Medical Bulletin 28/ August/ 2024 - Video

A recent study published in the journal Proceedings of the National Academy of Sciences indicates that a common chemotherapy supplement called folinic acid weakens the cancer’s defences in pancreatic ductal adenocarcinoma (PDAC).

The battle against cancer resembles an arms race, with immunotherapy emerging as one of the most powerful tools available to clinicians. Immune checkpoint therapy has become a standard treatment for various cancers. Nevertheless, it often proves ineffective for the majority of patients with pancreatic ductal adenocarcinoma (PDAC)

Previously, it was believed that pancreatic ductal adenocarcinoma (PDAC) did not provoke an immune response, however, recent researchers have proved that immune cells do indeed attack the tumours. The problem is that these cells have difficulty penetrating the aggressive tumours, allowing pancreatic ductal adenocarcinoma to evade destruction.

Recently, researchers have found that folinic acid, a common chemotherapy supplement, weakens cancer's defences in mice. They discovered that folinic acid boosts the levels of two key anti-cancer immune molecules in pancreatic ductal adenocarcinoma: natural killer T (NKT) cells and type-I interferons. This results in a stronger immune response, slower tumour growth, and longer survival in mice.

Scientists further revealed that pancreatic ductal adenocarcinoma defends itself against immune cells by creating a nearly impenetrable barrier using two proteins—CXCR4 and CXCL12. However, when the team treated pancreatic ductal adenocarcinoma tumors with folinic acid, this shield showed vulnerabilities.

The increased levels of NKT cells and type-I interferons acted as markers, revealing paths through pancreatic ductal adenocarcinoma's defenses. This allowed immune cells that had been barred from entering the tumour to penetrate the barrier and begin attacking the cancer.

Reference: Li, J., Moresco, P., & Fearon, D. T. (2024). Intratumoral NKT cell accumulation promotes antitumor immunity in pancreatic cancer. Proceedings of the National Academy of Sciences, 121(30), 2403917121. https://doi.org/10.1073/pnas.2403917121.

The findings were published in Nature Chemistry reveals that protein targets of cancer proteins when disrupted with particular chemical compounds or small molecules may help to stop cancer cell growth, potentially leading to the creation of more effective and targeted cancer treatments.

In the study, scientists outlined activity-based protein profiling (ABPP), a technique that allows for the global capture of protein activity. The research team applied this technique alongside another approach to identify both the proteins and specific sites that interacted with a set of stereo probes chemical compounds designed to selectively and permanently bind to proteins. These stereo probes help investigate protein functions and uncover potential drug targets.

The research team’s stereo probes were electrophilic, designed to permanently bind to proteins, specifically targeting the amino acid cysteine. Cysteine is commonly found in proteins, including those in cancer cells, and plays a key role in forming essential structural bonds.

When chemicals interact with cysteine, they can disrupt these bonds and cause protein malfunction, which impedes cell growth. Many cancer drugs work by irreversibly binding to cysteines in proteins.

To determine which specific proteins interacted with the stereo probes, the team employed a technique called protein-directed activity-based protein profiling (ABPP). This method revealed over 300 individual proteins that reacted with the stereoprobe compounds. However, the researchers sought to go further by pinpointing the exact locations of these interactions.

Each stereoprobe molecule has two main components: the binding part and the electrophilic part, the stereoprobe molecule can enter and it blocks the protein from binding to other proteins—ultimately preventing cell division.

Reference: Njomen, E., Hayward, R.E., DeMeester, K.E. et al. Multi-tiered chemical proteomic maps of tryptoline acrylamide–protein interactions in cancer cells. Nat. Chem. (2024). https://doi.org/10.1038/s41557-024-01601-1

A recent study published in the journal Neurology finds that acute kidney injury is linked to a higher risk of developing dementia.

Acute kidney injury (AKI), which involves a rapid decline in kidney function, is fairly common among older adults and is linked to higher rates of illness and death. Previous studies have suggested a potential link between AKI and brain injury.

The study explored the link between acute kidney injury (AKI) and various forms of dementia by analyzing data from over 300,000 individuals aged 65 and older. Approximately 25% of participants experienced at least one episode of Acute kidney injury during an average follow-up period of 12 years, and 16% were diagnosed with dementia.

Individuals who had Acute kidney injury faced a 49% higher risk of developing any type of dementia. When examining specific types of dementia, the risk was 88% higher for Lewy body dementia or dementia linked to Parkinson’s disease, 47% higher for vascular dementia, and 31% higher for Alzheimer’s disease. The risk was notably greater for those with severe kidney damage requiring hospitalization or inpatient care.

The subsequent phase of the research will focus on investigating the underlying biological mechanisms that connect acute kidney injury (AKI) to the development of dementia.

The researchers plan to examine how various medications, lifestyle modifications, and follow-up monitoring strategies following an episode of acute kidney injury might influence the risk of developing dementia.

Reference: Xu, H., Eriksdotter, M., Garcia-Ptacek, S., Ferreira, D., Ji, D., Bruchfeld, A., Xu, Y., & Carrero, J. J. (2024). Acute kidney injury and its association with dementia and specific dementia types. Neurology, 102(1), 123-134. https://doi.org/10.1212/WNL.0000000000209751

A recent paper published in Nature Communications reveals the efficacy of delivering a COVID-19 vaccine via the nasal passages.

These vaccines are live attenuated intranasal vaccine, called CDO-7N-1 which are delivered through intranasal passages that induces robust mucosal and systemic neutralising antibody and T-cell subset responses when tested in mice which was triggered by a single immunisation.

The virus that causes COVID-19, known as SARS-CoV-2, has led to more than 700 million infections and 7 million deaths around the world so far. It still poses a serious threat to people who are vulnerable.

Most current vaccines are made to target the spike protein of the SARS-CoV-2 virus, specifically the part of this protein that most antibodies attack. These vaccines worked well against earlier virus variants like alpha, beta, gamma, and delta. However, their effectiveness in preventing symptoms has dropped significantly with the arrival of new variants that have changes in the spike protein.

Live-attenuated vaccines (LAVs) have several key benefits compared to other types of vaccines. They produce strong and lasting immune responses, often with just one dose. Because live-attenuated vaccines contain the entire virus, they trigger a broad immune response, unlike vaccines that use only a single antigen (such as the spike protein) which targets a narrower range.

The vaccine has been licensed to Indian Immunologicals Ltd, a major vaccine manufacturer.

Reference: Liu, X., Ng, W.H., Zusinaite, E. et al. A single-dose intranasal live-attenuated codon deoptimized vaccine provides broad protection against SARS-CoV-2 and its variants. Nat Commun 15, 7225 (2024). https://doi.org/10.1038/s41467-024-51535-y