly held perception of herding dogs working in concert with humans, but Quinlan noted that in many cultures, herding dogs often work alone whereas hunting requires a more intense cooperation.

This study adds evidence to the evolutionary theory that dogs and humans chose each other, rather than the older theory that humans intentionally sought out wolf pups to raise on their own. Either way, there have been clear benefits for the dogs, Chambers said.

"Dogs are everywhere humans are," she said. "If we think that dogs are successful as a species if there are lots of them, then they have been able to thrive. They have hitched themselves to us and followed us all over the world. It's been a very successful relationship."

The cover for issue 2 of Oncotarget features Figure 4, "Combination therapy TA99/ICB reduced the lung tumor burden in the B16 model of metastases," published in "Improved therapeutic efficacy of unmodified anti-tumor antibodies by immune checkpoint blockade and kinase targeted therapy in mouse models of melanoma" by Pérez-Lorenzo, et al. which reported that here, the authors showed that removing immune suppression and enhancing stimulatory signals increased the anti-tumor activity of unmodified TA99 antibodies with a significant reduction of growth of solid tumors and lung metastases in mouse models of melanoma.

Immune checkpoint blockade enhanced the efficacy of TA99, which was associated with greater CD8 /Foxp3 , NK1.1 and dendritic cell infiltrates, suggestive of an increased anti-tumor innate and adaptive immune responses.

Moreover, they found an improved therapeutic effect when YUMM tumor-bearing mice were treated with TA99 combined with MEKi and immune checkpoint blockade.

The Oncotarget findings suggest that MEKi induced an increased expression of tumor-associated antigens, which in combination with anti-tumor antibodies, generated a robust adaptive anti-tumor response that was sustained by immune checkpoint inhibition therapy.

The Oncotarget findings suggest that MEKi induced an increased expression of tumor-associated antigens, which in combination with anti-tumor antibodies, generated a robust adaptive anti-tumor response that was sustained by immune checkpoint inhibition therapy.

The authors postulate that combining anti-tumor antibodies with standard-of-care strategies such as immune checkpoint blockade or targeted therapy, will improve therapeutic outcomes in cancer.

Dr. Angela M. Christiano from The Columbia University said, "It is well accepted that tumor development and progression is usually controlled by immunosurveillance mechanisms in which specific and non-specific immunological responses are constantly mounted against tumor cells."

Passive administration of anti-tumor antibodies generally functions by targeting malignant cells through IgG-mediated antibody-dependent cellular cytotoxicity, which is a rapid but relatively short-acting anti-tumor response.

Alternatively, they and others also demonstrated that the administration of anti-tumor antibodies induces long-lasting FcR-dependent tumor specific immunity in the host, with kinetics consistent with an induced adaptive immune response against the tumor.

In this model, anti-tumor antibodies, alone or in combination with chemotherapy, will promote innate cell-mediated ADCC, and the capture and processing of antigens by antigen presenting cells, with the subsequent stimulation and homing of antigen-specific effector T lymphocytes to the tumor site, leading to tumor elimination, a phenomenon the researchers and others referred to as the “vaccinal effect”.

With the use of the B16 and YUMM mouse models of melanoma and the anti-TYRP1 mouse monoclonal antibody TA99, we demonstrated that the therapeutic effects of these unmodified anti-tumor antibodies can be enhanced by ICB through the stimulation of both innate and adaptive anti-tumor immune responses.

In addition, they found that the MEK inhibitor -induced increased expression of melanosomal antigens further enhanced the anti-melanoma response to combination therapy with anti-tumor antibodies and immune checkpoint blockade in mouse models of melanoma.

The Christiano Research Team concluded in their Oncotarget Research Paper, "Together with our preclinical data, these results invite further clinical investigation of unmodified anti-tumor antibodies in combination with ICB and targeted therapies, and may represent promising and innovative therapeutic interventions for the successful management of patients with advanced melanoma and other cancers."

