Multi-gene Testing Could Detect More Hereditary Cancer Syndromes (Medicine)

Up to 38.6% of people with colon cancer who have a hereditary cancer syndrome — including 6.3% of those with Lynch syndrome — could have their conditions remain undetected with current universal tumor-screening methods, and at least 7.1% of people with colorectal cancer have an identifiable inherited genetic mutation, according to new data published by scientists at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

Experts say their data, which was gathered from a cohort of more than 3,300 colorectal cancer patients treated at 51 hospitals across Ohio, makes a strong scientific argument for implementing multi-gene panel testing as part of the standard of care for all colorectal cancer patients.

“Finding ways to identify high-risk individuals among colorectal cancer patients is critically needed to better manage this disease and proactively identify family members who may also be impacted,” says Rachel Pearlman, MS, LGC, first author of the study and a genetic counselor/researcher at the OSUCCC – James. “Genetic screening has changed dramatically in the past 10 years, allowing us to screen individuals for numerous known genetic mutations for much lower costs. This is a powerful tool that we need to embrace more broadly for cancer prevention and surveillance.”

Study Methods and Results

For this study, OSUCCC – James researchers wanted to know if using a multi-level genetic testing approach could better identify hereditary genetic risk factors (passed down through families) that dramatically increase a person’s lifetime risk of cancer but often go undetected until cancer occurs.

Researchers identified 3,310 adults who had undergone surgery for invasive colorectal cancer from January 2013 to December 2016. Individuals were recruited as part of the Pelotonia-funded Ohio Colorectal Cancer Prevention Initiative (OCCPI), a statewide research initiative led by Heather Hampel, MS, LGC. Hampel is a member of the OSUCCC – James Molecular Carcinogenesis and Chemoprevention Program, as well as a professor and associate director of the Division of Human Genetics at the Ohio State College of Medicine.

The study was launched to screen newly diagnosed colorectal cancer patients and their biological relatives for Lynch syndrome, a cancer-causing condition that occurs if a person inherits a mutation in one of four genes. People with Lynch syndrome are at higher risk to develop colorectal, endometrial (uterine), ovarian and stomach cancer than average-risk individuals.

All study participants received universal tumor screening for mismatch repair (MMR) deficiency. This characteristic is common in tumors from patients with Lynch syndrome and suggests that the tumor would respond well to immunotherapy, which is a novel cancer treatment using your body’s own immune system to fight the tumor, if necessary.

Individuals who met at least one of the trial-inclusion criteria also received multi-gene panel testing to identify harmful mutations. Genetic testing criteria included: MMR deficiency; colorectal cancer diagnosis before age 50; multiple primary tumors (colorectal cancer/endometrial cancer); or a first-degree relative with colorectal or endometrial cancer.

Researchers report in this new analysis that about 16% (525 patients) of participants had MMR deficiency, and about 7% had an inherited mutation. The scientists note that if universal tumor screening for Lynch syndrome had been the only method used to screen for hereditary cancer syndromes, more than 38% of patients who tested positive would have been missed — including more than 6% of individuals found to have Lynch syndrome through multi-gene testing methods.

“This is a significant and important discovery. By using pan-cancer multi-gene panel testing for all colorectal cancer patients, we could identify many individuals who are at increased risk for future cancer development and identify actionable therapeutic targets for their current cancer,” says Hampel, senior author of the study. “Adopting modern testing methods as part of standard clinical practice for patients with colorectal cancer could literally save thousands of lives through early detection and surveillance of other family members who are at increased risk to develop the cancer based on inherited genetic mutations.”

Co-authors in the study include Wendy Frankel, MD; Benhamin Swanson, MD; Dan Jones, MD, PhD; Weiqiang Zhao, MD, PHD; Rachel Pearlman, MS, CGC; Ahmet Yilmaz, PhD; Kristin Miller, BS; Jason Bacher, BA; Christopher Bigley, MS; Lori Nelsen, BA; Paul J. Goodfellow, PhD; Richard M. Goldberg, MD; Electra Paskett, PhD, MSPH; Peter G. Shields, MD; Jo L. Freudenheim, PhD; Peter P. Stanich, MD; Ilene Lattimer, BSN; Mark Arnold, MD; Thomas W. Prior, PhD; Mitchell Haut, MD; Matthew F. Kalady, MD; Brandie Heald, MS, CGC; Ian Paquette, MD; David J. Draper, MD; Joanna M. Brell, MD; Sameer Mahesh, MD; Kisa Weeman, MD; Shyamal Bastola, MD; Jeffrey Zangmeister, MD; Aruna Gowda, MD; Filix Kencana, MD; Albert Malcolm, MD; Yinong Liu, MD; Sharon Cole, MD; Charles Bane, MD; Chaoyang Li, MD; Esther Rehmus, MD; Colin C. Pritchard, MD, PhD; Brian H. Shirts, MD, PhD; Angela Jacobson, MS, CGC; Shelly A. Cummings, MS, CGC; Albert de la Chapelle, MD, PhD; and Heather Hampel, MS, LGC.

