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MD Anderson research highlights for June 30, 2021

HOUSTON - The University of Texas MD Anderson Cancer Center's Research Highlights provides a glimpse into recently published studies in basic, translational and clinical cancer research from MD Anderson experts. Current advances include expanded use of a targeted therapy for a new group of patients with leukemia, molecular studies yielding novel cancer therapeutic targets, insights into radiation therapy resistance and a community intervention to reduce cervical cancer rates.

Using acalabrutinib as initial treatment for chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a cancer that occurs in the blood, bone marrow, lymph nodes, liver and spleen. It is the most common leukemia in adults, and while there are treatments to control and manage the disease, it is difficult to cure. A clinical trial led by William Wierda, M.D., Ph.D., demonstrated that acalabrutinib, a drug that selectively inhibits Bruton's tyrosine kinase, can safely and effectively treat CLL. While the drug was previously used for relapsed CLL, this trial provides evidence for expanding its use for patients who have not yet received chemotherapy or another treatment. Of the 99 treated patients, 97% responded to the treatment and, after 53 months of follow-up, 85 patients remained on treatment. Thirty-eight percent of patients experienced side effects, such as infection, hypertension and atrial fibrillation. Since acalabrutinib showed durable efficacy and long-term safety in this trial, it can be considered an initial therapeutic option for symptomatic patients with CLL. Learn more in Blood.

DNA-cutting enzyme may be a novel cancer treatment target

During DNA replication, a structure known as the replication fork is formed at the interface between new and old DNA. Stalls at the fork can lead to replication stress and genome instability, a hallmark of cancer. Research led by Chi-Lin Tsai, Ph.D., and John Tainer, Ph.D., at MD Anderson find that exonuclease V (EXO5), a DNA-cutting enzyme, plays a critical role in restarting stalled replication forks. The researchers resolved the protein structures for EXO5 alone and bound to DNA, leading to a new understanding of its interaction with DNA and other protein partners, critical for structural-based drug discovery. Their work suggests that EXO5, which is mostly elevated in tumors that correlate with poor patient survival, may be targeted as a novel treatment strategy. Learn more in Molecular Cell.

Cancer cells reprogram the Golgi apparatus to increase pro-tumor protein secretion

Increased secretion of pro-tumor signaling proteins by cancer cells can reorganize the surrounding microenvironment to promote tumor growth, enable metastasis and drive therapeutic resistance. Two new studies from the lab of Jonathan Kurie, M.D., reveal how genetic alterations in cancer lead to hypersecretion by the Golgi apparatus and point to possible therapeutic strategies to block these pathways. Work led by Xiaochao Tan, Ph.D., published in Science Advances, found that loss of TP53 reprograms Golgi proteins to create a positive feedback loop that promotes secretion of pro-metastatic proteins. Blocking these Golgi proteins impaired growth and metastasis of p53-deficient cancers and inhibited immune suppression in the tumor microenvironment. A study led by Lei Shi, Ph.D., published in Proceedings of the National Academy of Sciences, found that lung cancers with a certain chromosomal alteration become addicted to synthesis of the PI4P lipid - part of the Golgi membrane - for increased secretion and cancer cell survival. This reliance on production of a specific lipid could be a vulnerability to target in genetically-defined lung cancers.

Protein plays previously unknown role in resistance to radiation therapy

Radiation therapy is one of the pillars of cancer care, used to generate DNA damage and eventual cell death in cancer cells. Normal cells can overcome much of this damage with normal repair processes while cancer cells typically cannot. However, some cancers exhibit resistance - making radiation therapy less effective. Research led by Qinglei Hang, Ph.D., and Li Ma, Ph.D., discovered a role for the protein DGCR8 in promoting resistance to radiation therapy, although it is normally involved in generating small RNA molecules called microRNAs. After ionizing radiation, DGCR8 is modified and stabilized, leading other proteins to form a complex and to repair the resulting DNA damage in cancer cells. The results suggest that targeting DGCR8 or its partners may be an approach to sensitize tumors to radiation and to overcome therapy resistance. Learn more in Nature Communications.

Neoadjuvant immunotherapy in resectable head and neck cancer

The standard of care for locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck (CSCC-HN) is surgery followed by radiation therapy. This aggressive treatment regimen can cause disfigurement and loss of functionality, and about 30% of patients experience disease recurrence. In a single-institution Phase II clinical trial, led by Neil Gross, M.D., 20 patients with resectable stage III-IVA CSCC-HN received two cycles of the PD-1 inhibitor cemiplimab before surgery. While cemiplimab is approved to treat unresectable CSCC-HN, this is the first study to report on neoadjuvant use for resectable CSCC-HN. Cemiplimab was safe and effective, with a pathologic response rate of 70%. As a result, many patients did not require radiation therapy and remain free of cancer nearly two years later. Response was associated with an inflamed tumor microenvironment, including enrichment of CD8+ T cells. Learn more in Clinical Cancer Research, a journal of the American Association for Cancer Research.

Discovering new treatment targets in KRAS-mutant pancreatic cancer

Pancreatic cancer remains one of the leading causes of cancer death in the United States. More than 90% of cases are caused by mutations in KRAS, but there are no available targeted therapies to block the most common KRAS mutations in pancreatic cancer. A research team led by Liang Yan, Ph.D., Wantong Yao, M.D., Ph.D., and Haoqiang Ying, Ph.D., used a mutant KRAS model of pancreatic cancer to find new targets downstream of KRAS signaling. They confirmed the RAF/MAPK signaling pathway as a critical downstream component, yet blocking this pathway with MEK inhibitors alone was ineffective. Their model also revealed significant reprogramming of cellular metabolism downstream of mutant KRAS. Blocking glucose metabolism sensitized pancreatic cancer cells to MEK inhibitor treatment, showing strong anti-tumor effects and suggesting this combination approach warrants further investigation. Learn more in Cancer Research, a journal of the American Association for Cancer Research.

A community program tackling high cervical cancer rates in the Rio Grande Valley

Significant cervical cancer disparities exist along the Texas-Mexico border in the Rio Grande Valley, where incidence and mortality rates are approximately 55% higher than in the U.S. overall. Cervical cancer is preventable with human papillomavirus (HPV) vaccination or through early diagnosis and treatment of precancerous cervical dysplasia. A team led by Kathleen Schmeler, M.D., implemented a comprehensive, community-based intervention to increase cervical cancer screening, diagnosis and treatment in the region. The program provided cervical cancer screening to 14,846 women over four years. A total of 2,030 women underwent colposcopy for abnormal results (179% increase over baseline) and 453 were treated for cervical dysplasia. Local providers were trained to perform the procedures and received free, bi-weekly continuing education via virtual telementoring using Project ECHO. Learn more in Perspectives in Public Health.

Credit: 
University of Texas M. D. Anderson Cancer Center

Repairing 'broken' hearts -- new promising surgical technique for heart attacks

video: A group of Chinese medical researchers has now been successful in devising a new surgical technique, called SurCOP, to repair ruptures caused by heart attacks.