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DOI - https://doi.org/10.18632/oncotarget.27868

Full text - https://www.oncotarget.com/article/27868/text/

Correspondence to - Angela M. Christiano - amc65@cumc.columbia.edu

Keywords -
anti-tumor antibodies,
targeted therapy,
immunotherapy,
combination therapies,
melanoma

About Oncotarget

Oncotarget is a biweekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with:

SoundCloud - https://soundcloud.com/oncotarget
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Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls

Journal

Oncotarget

DOI

10.18632/oncotarget.27868

The cover for issue 1 of Oncotarget features Figure 2, "Results in clinical trials," published in "Drug resistant cells with very large proliferative potential grow exponentially in metastatic prostate cancer" by Blagoev, et al. which reported that most metastatic cancers develop drug resistance during treatment and continue to grow, driven by a subpopulation of cancer cells unresponsive to the therapy being administered.

There is evidence that metastases are formed by phenotypically plastic cancer cells with stem-cell-like properties.

Currently, the population structure and growth dynamics of the resulting metastatic tumors is unknown.

Here, using scaling analysis of clinical data of tumor burden in patients with metastatic prostate cancer, the Oncotarget authors show that the drug-resistant, metastasis-causing cells are capable of producing drug-resistant, exponentially growing tumors, responsible for tumor growth as a patient receives different treatments.

The Oncotarget authors show that the drug-resistant, metastasis-causing cells are capable of producing drug-resistant, exponentially growing tumors, responsible for tumor growth as a patient receives different treatments

Dr. Krastan B. Blagoev from The National Science Foundation, as well as The Johns Hopkins University, said, "Tissue homeostasis is maintained by a small number of stem cells capable of symmetrical and asymmetrical cell division, with symmetrical cell division ensuring that the number of stem cells remains constant when a stem cell is lost and asymmetrical cell division maintaining the stem cell number constant when all stem cells are present."

Currently, it is thought that cancers emerge from one or both of these two cell populations, and cancer cells possessing stem cell markers and capable of proliferating when grafted in animal models have been identified in leukemia and solid tumors, and have been called cancer stem cells.

The epithelial to mesenchymal transition has been implicated in cancer cells and there is evidence that the metastatic-capable cells are somewhere on the spectrum between fully epithelial and fully mesenchymal cells while the metastasizing cells are phenotypically plastic and capable of moving along that spectrum.

Recently it was reported that the WNT/ß-Catenin pathway drives prostate cancer cells into symmetric cell divisions, suggesting that these cancer cells have lost the ability to divide asymmetrically.

The inner surface of the ducts is covered with epithelial luminal cells, which are surrounded by epithelial basal cells and scattered among them are neuroendocrine cells.

The Blagoev Research Team concluded in their Oncotarget Research Paper that the environment where normal stem cells reside in the stem cell niche populated with supporting cells and having an organized tissue architecture.

In contrast, cancers lose the polarized structure of the cells present in normal tissue, grow as bulk cell masses, and break the basal membrane surrounding the prostate to metastasize to distant cites.

Both mechanisms may be in play and further research is needed to characterize the architecture of the metastatic tumors and the operating cell division mechanisms. Currently, the origin of these symmetrically dividing cells is unclear.

One possibility is that one or more cancer stem cells begin to divide symmetrically overtaking the asymmetrically dividing cells.

Observation of the tumor at the individual cell level as well as monitoring of molecular markers of individual cells will be necessary to resolve the drivers behind phenotypic cell decisions in normal and cancerous tissues.