Featured image: Heather Hampel and Rachel Pearlman with Albert de la Chapelle © OSU

Reference: Rachel Pearlman, Wendy L. Frankel, Benjamin J. Swanson, Dan Jones, Weiqiang Zhao, Ahmet Yilmaz, Kristin Miller, Jason Bacher, Christopher Bigley, Lori Nelsen, Paul J. Goodfellow, Richard M. Goldberg, Electra Paskett, Peter G. Shields, Jo L. Freudenheim, Peter P. Stanich, Ilene Lattimer, Mark Arnold, Thomas W. Prior, Mitchell Haut, Matthew F. Kalady, Brandie Heald, Ian Paquette, David J. Draper, Joanna M. Brell, Sameer Mahesh, Kisa Weeman, Shyamal Bastola, Jeffrey Zangmeister, Aruna Gowda, Filix Kencana, Albert Malcolm, Yinong Liu, Sharon Cole, Charles Bane, Chaoyang Li, Esther Rehmus, Colin C. Pritchard, Brian H. Shirts, Angela Jacobson, Shelly A. Cummings, Albert de la Chapelle, and Heather Hampel, “Prospective Statewide Study of Universal Screening for Hereditary Colorectal Cancer: The Ohio Colorectal Cancer Prevention Initiative”, Precision Oncology no. 5 (2021) 779-791. Published online May 5, 2021.

Provided by Ohio State University

Insulin is Necessary For Repairing Olfactory Neurons (Medicine)

Findings point to possible treatment for smell loss

Researchers have known for some time that insulin plays a vital role in regeneration and growth in some types of neurons that relay environmental sensory information to our brains, such as sight. However, they know relatively little about the role of insulin in the sense of smell. Now, investigators at the Monell Chemical Senses Center have shown that insulin plays a critical role in the maturation, after injury, of immature olfactory sensory neurons (OSNs). The team published their findings in eNeuro earlier this month.

“Our findings suggest that applying insulin into the nasal passage could be developed as a therapy for injury caused by a host of issues,” said first author Akihito Kuboki, MD, a postdoctoral fellow in the lab of Johannes Reisert, PhD.”

Knowing that insulin is part of the body’s repair pathway for visual neurons, Kuboki suspected that the hormone might also play a role in the maturation of OSNs after injury. He also notes there are many insulin receptors in the olfactory region of the brain. Taking these factors into account, Kuboki concluded that insulin may also be involved in the sense of smell.

“Although scientists don’t yet have a clear idea of how it works, we know that insulin plays a key role in preventing cell death,” said Kuboki. “If insulin levels are reduced, diabetes patients have a high susceptibility to cell death, which can cause smell loss.” He is pursuing this research path to shed light on why people with diabetes often suffer from smell loss, or anosmia.

The research team induced diabetes type 1 in mice to reduce levels of circulating insulin reaching the OSNs. The reduced insulin interfered with the regeneration of OSNs, resulting in an impaired sense of smell. They analyzed how the structure of the olfactory tissue in the nasal cavity and the olfactory bulb is impaired by comparing the number of mature OSNs and how well the axons of OSNs reached the olfactory bulb. The team also recorded odorant-induced responses in the OSNs in the nasal cavity. An odor-guided behavioral task, in which the mice needed to find a cookie reward depending on their ability to smell, measured olfactory function.

In addition, the team injured OSNs, which have a unique ability to regenerate in mammals. This approach allowed the investigators to ask whether OSNs required insulin to regenerate, which they found to be true. What’s more, they discovered that OSNs are highly susceptible to insulin deprivation-induced cell death eight to 13 days after an injury. This time window indicates that during a critical stage newly generated OSNs are dependent on insulin. They also found that insulin must be applied to regenerating OSNs at this critical time point in the neurons’ growth to be able to restore a mouse’s sense of smell.

Also of significance, the team found that insulin promotes regeneration of regenerating OSNs in both type 1 diabetic and nondiabetic mice. “Even in nondiabetic mice, we found that insulin can promote the regeneration of OSNs, which suggests that this could be a therapy for olfactory dysfunction in patients without diabetes,” said Kuboki. Specifically, the team only examined the OSN regeneration process after injury in type 1-diabetic mice and did not examine the effects of type 2 diabetes, but plan to in the future.

“Our findings suggest that insulin plays important roles when OSNs need to regenerate after severe injury that induces cell death in many OSNs,” said Kuboki. “From this, we hope that an insulin spray can be potentially applied to treat smell loss for various reasons, including head trauma and viral infection.”

Other members of the research team are Ichiro Matsumoto, PhD, from Monell; Nobuyoshi Otori, MD, PhD and Hiromi Kojima, MD, PhD, from Jikei University School of Medicine; and Shu Kikuta, MD, PhD and Tatsuya Yamasoba, MD, PhD, from the University of Tokyo.