Image: 
<em>Chinese Medical Journal</em>

Heart attack, medically known as myocardial infarction (MI), is a common heart condition. MI is caused by problems in blood supply to parts of the heart. In severe cases, MI could be accompanied by ruptures in the wall separating different parts of the heart, such as in the ventricular septum (a wall that separates the right ventricle that pumps deoxygenated blood to the lungs for oxygenation, from the left ventricle that pumps oxygenated blood to rest of the body). Not surprisingly, without appropriate surgical intervention, a VSR due to MI increases the chances of death.

Current surgical techniques used to close VSR due to MI have proven ineffective in several situations, which put a group of Chinese medical researchers to work. These researchers from The First Affiliated Hospital of Zhengzhou University and Capital Medical University in China specifically worked on VSR due to MI accompanied by life-threatening fluctuations in blood pressure, or hemodynamic instability (HI). The researchers successfully devised a surgical technique that improved outcomes in patients suffering from VSR and HI due to MI (VSR-HI-MI), according to a study published in Chinese Medical Journal. Further explaining the motivation of their study, Dr. Chao Liu (first author of the study) says, "We aimed to present a novel surgical repair technique that can be safely, feasibly, and effectively used in hemodynamically unstable patients with VSR in the acute phase."

The medical researchers, who aimed to save the lives of patients with VSR-HI-MI, call their novel surgical technique as SurCOP, a method combining devices called an occluder and a patch. While the occluder is used to repair the "hole" in the heart, the patch (derived from biocompatible materials) is used to close it. This is an upgraded version of the conventionally used surgical method in which only a simple patch is used. The doctors then tested the improved technique on nine consenting patients with VSR-HI-MI and compared the outcomes to 54 others. The results showed that the procedure had an impressive 100% success rate. Also, compared to a bleak 10% survival rate if managed conservatively, SurCOP achieved a promising 77.8% survival rate when a median follow-up time of 187 days were considered. Importantly, none of the patients who underwent SurCOP developed VSR after the surgery.

These are incredibly promising findings. Overall, the study highlights how well the surgical technique of SurCOP, tackles the clinical problems posed by VSR-HI-MI. Elated at the success of the study, Dr. Liu concludes, "Our experience has shown that the SurCOP technique is a safe, easy-to-manipulate, and effective method. We hope that we could receive feedback from surgeons who will attempt performing this alternative therapeutic technique and work together to improve the prognosis of patients with VSR."

Indeed, the world can now heal a little better from complications arising from heart attacks.

Credit: 
Cactus Communications

Human stem cells enable model to test drug impact on brain's blood barrier

image: Isabelle Matthiesen prepares the brain-on-chip device for testing.

Image: 
Saskia Ludwig

Using an experimental model to simulate the blood-brain barrier, scientists in Sweden reported in unprecedented detail how antioxidants protect the brain from inflammation caused by neurodegenerative diseases such as Alzheimer's and Parkinson's.

The study, conducted as a proof of concept by brain model developers at KTH Royal Institute of Technology in Stockholm, showed in minute-by-minute detail how the blood-brain barrier reacts to high levels of inflammation after the administration of a next-generation derivative of the widely-used anti-inflammatory drug, NAC (N-acetylcysteine).

The testing of NACA (N-Acetylcysteine Amide) for the first time with human stem cell-derived cells showed that the breakdown of the barrier under high loads of inflammation is "actually more complex than we thought," says KTH researcher Thomas Winkler.

The findings were published in the journal, Small.

"This was the first test of this NACA compound with human stem cells," Winkler says. "The results show that we can use this to test other derivatives of the NAC compound--as well as different antioxidants--and see if we find anything that has even higher neural protection."

Co-author Isabelle Matthiesen, a PhD student at KTH, says that the research is not meant to provide definitive proof of how anti-inflammatories affect the brain; yet the results provide encouraging evidence that the model could replace testing drugs on animals before clinical trials.

"We successfully based the barrier on human stem cell-derived cells so this model is relevant to drugs being testing for humans, while other models are made with animal cells or are too simple to monitor closely," Matthiesen says.

The researchers' "brain-on-chip" model is actually a two layered set-up where small channels carry simulated blood and inflammation agents, as well as anti-inflammatory drugs, through compartments simulating the perivascular space within the brain, and the external vascular system.

Just as in a real brain, these two areas are separated by a blood brain barrier--a membrane of cells that line the blood vessels of the brain.

This layer is held together by tight junctions that prevent small molecules from diffusing through the gaps between the cells. The barrier serves as a filter to prevent harmful substances from passing into the brain tissue from the bloodstream.

In the model, the barrier is represented by a membrane of cells derived from the stem cells of a single patient, knitted together with proteins.

Cell activity is monitored by electronic sensors which are able to take measurements every minute, as the barrier is exposed to stress similar to that which neurodegenerative diseases cause.

Winkler says that the minute-by-minute detail is important because many cellular processes happen quickly.

"As an example, when you first administer a drug, it causes a huge change in cells, then levels out," Winkler says. "In the typical methods of testing drugs, you wouldn't see those rapid changes.

"We can now see that the breakdown of the blood brain barrier happens fast under stress and we could see how that could be prevented with the anti-oxidant," he says.

Credit: 
KTH, Royal Institute of Technology

Lack of exercise while in quarantine had adverse effects on the health of women aged 50-70

image: Tests performed after the first 16 weeks of COVID-19-induced confinement showed loss of muscle strength and diminished aerobic capacity, as well as an increase in cholesterol and glycated hemoglobin.

Image: 
EEFERP-USP

In a study involving 34 women aged 50-70, researchers at the University of São Paulo (USP) in Brazil performed objective measurements of the impact on the subjects' health of the decrease in physical activity observed during the period of social distancing and isolation imposed by COVID-19. Tests conducted after the first 16 weeks of confinement pointed to a deterioration in their overall health, including loss of muscle strength and diminished aerobic capacity, as well as elevated levels of cholesterol and glycated hemoglobin, both of which are risk factors for metabolic disorders.

The study was supported by São Paulo Research Foundation - FAPESP
and reported in an article published
in the journal Experimental Gerontology.

"It's important to stress that these women were already considered physically inactive before the pandemic, in the sense that they didn't exercise regularly. With confinement, they became even more sedentary, abandoning such activities as walking the dog, going shopping, playing with grandchildren, walking to the bus stop, or walking to work," Carlos Bueno Junior, last author of the article, told. Bueno Junior is a professor at the University of São Paulo's Ribeirão Preto School of Physical Education and Sports (EEFERP-USP).

Designed before the pandemic in partnership with Ellen de Freitas, another professor at EEFERP-USP, the study originally set out to analyze the effects of different physical training programs on groups of volunteers with varying profiles.