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DOI - https://doi.org/10.18632/oncotarget.27855

Full text - https://www.oncotarget.com/article/27855/text/

Correspondence to - Krastan B. Blagoev - krastan@jhu.edu

Keywords -
drug resistance,
metastatic prostate cancer,
exponential growth,
tumor kinetics,
cancer stem cells

About Oncotarget

Oncotarget is a biweekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with:

SoundCloud - https://soundcloud.com/oncotarget
Facebook - https://www.facebook.com/Oncotarget/
Twitter - https://twitter.com/oncotarget
LinkedIn - https://www.linkedin.com/company/oncotarget
Pinterest - https://www.pinterest.com/oncotarget/
Reddit - https://www.reddit.com/user/Oncotarget/

Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls

DOI

10.18632/oncotarget.27855

The cover for issue 52 of Oncotarget features Figure 1, "Volcano plots of DNA methylation in tumor tissues compared with nontumor tissue," published in "Reduction of T-Box 15 gene expression in tumor tissue is a prognostic biomarker for patients with hepatocellular carcinoma" by Morine, et al. which reported that the authors conducted a genome-wide analysis of DNA methylation of the tumor and non-tumor tissue of 15 patients with Hepatocellular carcinoma (HCC), and revealed TBX15 was the most hypermethylated gene of the tumor.

Another validation set, which comprised 58 HCC with radical resection, was analyzed to investigate the relationships between tumor phenotype and TBX15 mRNA expression.

TBX15 mRNA levels in tumor tissues were significantly lower compared with those of nontumor tissues.

Multivariate analysis identified low TBX15 expression as an independent prognostic factor for overall and disease-free survival.

Therefore, genome-wide DNA methylation profiling indicates that hypermethylation and reduced expression of TBX15 in tumor tissue represents a potential biomarker for predicting poor survival of patients with HCC.

Reduced expression of TBX15 in tumor tissue represents a potential biomarker for predicting poor survival of patients with HCC

Dr. Yuji Morine from the Tokushima University Graduate School said, "Hepatocellular carcinoma (HCC) is the sixth most prevalent human cancer and third-highest cause of cancer-related deaths worldwide, and its incidence is significantly increasing."

Several genome-wide studies of the molecular alterations in tumor and non-tumor liver tissues addressed DNA, mRNA, and microRNA expression as well as epigenetic alterations to predict recurrence and hepatocarcinogenesis after treating patients with curative intent according to distinct gene expression or alteration patterns.

Here the Oncotarget authors focused on the epigenetic alterations of the genomes of the tumor and non-tumor cells of patients with HCC to identify the mechanisms of tumor progression and hepatocarcinogenesis because of global DNA hypomethylation or cancer specific DNA hypermethylation occurs in certain carcinomas.

They firstly chose long interspersed nuclear element-1 sequences that provided a surrogate marker of global DNA methylation levels and detected hypomethylation of LINE-1 in HCC tissues, which was significantly associated with poor prognosis of patients with HCC through the activation of MET.

Further, they investigated epigenetic characteristics with array-based analysis of DNA methylation using the Illumina Human Methylation 450 BeadChip and identified specific DNA methylation profiling in nontumor liver tissue of patients without HCV and HBV detectable infection, which possibly contributed to the development of HCC.

In this study, they analyzed DNA methylation profiles in tumor tissue of HCC using those case series of their recent study, and found the most hypermethylated gene in tumor compared with nontumor tissues, encodes T-box 15, implicating TBX15 as a candidate regulator of tumor progression.

The Morine Research Team concluded in their Oncotarget Research Paper that together, the present and previous findings support the importance of conducting further investigations to determine the role of TBX15 in cancer, particularly in tumor progression.

Second, selection bias was possible, because of the retrospective one.

Third, the authors did not determine the actual mechanism of TBX15 for tumor malignancy in a basic experiment.

Those issues should be solved in several cancers, to clarify the true function of TBX15 for tumor malignancy in each cancer.

In conclusion, reduced expression of TBX15 may serve as a potential biomarker for predicting tumor progression and poor survival as well as a target for antitumor therapy in HCC.

