Simple peptide modification could unlock a whole class of targets for drug discovery

Traditional cancer treatments have been largely unfocused in that they indiscriminately kill dividing cells, cancer or otherwise, which often leads to significant toxic side effects in patients. Targeted therapies on the other hand, try to inhibit one or more abnormal proteins that are found in proliferating cancer cells resulting in programmed cell death. One or more mutations in the p53 gene are found in at least 50% of all human cancers. These mutations begin a sequence of events that leads to loss of control of cell growth and proliferation. Due to its central importance in many human cancers, drugs that restore function to mutated p53 proteins have been described as one of the three holy grails of cancer research. Targeting specific abnormal proteins found only in cancer cells could be expected to be associated with less toxicity in normal healthy cells.

The idea of an upper limit of protein intake is controversial. Some experts believe the recommended amounts are too low. Others believe we are overconsuming protein. In general, the average person (not a body builder or an elite athlete) does not need high levels of protein and should not exceed 2 grams per kilogram; or about 125 grams per day for a 140-pound person. A main concern with taking in too much protein is an overall dietary imbalance. Consuming excessive protein may lead to inadequate intake of carbohydrates and fats. It's important to maintain a well-rounded diet that includes a balance of all three macronutrients for overall health. In addition, if you increase your protein intake without increasing physical activity, you may be taking in too many calories without expending enough, which could result in weight gain. There is also some evidence that eating a relatively high-protein diet can be problematic for individuals with pre-existing kidney conditions. A diet high in animal protein may pose a higher risk of kidney stones.

The study began with a bowl of mouse chow. Rather than start piecewise, one food after another, the researchers screened regulatory T cells from mice given a normal diet. They looked for what the regulatory T cells were attaching to, then mapped them backward to specific parts of the chow. They found three proteins-more specifically, they found small, specific bits of those proteins called epitopes-that the regulatory T cells recognized. The epitopes were found in three different food proteins: one from corn, one from wheat, and one from soybean. Notably, all three epitopes are from seed proteins, suggesting that these highly abundant plant proteins are commonly recognized by the immune system's tolerance mechanisms. Furthermore, the most abundant T cells were those reactive to the corn epitope, which makes sense given that corn is not a common allergy. Soy, on the other hand, is one of the major allergies in humans, so the identification of a soybean epitope is especially exciting, notes Blum. Additionally, the mammalian receptor that interacts with the identified soybean epitope also interacts with sesame, helping explain cross-tolerance, or when a tolerance to one food infers a tolerance to another. With the new epitopes identified, the researchers had a few follow-up questions, like where do these regulatory T cells live? And how do they perform in an inflamed versus a healthy environment? They used mice and cell culture models to answer these questions, finding that the regulatory T cells are primarily located in the gut and their activities vary based on whether they are in an inflamed or healthy environment, either working to reduce inflammation or sustain an absence of inflammation.

Enantiomeric separations by HPLC is by far the most important technique. Mass spectrometry is more or less useless for qualitative analysis because enantiomerics have exactly the same mass, but it is useful as a sensitive detector for HPLC.

Certainly. We're keenly exploring extracellular vesicles as mediums for cells to communicate. These cell made vesicles often carry microRNAs and other non-coding RNAs, presenting a unique avenue to understand how neurons modulate their environment, which is especially interesting in neurological conditions. We are exploring extracellular vesicles as these tools with which cells can communicate and transfer gene expression patterns. And we're looking at, for example, how early life brain tumours such as medulloblastoma can impact neuron development and activity and how this can affect later life pain processing and neurological conditions. This has been possible via funding from the Medical Research Foundation, which supported a big collaboration between the labs of Gareth Hathway, Beth Coyle, Vicky James, Anna Grabowska and myself in Nottingham.