A first set of examinations and tests took place in February 2020, before the start of the study proper, to record weight, body mass index (BMI), fat mass, waist circumference, blood pressure, handgrip strength (measured with a dynamometer), and diet (via a questionnaire). The women were also asked to do a test known as the six-minute walk to measure their cardiovascular capacity. Finally, blood samples were collected to analyze white and red blood cell count, cholesterol, glycemia, insulin and glycated hemoglobin (risk factors for type 2 diabetes).

"The plan was to repeat all the exams after they completed the exercise protocol, but the pandemic prevented this. Instead, we adapted the project to evaluate the health impact of the social changes caused by COVID-19, especially in older people. We already had the baseline measurements. We redid the tests after the first 16 weeks of confinement, following all the protocols to avoid contagion," Bueno Junior said.

Master's candidates João Ribeiro de Lima and Gabriela Abud collaborated in the study, and are the first and second authors of the article.

Results

The second battery of tests showed no changes in weight, BMI, fat mass, or waist circumference. However, on average there was a rise of 39.8% in levels of insulin and an increase of 9.7% in glycated hemoglobin. Blood sugar rose 1.3%, but this was not considered significant.

Total cholesterol rose 8%. Blood platelets fell 10%, a change considered significant: the causes and implications of this phenomenon are being investigated.

The grip test showed a 5.6% drop in muscle strength. The six-minute walk test showed a 4.4% loss of aerobic capacity.

"Some of these parameters, such as muscle strength and aerobic capacity, were already below the ideal for this age group because of the volunteers' lifestyle," Lima said. "The study showed that in the context of the pandemic something that was bad became even worse. The risk of chronic disease increased, and existing cardiovascular or metabolic problems worsened."

According to Abud, the answers to the questionnaire showed that diet did not deteriorate during the period, so the adverse effect on health observed in the study had to be due mainly to the decrease in physical exercise. "Many of these women had jobs and a hectic routine before the pandemic, even though they didn't practice sports or get regular exercise," she said. "Some reported feeling more stressful owing to confinement, and this may also have contributed to the overall deterioration in their health."

The researchers believe the findings should serve as a warning to government and society in general. "In a period of only 16 weeks, there were significant changes in some of the parameters, and the prolonging of the public health crisis tends to make the implications for the health of sedentary older people even more severe. We need to think about ways of promoting physical activity safely during this period," Lima said.

For Bueno Junior, getting exercise during periods of social distancing or isolation is vitally important not only to physical but also to mental health. "One possibility is exercising at home with the aid of virtual platforms," he said. "For older people or anyone with physical limitations, however, it's important to have some kind of personalized professional guidance while training, because the risk is greater."

According to Lima, the results of the study show that besides the time dedicated to exercise and training, what people do during the rest of the day is also significant and should be evaluated. "Many believe that just because they work out in the gym for an hour they're free to eat whatever they like or remain seated for the rest of their free time watching TV," he said. "That's not really the case, however. It's vital to reduce the time spent sitting or lying down."

Credit: 
Fundação de Amparo à Pesquisa do Estado de São Paulo

COVID-19 vaccine reduces severity, length, viral load for those who still get infected

Individuals who contract COVID-19 even after vaccination are likely to have a lower viral load, experience a shorter infection time and have milder symptoms than people who are unvaccinated, according to research that includes data from ongoing University of Arizona Health Sciences studies.

"If you get vaccinated, about 90% of the time you're not going to get COVID-19," said Jeff Burgess, MD, MS, MPH, associate dean for research and professor at the Mel and Enid Zuckerman College of Public Health and principal investigator of the Arizona Healthcare, Emergency Response, and Other Essential Workers Surveillance (AZ HEROES) study. "Even if you do get it, there will be less of the virus in you and your illness is likely to be much milder."

While the COVID-19 vaccines are proving to be highly effective in preventing COVID-19 infection, no vaccine is 100% effective and breakthrough infections do occur. Among 3,975 participants in two studies, SARS-CoV-2 infections were identified in five participants who were fully vaccinated and 11 who were partially vaccinated, as well as in 156 unvaccinated participants. Approximately half of the participants were from Arizona study sites.

Researchers found that study participants who were partially or fully vaccinated with the Pfizer and Moderna messenger RNA vaccines at the time of infection had a viral load that was 40% less than that of unvaccinated participants. Viral load - the amount of SARS-CoV-2 virus found in a test sample - is not an indicator of how contagious an individual is, though early COVID-19 research suggests viral load could play a role in disease severity and secondary transmission.

In addition to disease severity, researchers looked at infection longevity. The majority of infections among unvaccinated participants were detected for two or more weeks, compared with only one week among vaccinated participants. That represents a 66% reduction in the risk that a vaccinated person will have a confirmed infection for more than one week.

Additionally, the risk of having COVID-19 with an accompanying fever was 58% lower for vaccinated participants, who reported two fewer days sick in bed, on average, and an overall length of illness that was six days shorter than that of unvaccinated people.

The paper, published in the New England Journal of Medicine, incorporates data from two ongoing CDC-funded studies: the AZ HEROES study and the Abt Associates-led Research on the Epidemiology of SARS-CoV-2 in Essential Response Personnel (RECOVER) study. Study participants - health care personnel, first responders, and other essential and frontline workers in eight U.S. locations - continue to undergo weekly nasal swabs to test for COVID-19, as well as quarterly blood tests.

Including data from Dec. 14 to April 10, researchers found that two doses of an mRNA COVID-19 vaccine were 91% effective against infection with SARS-CoV-2, the virus that causes COVID-19. Additionally, the report indicated a single dose of vaccine proved 81% effective against SARS-CoV-2 infection. This is on par with study data published in the U.S. Centers for Disease Control and Prevention's Morbidity and Mortality Weekly Report on March 29.

"We are still seeing the same high levels of vaccine effectiveness, so we feel good about that," Dr. Burgess said. "But more importantly, we've added a number of measures of the severity of infection among individuals who have been vaccinated as a comparison to those who haven't, and we measured how much virus there is and for how long."

In addition to continuing research into COVID-19 immunity and vaccine efficacy, AZ HEROES researchers are beginning to examine the frequency of SARS-CoV-2 variants. The study was originally funded with a $7.7 million CDC grant.

"We recently were awarded another year of funding," said AZ HEROES research team member Karen Lutrick, PhD, assistant professor in the Department of Family and Community Medicine at the College of Medicine - Tucson. "We really appreciate the participation of all of our AZ HEROES and RECOVER participants, because without them and their work, we wouldn't have this information to share."

Credit: 
University of Arizona Health Sciences

Reducing need for blood transfusion during heart surgery is focus of new practice guideline

CHICAGO (June 30, 2021) -- Four leading medical specialty societies released a new clinical practice guideline today that includes recommendations for reducing blood loss during heart surgery and improving patient outcomes. The document, a multidisciplinary collaboration among The Society of Thoracic Surgeons, the Society of Cardiovascular Anesthesiologists, the American Society of ExtraCorporeal Technology, and the Society for the Advancement of Patient Blood Management, is available online in The Annals of Thoracic Surgery and two other journals.