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DOI - https://doi.org/10.18632/oncotarget.27852

Full text - https://www.oncotarget.com/article/27852/text/

Correspondence to - Yuji Morine - ymorine@tokushima-u.ac.jp

Keywords -
genome-wide analysis,
methylation,
tumor suppressor gene,
prognostic biomarker,
hepatocellular carcinoma

About Oncotarget

Oncotarget is a biweekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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DOI

10.18632/oncotarget.27852

Aging-US recently published "Transforming growth factor beta type 1 (TGF-β) and hypoxia-inducible factor 1 (HIF-1) transcription complex as master regulators of the immunosuppressive protein galectin-9 expression in human cancer and embryonic cells" which reported that for the first time that in human cancer as well as embryonic cells, the transcription factors hypoxia-inducible factor 1 and activator protein 1 are involved in upregulation of transforming growth factor beta 1 expression, leading to activation of the transcription factor Smad3.

This process triggers upregulation of galectin-9 expression in both malignant and embryonic cells.

Dr. Vadim V. Sumbayev from The Universities of Kent and Greenwich and Dr. Elizaveta Fasler-Kan from The University of Bern as well as The University of Basel and University Hospital Basel said, "Galectin-9 is one of the crucial proteins used by various types of cancer cells to suppress cytotoxic immune responses and thus, escape immune surveillance"

Some cancer cells are capable of secreting this protein, while other cancer cells translocate galectin-9 onto the surface and use it to impair anti-cancer activities of cytotoxic lymphoid cells such as cytotoxic T lymphocytes and natural killer cells.

When complexed with Tim-3 on the cell surface, galectin-9 induces downstream signalling of differential intensity, depending on the type of human myeloid and lymphoid cells.

Human cancer cells express significantly higher levels of galectin-9 compared to healthy human cells.

Here the Aging-US authors report for the first time that in human breast cancer, AML and embryonic cells, HIF-1 and AP-1 upregulate the expression of TGF-β, leading to the activation of Smad3 through autocrine action.

This process subsequently upregulates galectin-9 expression in both malignant and embryonic cells, but not in mature healthy human cells.

The Sumbayev/Fasler-Kan Research Team concluded in their Aging-US Research Paper, "These finding demonstrate a self-supporting mechanism of galectin-9 expression operated by human AML, breast and colorectal cancer as well as embryonic cells. Our results suggest the possibility of using TGF-β signalling as a potential highly efficient target for cancer immunotherapy."

"The Aging-US authors report for the first time that in human breast cancer, AML and embryonic cells, HIF-1 and AP-1 upregulate the expression of TGF-β"

Aging-US Issue 1 Volume 13 features "PAM (PIK3/AKT/mTOR) signaling in glia: potential contributions to brain tumors in aging" which reported that despite a growing proportion of aged individuals at risk for developing cancer in the brain, the prognosis for these conditions remains abnormally poor due to limited knowledge of underlying mechanisms and minimal treatment options.

While cancer metabolism in other organs is commonly associated with upregulated glycolysis and hyperactivation of PIK3/AKT/mTOR pathways, the unique bioenergetic demands of the central nervous system may interact with these oncogenic processes to promote tumor progression in aging. Specifically, constitutive glycolysis and PIK3/AKT/mTOR signaling in glia may be dysregulated by age-dependent alterations in neurometabolic demands, ultimately contributing to pathological processes otherwise associated with PIK3/AKT/mTOR induction.

Although several limitations to this theoretical model exist, the consideration of aberrant PIK3/AKT/mTOR signaling in glia during aging elucidates several therapeutic opportunities for brain tumors, including non-pharmacological interventions.

Dr. Kamel Khalili from Temple University said, "Cancer in the brain is significantly less common than in other organs, but disproportionately contributes to higher rates of mortality"

Since metabolic syndrome is an independent risk factor for worse prognosis in patients with certain CNS tumors, bioenergetic processes in particular are emerging as important variables in tumor neuropathology.

Among primary cell types implicated in tumor pathogenesis, minimal contributions are observed from non-glia; less than 10% of all tumors manifest as lymphomas, meningiomas, embryonal tumors, or choroid plexus carcinomas, among others.

