Medical Bulletin 10/ April/ 2024

A new UCLA-led research suggested that mutation in a protein regulating natural killer (NK) cells’ function is at the root of immune deficiency in some people with a rare genetic condition characterized by cognitive and developmental delay, seizures, and other manifestations.

The findings, published in the journal Nature Immunology, were the first to observe that these people are immune deficient and point to lipid supplementation with oleic acid as a potential therapy.

“Human NK cell deficiencies are rare but lead to a dramatic increase in vulnerability to viral infections. Clinically, we still don’t know a lot of genes that can result in NK cell deficiency when mutated. Our findings identify NK cell defects associated with MEF2C insufficiency syndrome that might explain the frequent infections that some of these patients experience,” said first author Joey Li of the UCLA-Caltech Medical Scientist Training Program.

Using CRISPR gene editing, the researchers screened 31 genes in human NK cells and found that MEF2C was a crucial driver for multiple functions in those cells. They also found that oleic acid enhanced the protective activity in cells from MEF2C insufficient people and normal NK cells. A loss or mutation in a gene called MEF2C disrupts the ability of NK cells to take up chemical compounds called lipids that are used to fuel crucial functions such as tumour cell killing and creating inflammatory molecules. They found that people with the rare neurological syndrome (MCHS) who have the mutation in this gene are particularly vulnerable to viral infections.

“Harnessing lipid metabolism to engineer better NK cell therapies may have promise in the realm of cancer immunotherapy, as previous studies have found that tumour-infiltrating immune cells can become metabolically impaired,” Li said. “In the realm of NK cell immunodeficiencies, we have noted a trend that multiple neurodevelopment disorders seem to be accompanied by NK cell defects. But more research is needed to solidify a link between NK cell function and neurodevelopmental disorders,” added Li.

Reference: Joey H. Li, Adalia Zhou, Cassidy D. Lee, Siya N. Shah, Jeong Hyun Ji, Vignesh Senthilkumar, Eddie T. Padilla, Andréa B. Ball, Qinyan Feng, Christian G. Bustillos, Luke Riggan, Alain Greige, Ajit S. Divakaruni, Fran Annese, Jessica Cooley-Coleman, Steven A. Skinner, Christopher W. Cowan & Timothy E. O’Sullivan; MEF2C regulates NK cell effector functions through control of lipid metabolism; Journal: Nature Immunology; DOI: 10.1038/s41590-024-01811-2

In a recent study, researchers at Huntsman Cancer Institute at the University of Utah found a surprising trend in families with male infertility: an increased risk of certain cancers.

The discovery published in the journal Human Reproduction could lead to a more personalised approach to cancer risk assessments, making cancer prevention more effective.

According to the National Institutes of Health, around 9% of men at reproductive age have experienced fertility problems.

“We know that men who experience infertility tend to have more health issues like cardiovascular disease, autoimmune conditions, earlier mortality, chronic health conditions, and cancer,” says Joemy Ramsay, PhD, the study's lead investigator, researcher at Huntsman Cancer Institute, and assistant professor in the Division of Urology­ at the University of Utah. “We wanted to look at whether the family members of these men were at higher risk for these conditions.”

In the study, Ramsay and her team used the Utah Population Database and observed parents, siblings, children, and even aunts, uncles, and cousins, of men who have been diagnosed with infertility. By observing several types of cancer at once, the team was able to develop an algorithm that clusters similar things together. This algorithm made it possible to identify roughly 13 characteristic patterns. The patterns were based on families possessing similar multi-cancer risks, instead of looking at only one cancer type at a time.

“Both cancer and subfertility are complex diseases and processes. This method helps create similar family groups, making it easier to uncover the reason behind a family being at high risk for certain diseases over others,” said Ramsay. “For families with male infertility, these findings may prompt additional conversations with their doctors. While the link is still not fully understood, it is important to have these conversations with our families, and bring your concerns to your medical team.”

Reference: Joemy M Ramsay, Michael J Madsen, Joshua J Horns, Heidi A Hanson, Nicola J Camp, Benjamin R Emery, Kenneth I Aston, Elisabeth Ferlic, James M Hotaling; Describing patterns of familial cancer risk in subfertile men using population pedigree data; Journal: Human Reproduction; https://doi.org/10.1093/humrep/dead270

A study published in the journal JAMA Network Open revealed that young people's decreased fitness may affect their future work ability. The association between low youth cardiorespiratory fitness and adulthood decreased work ability persisted until the end of working life.

Cardiorespiratory fitness, which measures the body's ability to deliver oxygen to muscles during physical activity, is closely linked to work ability in individuals. Higher levels of cardiorespiratory fitness typically correlate with better work ability, as it enhances endurance, reduces fatigue, and improves overall physical capacity. The association of fitness with work ability has been demonstrated in cross-sectional studies. Evidence from experimental and observational studies have shown that sufficient levels of cardiorespiratory fitness and musculoskeletal fitness and a healthy body weight benefits work ability.

In the study, the participant's baseline physical fitness was measured in school between the ages of 12 and 19. Work ability was self-assessed twice during working life, between the ages of 37 and 44 and then between the ages of 57 and 64. The samples included fitness measurements for cardiorespiratory fitness (CRF), musculoskeletal fitness (MF) and BMI.

The results showed that low cardiorespiratory fitness in adolescence was associated with decreased work ability and higher rates of absence due to illness in the middle of working life, and with decreased work ability at the end of working life.

The findings suggested that low CRF in youth is associated with poor workability at the middle and end of working life, which highlights the informative and prognostic value of CRF assessment early in youth. Enhancing CRF in the first decades of life might contribute to better work capacity and productivity, which would have implications for health, quality of life, society, and the economy.

Reference: Perttu T. T. Laakso, Francisco B. Ortega, Pertti Huotari, Asko J. Tolvanen, Urho M. Kujala, Timo T. Jaakkola. Adolescent Cardiorespiratory Fitness and Future Work Ability. JAMA Network Open, 2024; 7 (3): e243861 DOI: 10.1001/jamanetworkopen.2024.3861