"As medicine evolves and we learn more, it always is important to review past assumptions, validate new information, and concisely present the best current recommendations," said senior author Susan D. Moffatt-Bruce, MD, PhD, MBA, from the Royal College of Physicians and Surgeons of Canada in Ottawa. "These recommendations are really centered on the patient and how they would want to be treated during complex cardiothoracic procedures."

Since 2011--when the guidelines were last updated--there has been a "remarkable increase" in minimally invasive procedures that has contributed to a favorable shift in blood product utilization and management, according to coauthor Victor A. Ferraris, MD, PhD, from the University of Kentucky College of Medicine in Lexington. As a result, the new practice guideline, which features 23 new or updated recommendations, marks the third iteration and the first in 10 years. "Blood management guidelines are a 'moving target' that change with the advent of new or modified evidence," he said.

It's important to note that in the previous guideline, the term "blood conservation" was used; the new recommendations yield to the broader term "patient blood management" (PBM).

PBM--developed in 2008--is a standard of care designed to optimize patient outcomes by minimizing blood loss, preventing anemia (a lower than normal number of red blood cells, resulting in a decreased capacity of the blood to carry oxygen to the body's tissues), and reducing the need for allogeneic blood transfusions (blood from donors rather than the patients themselves). This approach also places patients at the heart of the decision-making process, ensuring that they are fully informed of the risks and benefits of their treatments and incorporating their values and choices into the treatment pathway. These major tenets of PBM are confirmed in the updated guideline.

"This guideline provides clinicians with a detailed assessment of patient blood management in the cardiac surgical patient--what has been proven to work and what has not--as well as the ability to incorporate these techniques with the most up-to-date evidence," said lead author Pierre R. Tibi, MD, from Yavapai Regional Medical Center in Prescott, Arizona.

Among the most important changes to the practice guideline is the adoption of PBM as a treatment of the whole patient, with blood considered a "liquid organ" or "vital entity" in taking care of the surgical patient, rather than focusing simply on when or when not to transfuse, explained Dr. Tibi.

Blood transfusions--which can be a critical and life-saving facet of cardiothoracic surgery patient care--are generally safe and have saved millions of lives, but they carry the risk of serious side effects, according to Dr. Tibi. Transfused blood has the potential to introduce disease and cause potent immunological reactions or even death; it does not work as well as a patient's own blood.

"Blood transfusions can be harmful to the body. Therefore, unless the proven benefit of blood transfusions outweighs the known risks, it is better to treat patients before, during, and after surgery in ways that decrease the risks of needing blood as much as possible for the best outcomes," he said.

These risks can be lessened through the use of PBM, helping ensure that a patient's own blood is adequate and transfusions are not needed. In fact, some hospital systems in the US have experienced as much as a 45% overall reduction in the rate of transfusions since starting PBM programs.

"Patient safety is well supported in this guideline, as it reduces the risks associated with blood transfusions," said Dr. Moffatt-Bruce.

For example, the guideline includes preoperative interventions related to identifying and managing anemia--a condition that is "extremely prevalent" in the cardiac surgical population, especially in elderly patients or those with other diseases. The most common cause of anemia is iron deficiency, occurring in up to 50% of anemic patients, according to the guideline. Historically, patients with preoperative anemia are more likely to require transfusions, so treating iron-deficiency anemia should be done before surgery. If successful, this can dramatically reduce the need for a blood transfusion.

The new guideline also suggests that in cardiac operations with cardiopulmonary bypass (CPB), the "well-established method" of red cell salvage via centrifugation may be routinely used. In this process, blood that the patient loses during the operation is collected, filtered, and washed by a machine before being reinfused into the patient. Red cell salvage is an important part of the blood conservation aspect of PBM.

Another new addition to the guideline is the recommendation to administer human albumin after cardiac surgery, which also has been shown to minimize the need for transfusion. This medicine typically is used to treat or prevent shock following serious injury, bleeding, or surgery by increasing the volume of blood plasma. Also, priming of the CPB circuit with a patient's own blood (known as "retrograde autologous priming") should be used wherever possible, according to the guideline. This "simple, safe, and effective process" has been shown to decrease transfusion rates, especially for cardiac operations that result in excessive blood loss.

"The guideline has been assembled by experts from different specialties and backgrounds who have reviewed the most recent data," said Dr. Moffatt-Bruce. "This guidance allows clinicians to standardize treatment with the knowledge that they are utilizing the best information while considering all aspects of patient care."

Dr. Tibi expects that some clinicians will be surprised by several of the recommendations, especially those that carry a "great deal of evidence" and likely will require changes to routine treatments for their patients undergoing cardiac surgery (e.g., the information related to the preoperative treatment of anemia and the assorted perfusion techniques).

For patients, it's important that their hospitals, surgeons, and care teams are aware of PBM and that they are utilizing the "best, most proven techniques available," Dr. Tibi advises. "Patients should certainly ask, 'What do you do so that my chances of receiving blood are minimized?'"

Credit: 
The Society of Thoracic Surgeons

The Southern diet - fried foods and sugary drinks - may raise risk of sudden cardiac death

DALLAS, June 30, 2021 -- Regularly eating a Southern-style diet may increase the risk of sudden cardiac death, while routinely consuming a Mediterranean diet may reduce that risk, according to new research published today in the Journal of the American Heart Association, an open access journal of the American Heart Association.

The Southern diet is characterized by added fats, fried foods, eggs, organ meats (such as liver or giblets), processed meats (such as deli meat, bacon and hotdogs) and sugar-sweetened beverages. The Mediterranean diet is high in fruits, vegetables, fish, whole grains and legumes and low in meat and dairy.

"While this study was observational in nature, the results suggest that diet may be a modifiable risk factor for sudden cardiac death, and, therefore, diet is a risk factor that we have some control over," said James M. Shikany, Dr.P.H., F.A.H.A., the study's lead author and professor of medicine and associate director for research in the Division of Preventive Medicine at the University of Alabama at Birmingham.

"Improving one's diet - by eating a diet abundant in fruits, vegetables, whole grains and fish such as the Mediterranean diet and low in fried foods, organ meats and processed meats, characteristics of the Southern-style dietary pattern, may decrease one's risk for sudden cardiac death," he said.

The study examined data from more than 21,000 people ages 45 and older enrolled in an ongoing national research project called REasons for Geographic and Racial Differences in Stroke (REGARDS), which is examining geographic and racial differences in stroke. Participants were recruited between 2003 and 2007. Of the participants in this analysis, 56% were women; 33% were Black adults; and 56% lived in the southeastern U.S., which is noteworthy as a region recognized as the Stroke Belt because of its higher stroke death rate. The Stroke Belt states included in this study were North Carolina, South Carolina, Georgia, Tennessee, Alabama, Mississippi, Arkansas and Louisiana.