As tumors of glial origin account for the vast majority of all CNS cancers, age-dependent variation in glial functioning may particularly contribute to tumor pathology in the brain.

Within the CNS, astrocytes in particular have long been associated with metabolic homeostasis and are the most common cell type associated with tumor pathology.

Given that glia are responsible for maintaining energy homeostasis of the CNS by utilizing similar metabolic pathways of cancer cells, chronic alterations in bioenergetic demands during aging.

The Khalili Research Team concluded in their Aging-US Review Article that in particular, the inhibition of PI3K's downstream effectors, AKT and mTOR, may prove to reliably mitigate proliferation, motility and viability in glioma cells.

Additionally, PI3K inhibitors are emerging as potent antagonistic agents in various types of cancer, including gliomas.

While cancer cells have been shown to overcome this inhibition, evidence from preclinical models suggest the combination of dietary manipulations as well as PI3K inhibitors can augment the inhibition of PAM signaling and increase therapeutic efficacy.

Compared to mice treated with PI3K inhibitors alone, mice maintained on a ketogenic diet during treatment display significantly decreased mortality rates following intracranial implantation of aggressive human gliomas.

Although further validation of these targets is required, the modulation of PAM signaling to mitigate glioma progression in the aging CNS may prove efficacious and merits consideration.

Aging-US published "Neuroprotective effects and mechanisms of action of nicotinamide mononucleotide (NMN) in a photoreceptor degenerative model of retinal detachment" which reported that here, the authors investigated nicotinamide mononucleotide, a precursor of nicotinamide adenine dinucleotide, in a retinal detachment induced photoreceptor degeneration.

NMN administration after RD resulted in a significant reduction of TUNEL photoreceptors, CD11b macrophages, and GFAP labeled glial activation; a normalization of protein carbonyl content, and a preservation of the outer nuclear layer thickness.

NMN administration significantly increased NAD levels, SIRT1 protein expression, and heme oxygenase-1 expression.

Delayed NMN administration still exerted protective effects after RD.

This Aging-US article concludes that NMN administration exerts neuroprotective effects on photoreceptors after RD and oxidative injury, suggesting a therapeutic avenue to treating photoreceptor degeneration.

Dr. Demetrios G. Vavvas from Harvard Medical School said, "Major photoreceptor degenerative diseases are primarily age-related eye disorders, leading to severe vision impairment or irreversible vision loss."

Despite distinct differences between these diseases, the separation of photoreceptors from the underlying retinal pigment epithelium or a loss of functional RPE, and eventual photoreceptor death is common to all of them.

Since photoreceptors are highly metabolic, nutrient deprivation from the separated RPE induces the pathological responses that result in permanent neuronal loss.

Fortunately, the separation of photoreceptors from the RPE can be well-modeled in animals.

To date, however, little is known about the role of NAD when photoreceptors are separated from the RPE and whether the NAD and SIRT1 may play a role in protecting photoreceptors during their separation from the underlying RPE.

The Vavvas Research Team concluded in their Aging-US Priority Research Paper, "our study demonstrates the neuroprotective effects of NMN supplementation in rescuing photoreceptor degeneration after RD. NMN treatment was associated with an increase in NAD+ and SIRT1 levels in the injured retina, leading to anti- apoptotic, anti-inflammatory, and antioxidant effects. The therapeutic effect of NMN may occur at least partially through the activation of SIRT1/HO-1 signaling. These results provide an impetus for studies in larger animals and humans with photoreceptor degeneration in a clinical setting"

They are among the largest predators ever to walk the Earth, but experts have discovered that some baby tyrannosaurs were only the size of a Border Collie dog when they took their first steps.

The first-known fossils of tyrannosaur embryos have shed light on the early development of the colossal animals, which could grow to 40 feet in length and weigh eight tonnes.