Featured image: High dependency of new neurons on insulin signaling. © Monell Chemical Senses Center, eNeuro

Reference: Akihito Kuboki, Shu Kikuta, Nobuyoshi Otori, Hiromi Kojima, Ichiro Matsumoto, Johannes Reisert and Tatsuya Yamasoba, “Insulin-dependent maturation of newly generated olfactory sensory neurons after injury”, eNeuro 27 April 2021, ENEURO.0168-21.2021; DOI:

Provided by Monell Chemical Senses Center

Cypriot Grapes Perform Well In Heat And On Taste (Agriculture)

Researchers at the University of Adelaide have found several grape varieties native to Cyprus, which tolerate drought conditions better than some international varieties popular in Australia, contain chemical compounds responsible for flavours preferred by Australian consumers.

The study published in OENO One  follows earlier research  with Cypriot grape varieties Maratheftiko and Xynisteri in particular, which showed they are well adapted to a hot climate and continue to perform well as the climate becomes hotter.

“This latest research adds further support for considering Cypriot varieties for use in Australia and other hot wine growing regions.”

University of Adelaide PhD student Alexander Copper.

Lead author and PhD student Alexander Copper, from the University of Adelaide’s School of Agriculture, Food and Wine, said: “With climate change placing greater strain on the resources needed to sustain viticulture, it is necessary for the global wine industry to investigate alternative grape varieties better suited to hotter climates.

“While the ability to tolerate hotter climates is critical for any alternative varieties considered, they also need to deliver on taste,” Mr Copper said.

In the new study, researchers looked at the role of polyfunctional thiols, which are aroma impact compounds generally known for their contribution to the ‘tropical’ aroma and flavour of Sauvignon blanc and, more recently, in Chardonnay. The study investigated five such thiols in Cypriot wines comprising the white variety Xynisteri, and two red varieties, Maratheftiko and Giannoudhi, comparing them to Australian Pinot Gris, Chardonnay and Shiraz wines.  

Researchers found that each white wine contained compounds responsible for ‘grapefruit’, ‘tropical fruit’ and ‘passionfruit’ aromas at well above their sensory threshold, whereas compounds associated with ‘struck flint’ and ‘meaty’ characters were much lower in concentration. A compound responsible for aromas likened to ‘roasted coffee’ was only detected in the Chardonnay and four of the Xynisteri wines. A final thiol, with aroma attributes of ‘blackcurrant’ and ‘boxwood’ was only detected in Pinot Gris and three Xynisteri wines.

Overall, researchers found the concentration of flavour compounds in the Cypriot wines was comparable to those in popular Australian wines such as Chardonnay and Sauvignon blanc.

Corresponding author Dr Dimitra Capone, an ARC Research Associate with the ARC Training Centre for Innovative Wine Production at the University of Adelaide, has more than 25 years experience in the area of aroma and flavour chemistry. Dr Capone said: “Finding the presence of these desirable flavour compounds in Cypriot grape varieties is exciting and opens up further questions regarding their sensory contributions at varying concentrations in Cypriot wines.” 

Mr Copper added: “In better understanding the thiol composition of Cypriot varieties, producers can better tailor their products to consumer preferences in a changing climate.”

The presence of flavour compounds enjoyed by consumers in the Cypriot wines aligns with the findings of the earlier consumer sensory project conducted by the researchers.

“The panel of wine experts in the sensory study identified flavours upon tasting Xynisteri wines that were comparable to Pinot Gris, which aligns with what we found when analysing the compounds present in both Pinot Gris and several varieties of Xynisteri,” said Mr Copper.

“In consumer trials, consumers ‘liked’ the flavour of the Cypriot varieties, and in one segment of consumers, Xynisteri was preferred to Pinot Gris.”

Since bringing the Cypriot vines to Australia for research at the University’s Waite campus, Mr Copper said they have been approached by several grape growers interested in the varieties, particularly Xynisteri.  In recent weeks the project has had discussions with renowned South Australian viticulturist Paul Georgiadis and the project will begin its first vineyard trials at Paulmara Wines in the Barossa Valley later this year.

“This latest research adds further support for considering Cypriot varieties for use in Australia and other hot wine growing regions,” he said.

Mr Copper’s PhD project is supported by an Adelaide Graduate Research Scholarship and a supplementary scholarship from Wine Australia.

Featured image: Alex Copper with propagated Xynisteri vines at Waite campus. © University of Adelaide

Reference: Copper, A. W., Collins, C., Bastian, S. E. P., Johnson, T. E., & Capone, D. L. (2021). Preliminary investigation of potent thiols in Cypriot wines made from indigenous grape varieties Xynisteri, Maratheftiko and Giannoudhi. OENO One, 55(1), 223–234.

Provided by University of Adelaide

Discovery of Flowering Gene in Cacao May Lead To Accelerated Breeding Strategies (Agriculture)

For the first time, Penn State researchers have identified a gene that controls flowering in cacao, a discovery that may help accelerate breeding efforts aimed at improving the disease-ridden plant, they suggested.

