The findings, published online by Nature Scientific Reports, may help explain some of the molecular processes driving higher rates of the disease — especially more aggressive forms of it — in African American women. ER-positive breast cancer accounts for about 70%-80% of all breast cancer cases, and African American women are 40% more likely to die from it than white women, said Zeynep Madak-Erdogan, a professor of nutritional sciences and of food science and human nutrition at the University of Illinois Urbana-Champaign and co-author of the paper.

Ashlie Santaliz-Casiano, a then-graduate student at the university, was the first author of the study. Madak-Erdogan, the corresponding author, oversaw the project along with Jonna Frasor, a professor of physiology and biophysics at the U. of I. Chicago; and Dr. Kent F. Hoskins, a professor of medicine in the UIC College of Medicine and director of the UIC Familial Breast Cancer Program. Researchers at Northwestern University, Northwestern Memorial Hospital and Northeastern University were partners on the project.

“Overall, we are pretty good at managing the disease, early diagnosing cases with mammography and treating them with drugs that were developed several decades ago,” Madak-Erdogan said.

“Although the tumors are often caught at earlier stages, patients from lower-income neighborhoods such as Chicago’s South Side are more likely to have poor outcomes. That suggests there are some biological factors driving these differing effects,” she said.

The study population included African American women and non-Hispanic white women ages 20-79 who were recruited at three hospitals in the Chicago area in 2018-19.

The team collected blood samples from 102 patients who were newly diagnosed with ER-positive breast cancer in stages 1-3, and 148 healthy women served as the control group. The samples were collected from control group participants at the time they enrolled in the study and from the patients with ER-positive breast cancer prior to breast surgery or other cancer treatment.

“The participants were matched on characteristics such as similar tumor types, similar body mass indices or other factors so we could examine the effects of their neighborhoods and economic backgrounds,” Madak-Erdogan said.

The team analyzed 83 metabolites in the women’s blood and found that African American women with ER-positive breast cancer had decreased circulating levels of amino acids — including the antioxidant methionine — compared with women in the healthy control group. Conversely, non-Hispanic white patients with the disease had significantly higher levels of fatty acids compared with African American women and those in the healthy control group.

The team hypothesized that methionine might be needed in greater volume to support increased DNA methylation — a mechanism that controls which genes get expressed — in African American patients with the disease, Madak-Erdogan said.

Hypermethylation is a possible biological mechanism that might explain poorer disease outcomes in African American women, she said. Aberrant hypermethylation in DNA can occur in the promoter and enhancer regions of cancer-related genes, including tumor suppressors, silencing their expression.

“Using the Pan-Cancer Atlas, a database of 33,000 tumors classified by genetic similarity maintained by the Cancer Genome Atlas Program, we mapped the metabolites to epigenetic regulatory systems,” said Santaliz-Casiano, currently a postdoctoral researcher at the National Cancer Institute in the National Institutes of Health. “We identified 291 genes associated with methylation activities that were expressed at higher rates — 15 of them at statistically significant levels — in African American women with ER-positive breast cancer.”

Poorer survival rates among African American women with the disease — but not non-Hispanic white women — were associated with higher expression of the gene NELFE, a protein complex that regulates enzymes involved in transcriptional activities for downstream target genes, she said.

Tumor cells utilize amino acids as alternative fuels and as precursors for processes such as DNA synthesis, constructing new blood vessels and promoting tumor cells’ rapid growth and proliferation.

In a previousstudy, published in the journal Cancer Research in 2019, a group led by Madak-Erdogan found that higher blood levels of free fatty acids “rewired” cancer cells’ metabolism, activating pathways that promoted tumor growth and proliferation in postmenopausal obesity-related cancer. The current study extends that work by identifying key differences by race: While higher fatty acid levels are good predictors of ER-positive breast cancer in non-Hispanic white women, higher amino acid levels are better predictors of the disease in African American women.