This study is the latest research to investigate the association between cardiovascular disease and diet - which foods have a positive vs. negative impact on cardiovascular disease risk. It may be the only study to-date to examine the association between dietary patterns with the risk of sudden cardiac death, which is the abrupt loss of heart function that leads to death within an hour of symptom onset. Sudden cardiac death is a common cause of death and accounted for 1 in every 7.5 deaths in the United States in 2016, or nearly 367,000 deaths, according to 2019 American Heart Association statistics.

Researchers included participants with and without a history of coronary heart disease at the beginning of the study and assessed diets through a food frequency questionnaire completed at the beginning of the study. Participants were asked how often and in what quantities they had consumed 110 different food items in the previous year.

Researchers calculated a Mediterranean diet score based on specific food groups considered beneficial or detrimental to health. They also derived five dietary patterns. Along with the Southern-style eating pattern, the analysis included a "sweets" dietary pattern, which features foods with added sugars, such as desserts, chocolate, candy and sweetened breakfast foods; a "convenience" eating pattern which relied on easy-to-make foods like mixed dishes, pasta dishes, or items likely to be ordered as take-out such as pizza, Mexican food and Chinese food; a "plant-based" dietary pattern was classified as being high in vegetables, fruits, fruit juices, cereal, bean, fish, poultry and yogurt; and an "alcohol and salad" dietary pattern, which was highly reliant on beer, wine, liquor along with green leafy vegetables, tomatoes and salad dressing.

Shikany noted that the patterns are not mutually exclusive. "All participants had some level of adherence to each pattern, but usually adhered more to some patterns and less to others," he explained. "For example, it would not be unusual for an individual who adheres highly to the Southern pattern to also adhere to the plant-based pattern, but to a much lower degree."

After an average of nearly 10 years of follow-up every six months to check for cardiovascular disease events, more than 400 sudden cardiac deaths had occurred among the 21,000 study participants.

The study found:

Overall, participants who ate a Southern-style diet most regularly had a 46% higher risk of sudden cardiac death than people who had the least adherence to this dietary pattern.
Also, participants who most closely followed the traditional Mediterranean diet had a 26% lower risk of sudden cardiac death than those with the least adherence to this eating style.
The American Heart Association's Diet and Lifestyle recommendations emphasize eating vegetables, fruits, whole grains, lean protein, fish, beans, legumes, nuts and non-tropical vegetable cooking oils such as olive and canola oil. Limiting saturated fats, sodium, added sugar and processed meat are also recommended. Sugary drinks are the number one source of added sugar in the U.S. diet, according to the Centers for Disease Control and Prevention, and the American Heart Association supports sugary drink taxes to drive down consumption of these products.

"These findings support the notion that a healthier diet would prevent fatal cardiovascular disease and should encourage all of us to adopt a healthier diet as part of our lifestyles," said Stephen Juraschek, M.D., Ph.D., a member of the American Heart Association's Nutrition Committee of the Lifestyle and Cardiometabolic Health Council. "To the extent that they can, people should evaluate the number of servings of fruit and vegetables they consume each day and try to increase the number to at least 5-6 servings per day, as recommended by the American Heart Association. Optimal would be 8-9 servings per day.

"This study also raises important points about health equity, food security and social determinants of health," he continued. "The authors describe the "Southern Diet" based on the U.S. geography associated with this dietary pattern, yet it would be a mistake for us to assume that this is a diet of choice. I think American society needs to look more broadly at why this type of diet is more common in the South and clusters among some racial, ethnic or socioeconomic groups to devise interventions that can improve diet quality. The gap in healthy eating between people with means and those without continues to grow in the U.S., and there is an incredible need to understand the complex societal factors that have led and continue to perpetuate these disparities."

This current research expands on earlier studies on participants from the same national stroke project, REGARDS. In a 2018 analysis, Shikany and colleagues reported that adults ages 45 and older with heart disease who had an affinity for the Southern diet had a higher risk of death from any cause, while greater adherence to the Mediterranean diet was associated with a lower risk of death from any cause. And in a 2015 study, the Southern diet was linked to a greater risk of coronary heart disease in the same population.

The large population sample and regional diversity, including a significant number of Black participants, are considered strengths of the REGARDS research project. However, potential limitations of this study include that that dietary intake was based on one-time, self-reported questionnaires, thus, it relied on the participants' memory. Self-reported diet can include inaccuracies leading to bias that could reduce the strength of the associations observed.

One usual association that remains unexplained is that among individuals with a history of heart disease, those who most adhered to the sweets dietary pattern had a 51% lower risk of sudden cardiac death than participants who followed that pattern the least. Researchers note that they found "no viable explanation for the inverse association of the sweets dietary pattern with risk of sudden cardiac death in those with a history of coronary heart disease."

Credit: 
American Heart Association

Diaries of infection preventionists give inside look at the unsung heroes of the pandemic

Arlington, Va., June 30, 2021 - Much has been rightfully made of the valiant work of doctors and nurses during the coronavirus pandemic. But what of infection preventionists (IP), whose job was to keep those workers and their facilities safe, and who many Americans do not even know exist?

At the Association for Professionals in Infection Control and Epidemiology's (APIC's), 48th Annual Conference, the head of infection prevention at a top New York City hospital presented an iterative diary, kept in real time by infection preventionists during the height of the pandemic, from March-July 2020.

Almost 50 IPs completed more than 150 surveys over 14 survey rounds during those four dark months and told of the fear that frontline medical workers felt.

"Fear of PPE shortages creating panic... Hoarding and possible theft of PPE...adding to crisis."

The surveys detail ways in which frontline medical workers lacked confidence in their own knowledge of basic infection prevention practices designed to safeguard them from infection and how IPs gained new visibility - and importance - among medical teams who once regarded them lightly.

"Lots of people [IPs] were shocked that they [staff] didn't know how to properly remove PPE."

"Never thought I'd see the day when consumption of product (hand soap, alcohol hand rub) was in such demand."

The IP respondents, from sixteen U.S. states and four countries, wrote that they put in an extraordinary amount of overtime - 68 hours per week in March and 51 hours in April.

"This week has seemed like 6 months shoved into a 7-day period."

Survey respondents also shared experiences about shortages of personal protective equipment (PPE). And when PPE shortages became a serious issue, "IPs became instantly more appreciated, and were sought out by hospital leadership for professional advice," said Tania N. Bubb, PhD, RN, CIC, FAPIC, Director of Infection Control at the Memorial Sloan Kettering Cancer Center in New York.

According to Bubb, who analyzed the survey findings and is presenting them at the APIC Conference, many IPs said they, "never before felt as validated as professionals."

But at the same time, there were contradictions, according to survey comments.

"I'm included at the decision-making table, but nobody will listen to me as an IP. I'm just there to listen to them. They are refusing to cancel elective surgeries and I fear we will be out of gloves in [a] month when this pandemic peak[s] and there will be no gloves for emergent surgeries."