A team of palaeontologists, led by a University of Edinburgh researcher, made the discovery by examining the fossilised remains of a tiny jaw bone and claw unearthed in Canada and the US.

Producing 3D scans of the delicate fragments revealed that they belonged to baby tyrannosaurs - cousins of T. rex - which, based on the size of the fossils, were around three feet long when they hatched.

The team's findings suggest that tyrannosaur eggs - the remains of which have never been found - were around 17 inches long. This could aid efforts to recognise such eggs in the future and gain greater insights into the nesting habits of tyrannosaurs, researchers say.

The analysis also revealed that the three-centimetre-long jaw bone possesses distinctive tyrannosaur features, including a pronounced chin, indicating that these physical traits were present before the animals hatched.

Little is known about the earliest developmental stages of tyrannosaurs - which lived more than 70-million-years-ago - despite being one of the most studied dinosaur families. Most tyrannosaur fossils previously studied have been of adult or older juvenile animals.

The study, published in the Canadian Journal of Earth Sciences, was supported by the Royal Society, Natural Sciences and Engineering Research Council of Canada, and National Science Foundation. It also involved researchers from the Universities of Alberta and Calgary, Canada, and Montana State and Chapman Universities, US.

Dr Greg Funston, of the University of Edinburgh's School of GeoSciences, who led the study, said: "These bones are the first window into the early lives of tyrannosaurs and they teach us about the size and appearance of baby tyrannosaurs. We now know that they would have been the largest hatchlings to ever emerge from eggs, and they would have looked remarkably like their parents--both good signs for finding more material in the future. "

Scientists from UNSW Sydney have developed a ceramic-based ink that may allow surgeons in the future to 3D-print bone parts complete with living cells that could be used to repair damaged bone tissue.

Using a 3D-printer that deploys a special ink made up of calcium phosphate, the scientists developed a new technique, known as ceramic omnidirectional bioprinting in cell-suspensions (COBICS), enabling them to print bone-like structures that harden in a matter of minutes when placed in water.

While the idea of 3D-printing bone-mimicking structures is not new, this is the first time such material can be created at room temperature - complete with living cells - and without harsh chemicals or radiation, says Dr Iman Roohani from UNSW's School of Chemistry.

"This is a unique technology that can produce structures that closely mimic bone tissue," he says.

"It could be used in clinical applications where there is a large demand for in situ repair of bone defects such as those caused by trauma, cancer, or where a big chunk of tissue is resected."

Associate Professor Kristopher Kilian who co-developed the breakthrough technology with Dr Roohani says the fact that living cells can be part of the 3D-printed structure, together with its portability, make it a big advance on current state-of-the-art technology.

Up until now, he says, making a piece of bone-like material to repair bone tissue of a patient involves first going into a laboratory to fabricate the structures using high-temperature furnaces and toxic chemicals.

"This produces a dry material that is then brought into a clinical setting or in a laboratory, where they wash it profusely and then add living cells to it," Professor Kilian says.

"The cool thing about our technique is you can just extrude it directly into a place where there are cells, like a cavity in a patient's bone. We can go directly into the bone where there are cells, blood vessels and fat, and print a bone-like structure that already contains living cells, right in that area."

"There are currently no technologies that can do that directly."

In a research paper published recently in Advanced Functional Materials, the authors describe how they developed the special ink in a microgel matrix with living cells.

"The ink takes advantage of a setting mechanism through the local nanocrystallisation of its components in aqueous environments, converting the inorganic ink to mechanically interlocked bone apatite nanocrystals," Dr Roohani says.

"In other words, it forms a structure that is chemically similar to bone-building blocks. The ink is formulated in such a way that the conversion is quick, non-toxic in a biological environment and it only initiates when ink is exposed to the body fluids, providing an ample working time for the end-user, for example, surgeons."

He says when the ink is combined with a collagenous substance containing living cells, it enables in-situ fabrication of bone-like tissues which may be suitable for bone tissue engineering applications, disease modelling, drug screening, and in-situ reconstruction of bone and osteochondral defects.

