Drug combination helps macrophages "eat" tumors

Release date: 2013-06-19

In order to avoid being destroyed by the immune system, cancer cells play some small means. When they divide into tumors, they avoid macrophages that are known to be immune cells that destroy dead cells and dangerous invaders. Nowadays, many cancer patients are treated with antibody drugs. Part of the role of these antibody drugs is to identify tumor cells in order for macrophages to destroy them. Although these drugs can prolong the lives of patients, they are not always very effective – in part because cancer cells fight back by sending a “don't eat me” signal to the immune cells. Now, researchers have designed a small protein in mice that can cut off this signal and dramatically increase the potency of antibody drugs to shrink tumors. Stem Weissman, a stem cell biologist at Stanford University in Palo Alto, Calif., has been working on a protein that is responsible for spreading the "Don't Eat Me" signal. This protein, called CD47, protects leukemia cells and other cancer cells from macrophages. Last year, Weissman's team reported that an antibody that blocks CD47 in tumor cells stimulates mouse macrophages to destroy tumors. The California Institute of Regenerative Medicine will provide a $20 million grant to test the safety of this anti-CD47 antibody in humans in the near future. Although this method has great potential, this antibody also has certain drawbacks - the relatively large size limits their ability to penetrate the tumor. In addition, they have toxic side effects, so Weissman's team worked with structural biologist Christopher Garcia in a laboratory at Stanford University to test another way to block CD47. Garcia's team and Weissman recently described their new research in the online edition of Science. The researchers began by working on a protein called SIRPα that protrudes from the surface of macrophages and is linked to CD47 to receive the “don't eat me” signal from tumor cells. Their idea is to use the free-floating, synthetic form of SIRPα to lock CD47. This design is designed to make the real SIRPα on macrophages not hit the cancer cells, so that macrophages are not blinded and let go through the cancer cells. Garcia's laboratory synthesized many versions of the SIRPα protein, determined their structure, and eventually found two forms of proteins that were 50,000 times more likely to bind to CD47 than the native SIRPα receptor. After adding the two proteins to a Petri dish with both cancer cells and macrophages, the researchers found that the synthesis of SIRPα protein did not work—the macrophages still ignored the presence of cancer cells. However, when the researchers put the tumor-specific antibody drugs into the culture dish - they found that the injection of antibody drugs allowed the macrophages to notice the cancer cells, and this combination gave the cancer cells in the culture dish and implanted Cancer cells in mice have a heavy punch. For example, when a single dose of the drug rituximab or SIRPα protein is administered, the lymphoma in the mouse will only slow down, in contrast to the combination of the drug and the SIRPα protein in the treatment, which makes the Tumors in most mice disappeared almost completely in at least 7 months. The addition of SIRPα to the trastuzumab, a drug for the treatment of breast cancer, can accelerate the rate of tumor shrinkage in breast cancer mice. Garcia explained: “SIRPα weakens the ability of cancer cells to protect themselves from damage.” Timo van den Berg, a cell biologist at the University of Amsterdam in the Netherlands, added: “These data are quite convincing and very exciting. Because most cells in the human body express CD47, these cells absorb the SIRPα protein, making it difficult for tumor cells to contact enough SIRPα protein. His team is working on an antibody that blocks the SIRPα receptor, which is mainly found in macrophages, as a way to prevent immune cells from receiving deceptive messages from cancer cells. Garcia replied that although he believes that the methods his team is working on will be very effective in patients, "blocking this information from another direction is also a viable strategy and worthy of research."

Source: Chinese Journal of Science

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