A weekly voluntary survey link was sent to IPs beginning on March 8, 2020. Following participant feedback, surveys were sent on a bi-monthly basis from May 15 - July 15, 2020. Bubb and colleagues used descriptive statistics to analyze quantitative data and thematic analysis for qualitative data.

Credit: 
Association for Professionals in Infection Control

Postmenopausal bleeding may be a sign of endometrial cancer in obese Asian women

CLEVELAND, Ohio (June 30, 2021)--The link between obesity and the risk of endometrial cancer has been well documented. A new study, however, shows that an even lower body mass index (BMI) than previously thought can signal an increased risk in Asian women with postmenopausal bleeding. Study results are published online today in Menopause, the journal of The North American Menopause Society (NAMS).

Endometrial cancer is the sixth most common form of cancer in women worldwide and is a leading cause of cancer death. Because there is currently no routine screening for endometrial cancer in asymptomatic women, it is important for healthcare professionals to be aware of added risk factors so that they can effectively intervene.

In this study, researchers using the Asian BMI standard for obesity (BMI ? 25 kg/m2) sought to determine the relationship between BMI and a subsequent diagnosis of endometrial cancer in Asian women. The threshold for being defined as obese in Asian women is lower than that used for classifying white women. Because roughly 90% of postmenopausal women with endometrial cancer have postmenopausal bleeding, the study specifically looked at women who had experienced postmenopausal bleeding.

On the basis of the results of the study, the researchers concluded that Asian women with a BMI of more than 25 kg/m2 were 1.57 times (57%) more likely to develop endometrial cancer. Such results should alert healthcare professionals to be especially vigilant when treating Asian women with postmenopausal bleeding who are obese.

Results are published in the article "Obesity increases endometrial cancer risk in Chinese women with postmenopausal bleeding."

"This study highlights the known relationship between BMI and endometrial cancer and suggests that the Asian BMI standard for obesity (? 25 kg/m2) helps to identify endometrial cancer in Asian women with postmenopausal bleeding. Key takeaways are that all women with postmenopausal bleeding should undergo evaluation, and obesity remains an important and modifiable risk factor for endometrial cancer, with a linear relationship between BMI and endometrial cancer risk," says Dr. Stephanie Faubion, NAMS medical director.

Credit: 
The Menopause Society

Oncotarget: mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC

image: Mechanism of the antitumor activity of the RAD001 (everolimus) + volasertib combination.

Image: 
Correspondence to - Didier Decaudin - Didier.decaudin@curie.fr

Oncotarget published "High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC" which reported that the aim of this study was therefore to define combination of treatment based on the determination of predictive markers of resistance to the mTORC1 inhibitor RAD001/Everolimus.

When looking at biomarkers of resistance by RT-PCR study, three genes were found to be highly expressed in resistant tumors, i.e., PLK1, CXCR4, and AXL.

The authors have then focused this study on the combination of RAD001 Volasertib, a PLK1 inhibitor, and observed a high antitumor activity of the combination in comparison to each monotherapy; similarly, a clear synergistic effect between the two compounds was found in an in vitro study.

Pharmacodynamics study demonstrated that this synergy was due to tumor vascularization decrease, increase of the HIF1 protein expression and decrease of the intracellular pH, and decrease of the Carbonic Anhydrase 9 protein that could not correct intracellular acidosis.

In conclusion, all these preclinical data strongly suggest that the inhibition of mTORC1 and PLK1 proteins may be a promising therapeutic approach for NSCLC patients.

All these preclinical data strongly suggest that the inhibition of mTORC1 and PLK1 proteins may be a promising therapeutic approach for NSCLC patients

Dr. Didier Decaudin from The Institut Curie said, "Specifically targeting the Pi3K signaling pathway in the treatment of non-small cell lung cancers (NSCLC) has now been proposed for more than ten years."

However, surprisingly, in the context of tumors defined by a Pi3K activation, very few clinical trials have tested single-agent Pi3K signaling pathway, all of them showing in fact a modest activity in molecularly unselected NSCLC patients, with the mTORC1 inhibitor everolimus, and the pan-Pi3K inhibitor Taselisib or Buparlisib.

Based on this rationale for the Pi3K pathway targeting in NSCLC, a huge number of clinical trials have consequently tested various Pi3K-based combination of treatments, including chemotherapies such as pemetrexed, taxanes, platinum salts, EGFR-TKi, radiotherapy, and others.

However, almost all of these combinations have been defined according to standard chemotherapies or NSCLC mutations, but not according to specific targets identified as biomarkers of resistance to Pi3K-targeting treatments.

The main strategy was therefore, using a panel of NSCLC PDXs, to define predictive markers of response to RAD001 therapy and to identify possible combinations of treatments that may be able to reverse RAD001 resistance.

Hence, using two well-documented Pi3K- and mTORC1-targeted therapies, i.e., BKM120 and RAD001, they have first evaluated in vivo responses in NSCLC Patient-Derived Xenografts, second defined marker of resistance to these two therapies that inhibition could pharmacologically be proposed, and finally evaluated a new identified and more relevant combination of treatments.

The Decaudin Research Team concluded in their Oncotarget Research Output that the determination of relevant Pi3K-based therapeutic combination was not supported, by the presence of actual molecular abnormalities, nor by physician therapeutic practices, but by the identification of predictive markers of resistance to Pi3K-based monotherapies.

The step-by-step methodology presented here highlights the useful of appropriate preclinical models of human cancers, such as PDXs; this methodology could be summarized, as follow:

Assessment and validation of an antitumor activity of a treatment X
Determination of predictive marker of resistance to the compound X
Identification of a second treatment Y able to reverse the dismal impact of a previously defined predictive marker of resistance, and
Validation of its clinical relevance in terms of its prognostic impact, assessment and validation of an antitumor activity of the combination of the treatments X Y, comprehensiveness, as far as possible, of the mechanisms of action of this new treatment combination, and, finally, clinical assessment in cancer patients.

This methodology may promote more relevant clinical trials and avoid non-efficient combinations, inacceptable toxicities, and expensive and time-consuming studies.

Credit: 
Impact Journals LLC

Liquid chalk highly effective in killing SARS-CoV-2 and influenza A viruses

image: Professor Jason Mackenzie with daughter Oceania Mackenzie.

Image: 
Phoebe Powell

Melbourne researchers have found that liquid chalk, commonly used in gyms to improve grip, acts as an antiseptic against highly infectious human viruses, completely killing both SARS-CoV-2 (the virus that causes COVID-19) and influenza A viruses.

University of Melbourne Professor Jason Mackenzie, a laboratory head at the Peter Doherty Institute of Infection and Immunity (Doherty Institute) wanted to investigate whether liquid chalk stopped SARS-CoV-2 transmission after conversations with his daughter - an elite rock climber heading to the Tokyo Olympics.

"Both of my daughters were lamenting the closure of gyms at the beginning of the pandemic, particularly my daughter Oceania who was trying to train for Olympic qualification," Professor Mackenzie said.

"There was an assumption that liquid chalk could act as an antiseptic as it has a really high alcohol content, but until now, there was no scientific evidence to support it.