Already there has been keen interest from surgeons and medical technology manufacturers. A/Prof. Kilian thinks while it's early days, this new bone-printing process could open up a whole new way of treating and repairing bone tissue.

"This advance really paves the way for numerous opportunities that we believe could prove transformational - from using the ink to create bone in the lab for disease modelling, as a bioactive material for dental restoration, to direct bone reconstruction in a patient," says A/Prof. Kilian.

"I imagine a day where a patient needing a bone graft can walk into a clinic where the anatomical structure of their bone is imaged, translated to a 3D printer, and directly printed into the cavity with their own cells.

"This has the potential to radically change current practice, reducing patient suffering and ultimately saving lives."

Next up the duo will be performing in vivo tests in animal models to see if the living cells in the bone-like constructs continue to grow after being implanted in existing bone tissue.

Overview:

Jihui Yuan (Assistant Professor, Department of Architecture and Civil Engineering, Toyohashi University of Technology) proposed a numerical bead model to predict the upward-to-downward reflection ratio of glass bead retro-reflective (RR) material purposed for urban heat island (UHI) mitigation and reducing energy consumption. It revealed that the retro-reflectivity of glass bead RR material gradually increases from morning to noon, at which time it begins to gradually decrease. These results will contribute to existing research on the absorption or reflection of solar radiation to improve urban thermal and lighting conditions, and to reduce building energy consumption.

Details:

Various measures for UHI mitigation and reduced building energy consumption have been widely implemented. Further, the solar reflectivity of the surrounding pavement and outer wall surfaces of a building are reported to be important factors that affect the air-conditioning load of the building, which is directly related to its energy use. Rooftops covered with diffuse highly reflective (DHR) materials (i.e., highly reflective paints) can reflect solar radiation to the sky if there are no high buildings in the vicinity. However, if there are high buildings nearby, much of the solar radiation will be reflected to neighboring buildings and roads, where it will be absorbed to exacerbate the UHI phenomenon. Thus, although DHR materials are widely applied to building facades, RR materials have been recommended as a replacement to mitigate the UHI phenomenon and reduce building energy consumption.

However, RR materials are still in the research and development phase and have not been used practically. Most research indicates that when the incident angles of sunlight become very large, the RR capacity is critically reduced, and the downward solar reflectivity, such as specular reflectivity, increases. In addition, the downward solar radiation from building facades not only negatively impacts pedestrians, but it also heats the urban environment through the heat absorbed by the ground surface; thus, downward solar radiation is regarded as a major contributor to the UHI phenomenon. Therefore, in consideration of how much a change in incident angle can affect the RR capacity and downward solar reflectivity of RR materials, a comprehensive prediction is needed.

Thus, Assistant Professor Jihui Yuan within the Department of Architecture and Civil Engineering at Toyohashi University of Technology, in collaboration with researchers at Osaka City University, proposed a glass bead numerical model to predict the upward-to-downward reflection ratio of glass bead-type RR materials. The results of this study have been published online in advance in the Elsevier journal Urban Climate in March 2021.

As mentioned previously, to better understand the reflection principle of glass bead-type RR materials, a glass bead numerical model was developed and simulated. The simulation was performed to evaluate glass bead-type RR material sunlight reflection by analyzing the retro-reflectivity and upward-to-downward reflection ratio of glass beads.

Future Outlook:

Future work will focus on exploring methods to suppress the downward reflecting light and on attempting to develop the RR materials that can minimize it. Future work will also focus on the development of more accurate models for the evaluation of the RR properties of RR materials, and on performing actual optical measurements of RR materials.

If we can predict directional reflection characteristics of RR materials applied to building facades, such as the upward-to-downward reflection ratio, then we would be able to apply these RR materials to the exterior surfaces in different directions to optimize the absorption or reflection of solar radiation; this would ultimately improve urban thermal and lighting conditions, and reducing energy consumption.