Medical Bulletin 29/ July/ 2024

In a recent study published in a journal cell report medicine, researchers discovered that many people with stage II or III colon cancer receive additional, or adjuvant, chemotherapy following surgery. However, clinical trials have shown that this treatment doesn’t improve the chances of survival for every patient. The findings indicated that a 10-gene biomarker that potentially predicts whether a stage II or III colon cancer patient will benefit from adjuvant chemotherapy.

The study, led by Steven Chen, Ph.D., a researcher at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, utilised application of machine learning and artificial intelligence to cancer research, primarily focusing on colorectal and breast cancer. Colon cancer patients’ tumours have many different genomic profiles, so the team aggregated gene expression profiles from six publicly available sources to create a 933-patient data set, making it one of the largest gene expression datasets for stage 2 and 3 colon cancer.

The team of data scientists carefully curated and rigorously tested their data to identify a precise gene signature for predicting chemotherapy responses. Their goal was to create a practical and concise signature, so they employed machine learning to analyse a vast network of potentially relevant genes. Through this process, they initially narrowed the list to 18 genes and then refined it further to just 10 key genes.

The researchers found that the gene signature could potentially predict whether immunotherapy would help some patients. It is important because there are not yet clear guidelines on which colon cancer patients might benefit from immunotherapy.

In conclusion, the findings suggested that the gene signature offers a promising tool for personalising treatment strategies, enabling more precise and effective use of chemotherapy. By distinguishing patients who are likely to benefit from adjuvant therapy from those who might not, the signature could help reduce overtreatment and improve overall outcomes. Future research should focus on integrating this signature into clinical practice and evaluating its impact on long-term survival and quality of life for colon cancer patients.

Reference: Chaohan Xu, Peng Xia, Jie Li, J. Joshua Smith, R. Daniel Beauchamp, X. Steven Chen; Discovery and validation of a 10-gene predictive signature for response to adjuvant chemotherapy in stage II and III colon cancer; cell report medicine; July 2024; DOI:https://doi.org/10.1016/j.xcrm.2024.101661

A study published in a journal of clinical investigation, uncovered new information about the role inflammation plays in mitigating liver fibrosis, which is associated with metabolic-associated fatty liver disease (MAFLD), one of the most common diseases in the world affecting up to 40 percent of the adults. While inflammation in the liver has long been considered a prerequisite to developing liver fibrosis, the scarring and thickening of tissue that can impair the liver’s ability to function, this new research suggested that reducing inflammation may not influence the extent of fibrosis.

The study looked specifically at a protein called lipopolysaccharide binding protein (LBP), which is involved in the body's immune response, and how LBP functions in mice. Findings showed that mice without LBP in their liver cells had lower levels of liver inflammation and better liver function but no change in fibrosis.

In addition to mouse models, the researchers also studied genetic analyses from large human datasets and human tissue samples from MAFLD patients at different stages in the disease, to examine the consequence of loss of LBP function. The evidence combined showed that the LBP does not alter scar tissue markers.

Researchers indicated a need to further explore how LBP influences inflammation and whether other factors can offer a more potent reduction in inflammation and have an impact on reducing fibrosis.

This study suggested that targeting inflammation may not be effective in reducing liver fibrosis in individuals with Metabolic Associated Fatty Liver Disease (MAFLD).

Despite inflammation being a known contributor to liver damage, the study’s findings indicated that therapies aimed at mitigating inflammation alone might not significantly improve fibrosis outcomes. This underscored the need for alternative or complementary strategies to address liver fibrosis in MAFLD, potentially focusing on other pathways or mechanisms involved in the disease's progression.

Reference: Dan Wang, Jihane N. Benhammou, Tamer Sallam; Hepatic lipopolysaccharide binding protein partially uncouples inflammation from fibrosis in MAFLD; J Clin Invest. 2024. https://doi.org/10.1172/JCI179752.