“These metabolic differences might suggest that there would be different screening strategies that could identify worse types of breast cancers,” Madak-Erdogan said. “These assays might enable earlier diagnosis based on patients’ blood. I imagine that it would not be difficult to design a cost-effective blood test for this purpose.

“The current standard screening is mammography, but it requires costly, dedicated equipment, as well as technicians and other trained professionals. If we could come up with a test to diagnose breast cancers earlier, especially those with potentially worse outcomes, that might be useful in clinics with limited resources.”

The paper was co-written by Dhruv Mehta, a then-graduate student at the U. of I. Co-authors at the U. of I. Chicago were: Oana C. Danciu, associate director of clinical research and professor, U. of I. Cancer Center; epidemiology professor Garth H. Rauscher; graduate students Hariyali Patel and Landan Banks; resident Ayesha Zaidi; and then-business administration associate Jermya Buckley.

Co-authors at Northwestern University were: clinical lead operations manager Lauren Schulte, and students Deanna Taiym and Lauren Ro Weller, all at the Robert H. Lurie Comprehensive Cancer Center; and, at the Feinberg School of Medicine, associate Natalie Pulliam, radiology professor Sarah M. Friedewald, breast surgery professor Seema Khan, obstetrics and gynecology professor J. Julie Kim and hematology/oncology professor William Gradishar.

Scott Hegerty, professor of economics and chair of anthropology, geography and environmental studies at Northeastern Illinois University, also co-wrote the study.

Now, researchers at the University of Missouri are one step closer to making the T cell army stronger. In a recent study, conducted in the Roy Blunt NextGen Precision Health building, the researchers found that by manipulating one molecular signaling pathway in the T cells that participate in clearing influenza virus in the lungs, the strength and longevity of immunological memory produced can be improved.

This finding can potentially support the future development of more effective vaccines and therapeutics to combat influenza and other respiratory infections with the ultimate goal of increasing the body’s immunological memory, which can both prevent and lessen the severity of infections and reinfections.

Emma Teixeiro and Mark A. Daniels, associate professors in the MU School of Medicine, led the NIH-funded study, which involved unique mouse models of influenza infection.

“Immunologists like myself have always wondered why T cells in the lungs after influenza infection disappear so quickly,” Teixeiro said. “This research can help us solve that problem by increasing the amount of T cells that can fight against infection. In this study, we have identified novel ways to improve the generation and long-term maintenance of protective immunity against influenza, and that is by manipulating a molecular target known as the IKK2/NFkB signaling pathway.”

Teixeiro added that T cells can recognize parts of viruses that do not mutate, so if researchers can better understand how to strengthen the T cells and extend the timeframe when they can do their job appropriately, the body’s immune system will ultimately be better suited to fight against infection and lessen the severity.

While the influenza virus was the focus of this particular study, gaining knowledge of the underlying molecular mechanisms and signaling pathways that regulate memory in tissues can be helpful to improve therapeutics for patients with cancer, autoimmunity or other respiratory infections.

“By unveiling the biochemical and molecular secrets of these T cells, we can provide valuable information to other scientists who work on optimizing vaccine strategies,” Teixeiro said. “The good news is there are already clinical treatments that do target this particular pathway we identified, so this study is a big step in the right direction, but we still have a long way to go.”

“IKK2/NFkB signaling controls lung resident CD8⁺ T cell memory during influenza infection” was recently published in Nature Communications. Coauthors on the study include Curtis J. Pritzl, Dezzarae Luera, Karin M. Knudson, Michael J. Quaney, Michael J. Calcutt and Mark A. Daniels.

In research published today in Nature Mental Health, an international team of researchers, including from the University of Cambridge and Fudan University, looked at a combination of factors including lifestyle factors, genetics, brain structure and our immune and metabolic systems to identify the underlying mechanisms that might explain this link.

According to the World Health Organization, around one in 20 adults experiences depression, and the condition poses a significant burden on public health worldwide. The factors that influence the onset of depression are complicated and include a mixture of biological and lifestyle factors.