"So we tested the theory against SARS-CoV-2, influenza A viruses and norovirus and we have shown that liquid chalk is very effective against both SARS-CoV-2 and influenza, both in transmission and recovery of the virus."

Using rock climbing as an example, this means that if someone coughed into their hand, then applied the chalk and climbed, there would be no recovery of the virus from their hand.

Or alternatively, if a surface had chalk on it and someone coughed onto it, it was found to be extremely effective at killing the virus.

"We tested four different types of chalk, and three worked incredibly effectively. The fourth was still effective, but not quite at the level of the others. We were surprised however, that norovirus - a virus that causes gastroenteritis - showed complete resistance to the liquid chalk," Professor Mackenzie explained.

"Our findings can help inform athletes and gym goers that they can stay safe when competing and working out, particularly in large-scale competitions, such as the upcoming Olympic Games in Tokyo."

This work was done in collaboration with Urban Climb who supplied the liquid chalk for testing and was published today in mSphere.

Credit: 
University of Melbourne

5-minute workout lowers blood pressure as much as exercise, drugs

image: Tom Heinbockel, a Masters student in the Integrative Physiology department at the University of Colorado Boulder, demonstrates using a Power Breathe device.

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(Photo by Casey A. Cass/University of Colorado)

Working out just five minutes daily via a practice described as "strength training for your breathing muscles" lowers blood pressure and improves some measures of vascular health as well as, or even more than, aerobic exercise or medication, new CU Boulder research shows.

The study, published June 29 in the Journal of the American Heart Association, provides the strongest evidence yet that the ultra-time-efficient maneuver known as High-Resistance Inspiratory Muscle Strength Training (IMST) could play a key role in helping aging adults fend off cardiovascular disease - the nation's leading killer.

In the United States alone, 65% of adults over age 50 have above-normal blood pressure - putting them at greater risk of heart attack or stroke. Yet fewer than 40% meet recommended aerobic exercise guidelines.

"There are a lot of lifestyle strategies that we know can help people maintain cardiovascular health as they age. But the reality is, they take a lot of time and effort and can be expensive and hard for some people to access," said lead author Daniel Craighead, an assistant research professor in the Department of Integrative Physiology. "IMST can be done in five minutes in your own home while you watch TV."

Developed in the 1980s as a way to help critically ill respiratory disease patients strengthen their diaphragm and other inspiratory (breathing) muscles, IMST involves inhaling vigorously through a hand-held device which provides resistance. Imagine sucking hard through a tube that sucks back.

Initially, when prescribing it for breathing disorders, doctors recommended a 30-minute-per-day regimen at low resistance. But in recent years, Craighead and colleagues have been testing whether a more time-efficient protocol--30 inhalations per day at high resistance, six days per week--could also reap cardiovascular, cognitive and sports performance improvements.

For the new study, they recruited 36 otherwise healthy adults ages 50 to 79 with above normal systolic blood pressure (120 millimeters of mercury or higher). Half did High-Resistance IMST for six weeks and half did a placebo protocol in which the resistance was much lower.

After six weeks, the IMST group saw their systolic blood pressure (the top number) dip nine points on average, a reduction which generally exceeds that achieved by walking 30 minutes a day five days a week. That decline is also equal to the effects of some blood pressure-lowering drug regimens.

Even six weeks after they quit doing IMST, the IMST group maintained most of that improvement.

"We found that not only is it more time-efficient than traditional exercise programs, the benefits may be longer lasting," Craighead said.

The treatment group also saw a 45% improvement in vascular endothelial function, or the ability for arteries to expand upon stimulation, and a significant increase in levels of nitric oxide, a molecule key for dilating arteries and preventing plaque buildup. Nitric oxide levels naturally decline with age.

Markers of inflammation and oxidative stress, which can also boost heart attack risk, were significantly lower after people did IMST.

And, remarkably, those in the IMST group completed 95% of the sessions.

"We have identified a novel form of therapy that lowers blood pressure without giving people pharmacological compounds and with much higher adherence than aerobic exercise," said senior author Doug Seals, a Distinguished Professor of Integrative Physiology. "That's noteworthy."

The practice may be particularly helpful for postmenopausal women.

In previous research, Seals' lab showed that postmenopausal women who are not taking supplemental estrogen don't reap as much benefit from aerobic exercise programs as men do when it comes to vascular endothelial function. IMST, the new study showed, improved it just as much in these women as in men.

"If aerobic exercise won't improve this key measure of cardiovascular health for postmenopausal women, they need another lifestyle intervention that will," said Craighead. "This could be it."

Preliminary results suggest MST also improved some measures of brain function and physical fitness. And previous studies from other researchers have shown it can be useful for improving sports performance.

"If you're running a marathon, your respiratory muscles get tired and begin to steal blood from your skeletal muscles," said Craighead, who uses IMST in his own marathon training. "The idea is that if you build up endurance of those respiratory muscles, that won't happen and your legs won't get as fatigued."

Seals said they're uncertain exactly how a maneuver to strengthen breathing muscles ends up lowering blood pressure, but they suspect it prompts the cells lining blood vessels to produce more nitric oxide, enabling them to relax.

The National Institutes of Health recently awarded Seals $4 million to launch a larger follow-up study of about 100 people, comparing a 12-week IMST protocol head-to-head with an aerobic exercise program.

Meanwhile, the research group is developing a smartphone app to enable people to do the protocol at home using already commercially available devices.

Those considering IMST should consult with their doctor first. But thus far, IMST has proven remarkably safe, they said.

"It's easy to do, it doesn't take long, and we think it has a lot of potential to help a lot of people," said Craighead.

Credit: 
University of Colorado at Boulder

College students experience significant grief reactions during global pandemic

A new study shows that colleges students are experiencing significant grief reactions in response to the COVID-19 pandemic. The paper, "College Student Experiences of Grief and Loss Amid the COVID-19 Global Pandemic," was recently published in OMEGA - Journal of Death and Dying.

"This study aimed to identify the most common non-death losses and grief reactions experienced by undergraduate and graduate college students amid the pandemic," said author Erica H. Sirrine, Ph.D., director of Social Work at St. Jude Children's Research Hospital. "What we found is that students across the U.S., even those who may not have experienced a COVID-related death, still reported a considerable number of losses and grief reactions, including avoidance and loss of control. This presents a need for practitioners to provide additional support to college students, especially those who experienced cumulative losses during the pandemic."

Sirrine, a clinical social worker and grief expert, led this research while serving as dean of the College of Behavioral and Social Sciences at Southeastern University in Lakeland, Florida.

Credit: 
St. Jude Children's Research Hospital

COVID-19 review: Analysis of 58 studies finds male sex and obesity are not associated with ICU mortality, but many factors are

A new analysis of 58 studies and 44305 patients published in Anaesthesia (a journal of the Association of Anaesthetists) shows that, contrary to some previous research, being male and increasing body mass index (BMI) are not associated with increased mortality in COVID-19 in patients admitted into intensive care (ICU).