Characterizing the Flowering Locus T gene in cacao, responsible for the production of florigen — a protein that triggers flowering in most plants — is important, according to study co-author Mark Guiltinan, J. Franklin Styer Professor of Horticultural Botany and professor of plant molecular biology. He expects this advancement to enable scientists to develop disease-resistant trees faster, which is critical because 20% to 30% of the world’s cacao crop is lost to disease annually.

“Breeding tree crops like cacao is very slow and can take 20 or more years to release a new variety,” he said. “Knowledge of the mechanisms of flowering may lead to methods to accelerate cacao breeding and to develop trees that produce fruit sooner than conventional varieties, which takes two to four years. Each year we move closer to these goals as we continue to explore the molecular biology of the cacao tree.”

To find the flowering gene in cacao, lead researcher Sarah Prewitt, doctoral candidate in plant science in the College of Agricultural Sciences, first looked at genes known to be responsible for flowering in the Arabidopsis plant, the genome of which has been studied widely for decades. Before finding the cacao flowering gene, she tested an Arabidopsis flowering gene in cacao to see how the plant developed.

Testing her theory, she overexpressed that gene to trigger very early flowering in cacao “plantlets” in the lab and showed that those tiny flowers produced grains of pollen that were viable.

“To find the flowering gene in cacao, we used a bioinformatics approach, taking the sequence of the gene from Arabidopsis and looking for similar genes in the cacao genome,” Prewitt said. “I found the cacao gene that promotes flowering because the sequences look very similar.”

The fungal disease black pod rot, shown here in cacao seed pods, is a serious problem in all areas of the world where the crop is grown. Caused by the fungus Phytophthora, black pod rot causes pod losses of up to 30% and kills as many as 10% of the trees annually. Researchers hope to breed disease-resistant trees, and finding the cacao flowering gene promises to speed up their efforts. © PlantVillage, Penn State

Geneticists consider the function of the florigen flowering gene to be “highly conserved,” Prewitt added. “That means the gene is extremely consistent — it does what it does in every plant genome that you look in,” she said. “The florigen flowering gene certainly has been looked at in a lot of plants, and it’s very reliable. It controls the timing of flowering.”

In findings published May 15 in BMC Plant Biology, the researchers reported on the role of cacao’s single flowering gene, Flowering Locus T, demonstrated by gene-expression analysis. They also documented the results of their introduction of the flowering gene from Arabidopsis into cacao. Overexpressing that gene resulted in “precocious” flowering in cacao tissue culture, they explained, which demonstrated the extremely similar function of florigen genes and the mechanisms that control flowering in both Arabidopsis and cacao.

While intriguing on a scientific level, the discovery of the cacao Flowering Locus T gene could have a potentially significant, real-world impact, Guiltinan noted, by helping to improve the lives of millions of cacao farmers in developing countries sooner than previously thought possible. He pointed out that the breeding of cacao varieties with high yields, disease resistance, resilience to climate change and desirable quality traits is an important component of a broader goal to develop sustainable farming systems for cacao.

“Better cacao varieties can increase the income, and thus the well-being, of cacao farmers who live in some of the most impoverished regions of the world, such as West Africa,” he said. “In turn, this will benefit the economies of these countries and the environment and will provide a sustainable source of the main raw ingredient for the chocolate industry.”

Also involved in the research were Siela Maximova, research professor of plant biotechnology, and Akiva Shalit-Kaneh, postdoctoral scholar in plant science.

Penn State’s College of Agricultural Sciences, the Huck Institutes of the Life Sciences, the Penn State Endowed Program in the Molecular Biology of Cacao and the U.S. Department of Agriculture’s National Institute of Food and Agriculture supported this work.

Featured image: In the research, embryonic cacao, over expressing the florigen gene, develop tiny flowers in tissue culture. This study is significant because cacao trees typically don’t flower until they are between three and eight years of age. Such early flowering promises to greatly speed up breeding to develop disease-resistant trees. © Sarah Prewitt, Penn State

Reference: Prewitt, S.F., Shalit-Kaneh, A., Maximova, S.N. et al. Inter-species functional compatibility of the Theobroma cacao and Arabidopsis FT orthologs: 90 million years of functional conservation of meristem identity genes. BMC Plant Biol 21, 218 (2021).

Provided by Penn State

Finerenone May Delay Onset Of AFib in Patients With Chronic Kidney Disease, Diabetes (Medicine)

Patients with chronic kidney disease and diabetes saw lower rates of heart rhythm disorder, other benefits

Patients with chronic kidney disease and Type 2 diabetes who took the experimental drug finerenone were about 30% less likely to develop the heart rhythm disorder atrial fibrillation (AFib) than those taking a placebo, according to data presented at the American College of Cardiology’s 70th Annual Scientific Session.