According to a study published in the journal life sciences, higher levels of belly and arm fat may increase the risk of neurodegenerative diseases like Alzheimer’s and Parkinson’s, while high muscle strength may decrease this risk.

In the study, researchers recruited 412,961 participants between the ages of 40 and 70 who were followed for an average of about nine years and found that 8,224 participants developed neurodegenerative diseases during this time—mainly Parkinson’s disease, Alzheimer’s disease and other forms of dementia.

The results revealed that participants with excess arm fat had an 18% greater risk of developing these diseases compared to participants with low levels of arm fat.

Participants with high levels of belly fat were also 13% more likely to develop these neurodegenerative diseases, and this risk was slightly higher in men than women.

However, there was one factor that consistently decreased risks among participants: Having high muscle strength lowered risks by over 25%.

Previous research found having higher levels of lean muscle mass—the difference between total body weight and body fat—decreases neurodegenerative disease risk, but the Neurology study researchers found inconsistent results on this factor, and suggested muscle quality may play a more important role in reducing risk than muscle quantity.

One reason high levels of belly fat increases this risk is due to a type of fat called visceral fat, which only lies around abdominal organs. Visceral fat is also called “hidden fat” because it’s located within the stomach and isn’t visible to the naked eye. Middle-aged people with excess visceral fat have increased levels of tau and amyloid proteins in their brains, which are both indicators of Alzheimer’s.

Around 35% and 22% of participants with excess belly and arm fat, respectively, developed some form of cardiovascular disease after the study began, but before the onset of neurodegenerative diseases. Cardiovascular diseases have been previously linked as risk factors for neurodegenerative disease. The researchers suggested early management of cardiovascular diseases in people with excess arm and belly fat may mitigate neurodegeneration.

Reference: Janaína Niero Mazon, Aline Haas de Mello, Gabriela Kozuchovski Ferreira, Gislaine Tezza Rezin; The impact of obesity on neurodegenerative diseases; Life Sciences; Volume 182; 2017; https://doi.org/10.1016/j.lfs.2017.06.002.

According to the recent study published in the journal JAMA oncology,men face risks of cancer from BRCA1 and BRCA2 genetic mutations that are most often associated with breast and ovarian cancers in women.

The study reviewed the most recent screening and treatment guidelines for men carrying an inherited damaging variant in two genes, BRCA1 and BRCA2. The review included updated recommendations for males with a family history of cancer and other risk factors that could help them, and their doctors understand cancer risks.

Men account for 50% of BRCA1/2 carriers and have an increased risk for prostate and other cancers; however, the current rate of testing for men is only one-tenth of the rate for women.

Because genes are inherited from generation to generation, there is a fifty percent chance that a male carrier of a BRCA1 or BRCA2 mutation shares this mutated gene with their biological offspring. The earlier people are aware of the possibility of carrying a BRCA1 or BRCA2 mutation, the more their medical care can be personalised and tailored to their specific situation: a hallmark of the promise of personalised medicine.

Despite the increased cancer risk for BRCA1 or BRCA2-carrying males, national guidelines on genetic testing and cancer screening have been slower to emerge for males, and national guidelines are now beginning to include more specific measures for males.

With less public awareness of the risk for males carrying BRCA1 or BRCA2 mutations, physicians and other healthcare professionals may not always be aware of the most up-to-date screening recommendations, which may exist in different places.

Screening men for BRCA1/2 mutations is crucial because these genetic variants, while often associated with breast cancer in women, also increase the risk of various cancers in men, including prostate and pancreatic cancer. Identifying BRCA1/2 mutations in men allows for early intervention, personalised monitoring, and preventive measures, which can significantly improve health outcomes and guide family planning.

Reference: Cheng HH, Shevach JW, Castro E, et al. BRCA1, BRCA2, and Associated Cancer Risks and Management for Male Patients: A Review. JAMA Oncol. Published online July 25, 2024. doi:10.1001/jamaoncol.2024.2185