To better understand the relationship between these factors and depression, the researchers turned to the UK Biobank, a biomedical database and research resource containing anonymised genetic, lifestyle and health information about its participants.

By examining data from almost 290,000 people — of whom 13,000 had depression — followed over a nine-year period, the team was able to identify seven healthy lifestyle factors linked with a lower risk of depression. These were:

• moderate alcohol consumption
• healthy diet
• regular physical activity
• healthy sleep
• never smoking
• low-to-moderate sedentary behaviour
• frequent social connection

Of all of these factors, having a good night’s sleep — between seven and nine hours a night — made the biggest difference, reducing the risk of depression, including single depressive episodes and treatment-resistant depression, by 22%.

Frequent social connection, which in general reduced the risk of depression by 18%, was the most protective against recurrent depressive disorder.

Moderate alcohol consumption decreased the risk of depression by 11%, healthy diet by 6%, regular physical activity by 14%, never smoking by 20%, and low-to-moderate sedentary behaviour by 13%.

Based on the number of healthy lifestyle factors an individual adhered to, they were assigned to one of three groups: unfavourable, intermediate, and favourable lifestyle. Individuals in the intermediate group were around 41% less likely to develop depression compared to those in the unfavourable lifestyle, while those in the favourable lifestyle group were 57% less likely.

The team then examined the DNA of the participants, assigning each a genetic risk score. This score was based on the number of genetic variants an individual carried that have a known link to risk of depression. Those with the lowest genetic risk score were 25% less likely to develop depression when compared to those with the highest score — a much smaller impact than lifestyle.

In people at high, medium, and low genetic risk for depression, the team further found that a healthy lifestyle can cut the risk of depression. This research underlines the importance of living a healthy lifestyle for preventing depression, regardless of a person’s genetic risk.

Professor Barbara Sahakian, from the Department of Psychiatry at the University of Cambridge, said: “Although our DNA — the genetic hand we’ve been dealt — can increase our risk of depression, we’ve shown that a healthy lifestyle is potentially more important.

“Some of these lifestyle factors are things we have a degree control over, so trying to find ways to improve them — making sure we have a good night’s sleep and getting out to see friends, for example — could make a real difference to people’s lives.”

To understand why a healthy lifestyle might reduce the risk of depression, the team studied a number of other factors.

First off, they examined MRI brain scans from just under 33,000 participants and found a number of regions of the brain where a larger volume — more neurons and connections — was linked to a healthy lifestyle. These included the pallidum, thalamus, amygdala and hippocampus.

Next, the team looked for markers in the blood that indicated problems with the immune system or metabolism (how we process food and produce energy). Among those markers found to be linked to lifestyle were the C-reactive protein, a molecule produced in the body in response to stress, and triglycerides, one of the primary forms of fat that the body uses to store energy for later.

These links are supported by a number of previous studies. For example, exposure to stress in life can affect how well we are able to regulate blood sugar, which may lead to a deterioration of immune function and accelerate age-related damage to cells and molecules in the body. Poor physical activity and lack of sleep can damage the body’s ability to respond to stress. Loneliness and lack of social support have been found to increase the risk of infection and increase markers of immune deficiency.

The team found that the pathway from lifestyle to immune and metabolic functions was the most significant. In other words, a poorer lifestyle impacts on our immune system and metabolism, which in turn increases our risk of depression.

Dr Christelle Langley, also from the Department of Psychiatry at the University of Cambridge, said: “We’re used to thinking of a healthy lifestyle as being important to our physical health, but it’s just as important for our mental health. It’s good for our brain health and cognition, but also indirectly by promoting a healthier immune system and better metabolism.”

Professor Jianfeng Feng, from Fudan University and Warwick University, added: “We know that depression can start as early as in adolescence or young adulthood, so educating young people on the importance of a healthy lifestyle and its impact on mental health should begin in schools.”

This study was supported by grants from organisations including the National Natural Science Foundation of China and the Ministry of Science, China*.