Last year, researchers reported that the trial, called FIDELIO-DKD, met its primary endpoint showing a significant benefit of finerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist, in terms of a composite of sustained decrease in kidney function, kidney failure and renal death. The new analysis reveals that patients derived these benefits regardless of their history with AFib and suggests that taking finerenone also reduced the rate of new-onset AFib.

“Finerenone can lower the risk of development of atrial fibrillation in patients with chronic kidney disease and diabetes and can be used as a therapeutic strategy to delay its onset,” said Gerasimos Filippatos, MD, from the National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital in Athens, Greece, and the study’s lead author. “It can also protect the heart and the kidney from further damage caused by chronic kidney disease and diabetes in these patients with or without pre-existing atrial fibrillation.”

Chronic kidney disease, diabetes and AFib are major public health concerns worldwide. Patients with chronic kidney disease and diabetes face an increased risk of developing AFib because these conditions can cause changes in the heart’s structure and electric signaling, leading to fast and erratic heart rhythms. During preclinical studies, finerenone was reported to slow these structural changes.

FIDELIO-DKD randomly assigned 5,674 patients with chronic kidney disease and diabetes to take finerenone or a placebo and tracked outcomes for a median of 2.6 years. The primary endpoint was a composite of kidney failure, renal death or sustained decrease in estimated glomerular filtration rate (a measure of kidney function) of 40% or more from baseline. The key secondary outcome included death by loss of heart function, nonfatal heart attack, nonfatal stroke or hospitalization for heart failure.

As previously reported, finerenone significantly lowered the risk of kidney events by 18% and the risk of cardiovascular events by 14% compared with placebo. For the new analysis, researchers assessed outcomes among patients with and without a history of AFib or atrial flutter (about 8% of participants had AFib or atrial flutter at the start of the trial) and the risk of patients developing AFib or atrial flutter during the study.

The results found the primary and secondary endpoints were significantly lower in patients taking finerenone regardless of their AFib status at the start of the study.

“The previously-reported kidney and heart protection with finerenone applied equally to patients with and without pre-existing atrial fibrillation,” Filippatos said.

In addition, new-onset AFib or atrial flutter was reported in 3.2% of patients taking finerenone and 4.5% of those taking a placebo, a significant difference in favor of finerenone.

Researchers said that previous findings from preclinical studies have suggested that finerenone may help reduce scarring and thickening of the heart tissue, possibly through its action of blocking mineralocorticoid receptors, a type of protein molecule present on many cell types in the heart and kidney that has been shown to be especially abundant in patients with AFib.

“Preventing or delaying the onset of atrial fibrillation in patients with chronic kidney disease and diabetes is particularly important since having atrial fibrillation can worsen chronic kidney disease and having diabetes can worsen atrial fibrillation symptoms,” Filippatos said. “Treatment in these patients can also be challenging because they are prone to developing blood clots [which can lead to stroke] and bleeding. Finerenone has the potential to reduce the burden of atrial fibrillation in these patients.”

Filippatos said that larger studies focused specifically on new-onset AFib would be needed to confirm the findings. Because participants underwent heart rhythm tests only once per year in FIDELIO-DKD, Filippatos said it is possible that researchers missed asymptomatic AFib or cases that were not apparent from tests. A separate trial is currently underway to examine finerenone’s effects in patients with less severe chronic kidney disease and diabetes.

This study was simultaneously published online in the Journal of the American College of Cardiology at the time of presentation. The study was funded by Bayer AG. Filippatos will be available to the media in a virtual press conference on Monday, May 17, at 12:15 p.m. ET / 16:15 UTC.

Filippatos presented the study, “Finerenone Reduces Onset of Atrial Fibrillation in Patients with Chronic Kidney Disease and Type 2 Diabetes” in JACC.

Provided by American College of Cardiology

Sacubitril/Valsartan Not Superior To Valsartan For Advanced Heart Failure (Medicine)

Trial finds no benefit from combination therapy for heart failure with reduced ejection fraction

Patients with heart failure with reduced ejection fraction (HFrEF) did not have better health outcomes if they took sacubitril/valsartan combination therapy compared with valsartan alone, according to new data presented at the American College of Cardiology’s 70th Annual Scientific Session.

Heart failure, a leading cause of hospitalization among adults over age 65, is a condition in which the heart becomes too weak to pump blood effectively to the rest of the body, causing fatigue and shortness of breath. For patients with severe heart failure, treatment options are limited to a mechanical heart pump or heart transplant. Doctors have sought ways to slow the progression of severe heart failure to delay the need for these invasive options.

The U.S. Food and Drug Administration has approved sacubitril/valsartan for treatment of heart failure, but the major clinical trial that led to the drug combination’s approval, called PARADIGM-HF, had relatively few participants with New York Heart Association (NYHA) Class IV heart failure, the most severe form of the disease. The new trial, called LIFE, was designed to determine whether sacubitril/valsartan is superior to valsartan alone in patients with severe HFrEF.