However, the study, by Dr Bruce Biccard (Groote Schuur Hospital and University of Cape Town, South Africa) and colleagues finds that a wide range of factors are associated with death from COVID-19 in ICU.

Patients with COVID-19 in ICU were 40% more likely to die with a history of smoking, 54% more likely with high blood pressure, 41% more likely with diabetes, 75% more likely with respiratory disease, around twice as likely with cardiovascular disease or cancer, and 2.4 times more likely to die with kidney disease, than patients without these risk factors. Other factors associated with an increased risk of death were the severity of organ failure, needing mechanical ventilation (by 2.5 times compared to non-ventilated ICU patients), and also elevated white blood cell counts and other markers of inflammation.

Analysing the reasons for the associations, the authors say age may effectively represent frailty in COVID-19 patients which impacts on a person's physiological reserve to overcome a critical illness. The risk factors of hypertension, smoking and respiratory disease may be linked by their association with angiotensin-converting enzyme (ACE) receptors in the body, as seen by the increased expression of ACE-2 receptors amongst smokers and patients with chronic obstructive pulmonary disease. The association between hypertension and cardiovascular disease and increased mortality may be linked to the risk of cardiac injury associated with the systemic inflammatory response to COVID-19 infection.

The authors say: "The findings confirm the association between diabetes, cardiovascular and respiratory comorbidities with mortality in COVID-19 patients. However, the reported associations between male sex and increasing BMI worsening outcomes are not supported by this meta-analysis of patients admitted to ICU. This meta-analysis provides a large sample size with respect to these risk factors and is a robust estimate of risk associated with male sex and BMI."

Credit: 
AAGBI

To adsorb or to do not adsorb? That is the question

image: The effectiveness of last-chance therapy for patients infected with drug-resistant bacteria depends on viruses specialized in fighting them. In contrast, their viability depends on the material of the container in which they are stored. Photo taken by courtesy of the biotechnological company Bioton S.A. Source: IPC PAS, photo: Grzegorz Krzyzewski

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Source: IPC PAS, photo: Grzegorz Krzyzewski

Prolonged exposure to antibiotics leads to the gain of bacteria's ability to defeat the drugs designed to fight them. Thus, if such antibiotic-resistant bacteria cause the infection, the only chance to use a specialized virus called phage infecting specific bacteria species. It is a powerful weapon against deadly diseases. At the same time, the effective treatment depends on factors that would not be suspected for years to impact the successful therapy. Recently, researchers from the Institute of Physical Chemistry, Polish Academy of Sciences led by dr. Jan Paczesny and Professor Robert Holyst explained why, in some cases, phage therapies might fail. They have revealed that the material used to store the phages has a tremendous effect on their number in the formulation used for treatment.

Antibiotics were used for many decades to treat various bacterial infections. Thanks to them, many diseases are easier to fight. Unfortunately, as long as antibiotics are widely applied in medical treatment, many bacteria develop resistance to antibiotics. As an effect, some of them can defeat all antibiotics that are currently available in the pharmaceutical market. What if someone infected with highly resistant bacteria and even the most potent antibiotic - vancomycin, does not work? Still, there is a chance to win the mortal fight. The solution is based on applying bacteriophages, also called phages. They are specialized viruses that can infect and kill bacteria without adverse effects on humans. That therapy is called Last Chance Viral Therapy and can be used against chronic diseases, e.g., urinary tract inflammation. Unfortunately, despite beneficial treatment and numerous trials, the number of active bacteriophages in the solution for injection can drastically decrease, making the treatment ineffective. Recently, scientists from the Institute of Physical Chemistry, Polish Academy of Scientists led by dr. Jan Paczesny and Professor Robert Holyst found out that the drop of the phage's concentration in a formulation depends on the container's properties used to store them. Surprisingly, depending on the polymer that is used to make the container, the phage can "sit" on the polymers' surface or not. That is caused by hydrophobicity, which is one of the most critical factors governing the adsorption of phages on surfaces. As an effect, even the same sets of containers purchased from different suppliers and manufacturers can have other superficial properties. Then, the internal walls can scavenge all phages from the bulk, leading to a reduced concentration in the formulation.

So, the number of active phages can drastically drop even many orders of magnitude depending on the containers' type used for the phages store. These differences can be caused by the additives used in polymers manufacturing, like plasticizers or slip agents. For that reason, researchers tested several types of polypropylene-based containers dedicated to laboratory use.

Dr. Paczesny remarks, "We verified if leachables are responsible for the observed effect of a decreasing number of active phages in polypropylene containers. We considered the possibility that leachables released from "unsafe" tubes could deactivate phages or leachables from "safe" tubes could protect phages against external factors (e.g., temperature). Next, we examined the adsorption of virions on the polypropylene containers' walls as a mechanism responsible for the observed effect. Uncontrolled adsorption of phages and their subsequent disappearance from the solution can cause severe errors and unrepeatable results. This is extremely important for phage therapies."

Researchers tested various containers with standard operations like mixing, heating, or prolonged storage of active phages. They presented that the drop of active phages number in bulk is dependent mainly only on plastic properties like wettability. They have also investigated the effect of phages' physical structure, including electrostatic properties of the phages' surface. Still, their results clearly point out that the type of plastic has tremendous meaning comparing the surface potential of phages when it comes to phages settling onto containers' walls. In this work, researchers proposed particular solutions for containers having specific properties like a treatment with a particular surfactant limiting the phage's adsorption onto the container surface. Within detailed studies, it was presented that their agglomeration causes the drop of the number of active phages in bulk onto containers' walls. Researchers have explained why phages tend to adsorb on more hydrophobic surfaces. When the aqueous solution with phages is stored in the container made with hydrophobic material like PP, the aggregation of phages onto walls is profitable energetically than their stay in the solution. It is caused by the water properties that have limited contact with hydrophobic walls when they are covered with phages.

"Our findings are of crucial importance not only for phage-related studies. Lack of reproducibility of measurements is becoming the most significant threat to the scientific community. Scientists might not even be aware that PP tubes vendor might provide seemingly the same product differing significantly from batch to batch. Sometimes this can lead to false conclusions. Or, as in the case of phages--it can prohibit the development of essential technologies due to low efficiency caused solely by improper containers." - claims dr. Paczesny

The studies presented in the Scientific Reports on 1st April 2021 present an important issue about the effectiveness of the Last Change Viral Phage Therapy. In case of sudden need of its application, the choice of container for the phages store seems to be the least important. However, as we can see here, such a factor has a tremendous impact on the number of active phages in the solution determining successful therapy.

Such a small step for phages can be a significant step for a patient who struggles with bacteria that can be killed only with phages. Presented data and proposed solutions solve non-repeatable results in infection treatment with phages, but, for sure, will improve all phage-based projects.

Credit: 
Institute of Physical Chemistry of the Polish Academy of Sciences