The trial found no significant improvements with the combination drug when compared with valsartan in terms of the primary endpoint: change in heart failure severity as measured by the area under the curve for N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. The results also showed no difference in terms of clinical outcomes, though results for some secondary and tertiary endpoints favored valsartan, including a finding that patients taking valsartan were significantly less likely to experience hyperkalemia (elevated potassium levels).

“The results of the LIFE trial show that sacubitril/valsartan is not superior to valsartan for lowering NT-proBNP levels in patients with advanced heart failure,” said Douglas L. Mann, MD, Lewin Distinguished Professor of Cardiovascular Disease at Washington University School of Medicine and the study’s lead author. “This is important because the type of heart failure patients studied in the LIFE trial were sicker than the patients in PARADIGM-HF. Although the trial did not have the statistical power to evaluate endpoints such as cardiovascular death and heart failure hospitalization, when you look at the totality of the data, everything was in favor of valsartan.”

For the trial, researchers enrolled 335 patients with advanced heart failure as defined by having reduced pumping capacity with an ejection fraction of less than 35% (a measure of the heart’s squeezing ability for which a value of 50-70% is considered normal) as well as other physiological and functional markers of severe heart failure. Participants were randomly assigned to take either sacubitril/valsartan or valsartan alone for 24 weeks.

About one-third of patients assigned to take sacubitril/valsartan were unable to tolerate the combination drug at the full dose used in previous trials due to side effects including hypotension (low blood pressure and dizziness) and worsening renal function. These patients took a reduced dose.

“Patients with advanced heart failure are a very difficult group of patients to treat. It has been widely assumed that sacubitril/valsartan would be effective in all patients with heart failure,” Mann said. “I think the drug works very effectively in patients with milder heart failure, but the results of the LIFE trial indicate that there is no evidence that sacubitril/valsartan is better than valsartan for more advanced heart failure, and there appears to be less hyperkalemia with valsartan.”

The combination of sacubitril/valsartan is thought to work in part by reducing the size of the heart and improving its pumping ability.

“We make the assumption that all heart failure patients are the same and therefore will respond the same to all therapies. However, the patient population with advanced heart failure is different from patients with less advanced heart failure because of the end organ changes that occur in the heart and kidneys. These end organ changes limit the ability of the failing heart to respond to conventional therapies to the same extent as occurs in patients with milder forms of heart failure. This is one of the lessons we learned from the LIFE trial,” Mann said.

The study was limited by its relatively short duration, Mann said. In addition, the sample size fell short of the planned enrollment of 400 patients since the trial was stopped early in response to the COVID-19 pandemic.

The study was funded by the National Institutes of Health with additional support from Novartis Pharmaceuticals Corporation through an investigator-initiated trial program.

Mann will present the study, “Sacubitril/Valsartan (LCZ696) in Patients with Advanced Heart Failure and Reduced Ejection Fraction: Results of The LIFE Trial,” on Monday, May 17, at 8 a.m. ET / 12:00 UTC, virtually.

Reference: Mann DL, Greene SJ, Givertz MM, Vader JM, Starling RC, Ambrosy AP, Shah P, McNulty SE, Mahr C, Gupta D, Redfield MM, Lala A, Lewis GD, Mohammed SF, Gilotra NA, DeVore AD, Gorodeski EZ, Desvigne-Nickens P, Hernandez AF, Braunwald E; LIFE Investigators. Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial. JACC Heart Fail. 2020 Oct;8(10):789-799. doi: 10.1016/j.jchf.2020.05.005. Epub 2020 Jun 10. Erratum in: JACC Heart Fail. 2020 Dec;8(12):1059. PMID: 32641226; PMCID: PMC7286640.

Provided by American College of Cardiology

Pirfenidone Reduces Scar Tissue in Patients With Heart Failure (Medicine)

Early-phase study suggests shrinking scarring could help those with preserved ejection fraction

Patients with heart failure with preserved ejection fraction who took the antifibrotic drug pirfenidone saw a significant reduction in a marker of heart muscle scarring compared with patients who received a placebo, based on findings from an early-phase trial presented at the American College of Cardiology’s 70th Annual Scientific Session.

“Observational data suggests that heart muscle scarring, or fibrosis, is an important disease process for heart failure prognosis,” said Chris Miller, MD, a cardiologist and National Institute for Health Research Clinician Scientist at the University of Manchester and Manchester University NHS Foundation Trust and the study’s lead author. “With cardiac MRI, we were able to select a group of patients in whom fibrosis appears to be important and then reduce that scarring. While further investigation is needed, it suggests that fibrosis is an effective treatment target.”

Heart failure means that the heart is no longer able to pump blood around the body properly, causing shortness of breath, swelling and fatigue. In about half of patients with heart failure, the forward pumping function of the heart, or ejection fraction, is normal. This is called heart failure with preserved ejection fraction, or HFpEF. While heart failure can involve multiple factors, scarring of the heart muscle is thought to be an important contributing factor in up to two-thirds of patients with HFpEF. This new trial suggests clinicians could one day use a personalized approach to prevent or reverse scarring in those individuals, thereby slowing the progression of heart failure, Miller said.

Pirfenidone is currently approved for treating adults with idiopathic lung fibrosis, or scarring in the lungs that makes it hard to breathe. While the mechanism of action has not been fully established, the drug is thought to work by inhibiting biological processes involved in scar formation. Preclinical studies suggest pirfenidone can both reduce scar tissue formation and reduce existing scarring in the heart.

Researchers enrolled patients with heart failure, an ejection fraction of 45% or higher and elevated natriuretic peptides (markers of fluid retention). Eligible patients underwent cardiac MRI scanning. Those who had evidence of scarring in the heart muscle, as indicated by an extracellular volume (a measurement of heart muscle scaring) of 27% or greater, were randomly assigned to take pirfenidone or a placebo daily. In total, 94 patients were randomized, with 47 assigned to each treatment group.

At one year, patients underwent a second cardiac MRI to measure change in heart muscle extracellular volume, the primary endpoint. Extracellular volume declined by 1.21% on average in patients who took pirfenidone compared with those receiving placebo, a reduction Miller said was likely to be clinically significant.

“Based on the data we have from previous observational studies, this amount of change in fibrosis could translate into a significant reduction in death and hospitalization for heart failure, but further work is needed to determine this,” Miller said.

The study also found evidence that fluid retention, measured using natriuretic peptides, improved in patients who took pirfenidone compared to those receiving placebo.

“The associated reduction in natriuretic peptides provides support for heart scarring having a causal role in heart failure and being an efficacious therapeutic target,” Miller said. “Hopefully this work can lead to further development of therapeutics that target heart fibrosis and scarring, and a phase three trial to see if pirfenidone improves patient outcomes.”

The most common adverse events were nausea, insomnia and rash.

The study was funded by the National Institute for Health Research (UK). The investigational medicinal product was gifted by Roche Products Limited. Immunoassay testing equipment and materials were gifted by Roche Diagnostics International Limited. Neither company had any role in study design or conduct, including data collection, management, analysis and interpretation; preparation, approval of, and the decision to submit the abstract/manuscript.

Reference: Lewis GA, Schelbert EB, Naish JH, Bedson E, Dodd S, Eccleson H, Clayton D, Jimenez BD, McDonagh T, Williams SG, Cooper A, Cunnington C, Ahmed FZ, Viswesvaraiah R, Russell S, Neubauer S, Williamson PR, Miller CA. Pirfenidone in Heart Failure with Preserved Ejection Fraction-Rationale and Design of the PIROUETTE Trial. Cardiovasc Drugs Ther. 2019 Aug;33(4):461-470. doi: 10.1007/s10557-019-06876-y. PMID: 31069575; PMCID: PMC6689029.

Provided by American College of Cardiology

Researchers Discover First Immune Stimulating Long Noncoding RNA Involved in Body’s Response to Cancer (Medicine)

The findings in human cells and animal models suggest potential approaches to improve immunotherapy treatment against cancer.

A long noncoding RNA whose function was previously unknown turns out to play an important role in promoting the body’s immune response against cancer and holds promise for enhancing the efficacy of anti-cancer immunotherapy.

That’s according to new findings reported in Nature Cell Biology by researchers at the University of Michigan Rogel Cancer Center.

The group dubbed the RNA they identified LIMIT — for long noncoding RNA inducing major histocompatibility complex class I and immunogenicity of tumor.

“LIMIT is easy to remember, but really it does the opposite. It stimulates immune functions against cancer,” says senior study author Weiping Zou, M.D., Ph.D., the Charles B. de Nancrede Professor of Pathology, Immunology, Biology, and Surgery at U-M.

Only a small part of the human genome contains genes that encode proteins. The rest includes more than 30,000 long “noncoding” RNAs, or lncRNAs, most of whose functions remain unknown.

LncRNAs are known to play some important roles in cancer, but very little is known about their roles in the context of the immune system’s response to cancer, Zou says.

“LncRNAs have mainly been studied in cancer models that lack a functioning immune system, leaving a big gap in our knowledge,” adds study first author Gaopeng Li, Ph.D., a research fellow in Zou’s lab. “When it works, immunotherapy can be amazingly successful, but doesn’t work in more than half of patients. We wanted to better understand what role lncRNAs play and whether there might be opportunities to target them to improve immunotherapy.”“If you get rid of this lncRNA, the mice are much less able to fight off the cancer.”Weiping Zou, M.D., Ph.D.

Immunotherapy tends to be most effective in patients with whose tumors are more susceptible to infiltration by the immune system’s T cells. By comparing cancers with low levels of T cell infiltration to those with high infiltration, the researchers discovered LIMIT through its association with positive markers of immune response.

After confirming that LIMIT was indeed a long noncoding RNA, the researchers conducted experiments in human tumor cells and mouse cells to better understand its function, explains Zou. And it turns out that LIMIT is regulated by interferon gamma, a cytokine that plays a central role in the body’s ability to mount an immune response against an invading threat.

Subsequent experiments in mice showed that LIMIT is a vital component of T cell infiltration into tumors.

“If you get rid of this lncRNA, the mice are much less able to fight off the cancer,” Zou says. “The T cells don’t go to the tumor and they don’t function normally.”

Ultimately, the research determined that LIMIT activates a family of genes known as GPBs (for guanylate binding proteins), leading to the activation of other important immune players: heat shock factor-1 (HSF1) and major histocompatibility complex class I (MHC-I).

Using CRISPR techniques to activate LIMIT boosted checkpoint therapy against the tumors in mouse models, while silencing LIMIT made the immunotherapy less effective.

“Very often, there is a loss of MHC-I and interferon gamma signaling in human tumors, which helps the cancer evade the immune system,” Zou says. “Our research suggests several new potential therapeutic approaches to overcome this. These include using CRISPR to activate LIMIT and improve MHC-I expression to boost the body’s immune response, and also targeting some of the downstream players in this signaling axis, like GBPs.”

Additional authors include Ilona Kryczek, Jutaek Nam, Xiong Li, Shasha Li, Jing Li, Shuang Wei, Sara Grove, Linda Vatan, Jiajia Zhou, Wan Du, Heng Lin, Ton Wang, Chitra Subramanian, James J. Moon, Marcin Cieslik, Mark Cohen, all of U-M.

This work was supported by grants from the National Cancer Institute (CA217648, CA123088, CA099985, CA193136, CA152470, CA216919, CA213566, CA120458) and the National Institutes of Health through a grant to the U-M Rogel Cancer Center (CA46592).

Featured image: Illustration of a T cell attacking a cancer cell. Roger Harris/Science Photo Library via Getty Images.

Paper cited: “LIMIT is an immunogenic lncRNA in cancer immunity and immunotherapy,” Nature Cell Biology. DOI: 10.1038/s41556-021-00672-3

Provided by Michigan Health Lab

‘Sticky’ Speech And Other Evocative Words May Improve Language (Language)

New study finds that iconicity in parents’ speech helps children learn new words

Some words sound like what they mean. For example, “slurp” sounds like the noise we make when we drink from a cup, and “teeny” sounds like something that is very small. This resemblance between how a word sounds and what it means is known as iconicity.

In her lab at the University of Miami, Lynn Perry, an associate professor in the College of Arts and Sciences Department of Psychology, previously found that children tend to learn words higher in iconicity earlier in development then they do words lower in iconicity. She also found that adults tend to use more iconic words when they speak to children than when they speak to other adults.

“That got us curious about why,” said Stephanie Custode, a doctoral student in psychology, who worked with Perry to answer questions posed by her prior work. “Does iconicity play a causal role in children’s language development, helping them learn new words, eventually even those words that have non-iconic, or arbitrary, sound-meaning associations?” 

For their new study, published in the journal Cognitive Science, the researchers explored whether parents’ who used iconic words as they played with novel objects with children between 1 and 2 helped them learn those objects’ names. The objects were novel toys and foods that the researchers made and gave names to, like the word “blicket” to describe a clay toy with a made-up shape. They found that when parents named a novel object, their children were more likely to remember those novel names later if the parent also used highly iconic words in the same sentence. This was true both for parents speaking English and Spanish.

“Consider when a parent teaches their child about ‘cats’ by talking about how they ‘meow,’ or about a sweater by talking about how ‘fuzzy’ it is, or about ‘honey’ by talking about how sticky it is,” Perry said. “The resemblance between the sound of a word like ‘sticky’ and the texture of the honey helps the child pay attention to that property. If the parent also says ‘honey’ while describing its stickiness, the child can form a stronger memory of that new word and its meaning, because they’re paying attention to its important properties—its sticky texture in this case.”  

The researchers found it was beneficial for parents to use iconic language specifically when they introduced a novel name. “If a parent talks about stickiness without saying the name ‘honey’, there’s no new name to associate with that sticky texture, and if a parent names the honey but talks about it being yellow, a word that doesn’t particularly sound like its meaning, the child might pay less attention to the honey and forget about it. In both cases, the child wouldn’t learn the new word ‘honey’,” said Perry.

From these findings, the researchers concluded that iconicity could be an important cue that parents and other caregivers can use to facilitate word learning.

Next the researchers plan to investigate whether using more iconic words can help children with language delays learn new words. They also are interested in studying how parents talk to children changes over time and whether they decrease their use of iconic language as they recognize that their child is becoming a stronger word learner.

The study, “What Is the Buzz About Iconicity? How Iconicity in Caregiver Speech Supports Children’s Word Learning,” is now available in Cognitive Science.

Provided by University of Miami