The intricate vascular “maze” in the tumor microenvironment is still one of the most difficult obstacles to cell therapy penetration and treatment of solid tumors. Recently, in a study published in Nature Cancer, scientists from the Perelman School of Medicine at the University of Pennsylvania and other institutions found through the study that combining CAR-T cell therapy with PAK4 inhibitor drugs may promote engineered cells to break through and attack tumors, thereby significantly improving the survival rate of mice.

The researchers found in the laboratory that vascularization of solid tumors is driven by genetic reprogramming of tumor endothelial cells caused by PAK enzymes, and knockout of this enzyme may reduce the abnormal vascularity of tumors and improve the infiltration of T cells and the immunotherapy treatment effect of CAR-T cells in a mouse model of glioblastoma, one of the most common malignant brain tumors, with more than 22,000 cases in the United States each year.

Researcher Yi Fan said that glioblastoma patients usually respond poorly to CAR-T cell therapy because it is difficult for CAR-T cells to enter the tumor. The results of this study suggest that the use of PAK4 inhibitors to turn off the genetic reprogramming of tumor endothelial cells may hopefully allow T cells and engineered T cells to reach the tumor to kill cancer cells.

First, the researchers screened and analyzed more than 500 kinases that regulate the activation of blood vessels in endothelial cells of glioblastoma patients. They found that PAK4, which could previously act as a driver of solid tumor growth, may be the culprit. Knockdown of the enzyme in endothelial cells using drugs may restore the expression of adhesion proteins, which are very important for recruiting immune cells and stimulating T cell infiltration into the tumor. Notably, knocking down the expression of PAK4 will transform the morphology of endothelial cells and transform them from a spindle-shaped appearance to a typical cobblestone shape, which reveals the formation pattern of vascular disorders. In other words, this makes the tumor microenvironment standardized.

In a mouse model of glioblastoma, the researchers found that inhibiting PAK4 may reduce vascular abnormalities, thereby improving T cell infiltration and inhibiting tumor growth in mice, and at the end of the experiment, approximately 80% of PAK4 knockout mice survived for at least 60 days, while all wild-type mice died within 40 days after tumor implantation. In another study using EGFRvIII-guided CAR-T cell therapy and PAK4 inhibitors, the researchers found that the growth of tumors in mice treated with the combination was reduced by nearly 80% compared with mice treated with CAR-T cells alone, and it is worth noting that even if mice in other groups died within 33 days after tumor implantation, 40% of mice survived the combination therapy.

Targeting PAK4 may provide a new opportunity to modify the tumor microenvironment, but also help improve T-cell-based cancer immunotherapy to treat solid tumors. The results of this paper support the view that scientists have previously proposed that vascular standardization achieved by inhibiting PAK4 may improve the transport of drugs and reduce the hypoxic condition of tumors, thereby improving the response rate of tumors to targeted therapy, radiotherapy and chemotherapy. Finally, researcher Fan said, “To our knowledge, this study is the first to reveal how to promote and improve cell therapy for cancer by reprogramming the entire vascular microenvironment with PAK4 inhibitors. Importantly, this therapy may not be limited to brain tumors. Since vascular abnormalities are a common feature of almost every solid tumor, they can also be used to treat other types of cancer such as breast cancer and pancreatic cancer.”

In a recent study, a team of scientists at the Agency for Science, Technology and Research (A * STAR) at Nanyang Technological University, Singapore, discovered the role of proteins in detecting the common cold virus and initiating immune responses against infection.

In a recent study published in Science, they showed that the NLRP1 protein found in the skin and respiratory tract is a sensor for detecting human rhinovirus (HRV). When NLRP1 breaks through the respiratory tract, it triggers an immune response that causes inflammation of the lungs and causes symptoms of the common cold.

HRV is a major cause of common colds and acute respiratory diseases in children and adults, and in severe cases leads to bronchitis and pneumonia.

The team stated that discovering the purpose of NLRP1 may lead to new treatments for common cold symptoms, an infection that affects millions of people each year. They plan to work with clinicians to develop drugs that “turn off” or block NLRP1 to reduce the severity of HRV related disease symptoms. However, the team pointed out that blocking NLRP1 protein in human lung cells did not increase viral load.

“Now, we know that NLRP1 is the ‘switch’ of inflammation after the detection of the common cold virus, and the next step is to figure out how to prevent its activation and minimize the triggered inflammatory response,” said assistant professor Fulin Zhong, author of the article.

Professor Zhong said their new insights into the function of the immune system could help scientists develop more effective therapies to treat other inflammatory diseases of the human respiratory tract.

“This work represents a major advance in our understanding of how the immune system uses specialized proteins to sense and defend against viral pathogens,” he said. “This knowledge will be useful in designing treatments for viral diseases including influenza and COVID-19.”

NLRP1 has been known to scientists for many years, but its exact purpose is unknown. It is a member of a family of proteins called “NLR” proteins that are sensors in the immune system that trigger the body’s response to invading pathogens.

When the team began their study in 2017, they hypothesized that NLRP1 could act as a sensor for viruses because it is highly abundant in human skin and lungs, which are usually exposed to surfaces of viral pathogens.

The team screened NLRP1 against several viruses to see if it would trigger activation of the protein. After months of testing, they observed that an enzyme produced by HRV called 3Cpro activated NLRP1 in human respiratory cells.

They found that the 3Cpro enzyme cleaves NLRP1 at specific points, triggering some form of inflammatory “cell death”, an important process for rapid clearance of pathogens such as HRV during infection.

Retractable needle safety syringes are one of the most popular and best-selling devices that have made their mark in the world of medical science. They are specially designed for injection purposes. The needle is inserted into the upper end of the syringe to bring the medicine or liquid to the desired region. These syringes have gained enormous popularity because of their easy to use, universal applicability, and rapid effects. One of the major advantages of retractable needle safety syringes is their universal acceptability.

While a majority of regional analysis and field surveys indicate widespread usage around the world, only a small percentage of global safety market players have yet developed a comprehensive package of products that can meet the needs of the changing patient population. However, as new technologies such as retractable needle safety syringes emerge and address common patient concerns, the market will continue to grow in size and offer more choices to pharmaceutical companies. Needle safety syringes feature an innovative design that is very safe to use. They are made out of durable rubber and feature two curved needle holes, one at the top for drawing the fluid and the other one at the bottom for dispensing the same.

Surgical tourniquets are one of the most common operations that a surgeon performs. It involves the use of a tournier, which is a short, curved piece of metal that is used to cover or tie off the wound. The surgeon then uses small scissors to amputate the tendons and ligaments as well as the blood vessels from the wound. The main purpose of this surgery is to relieve pain and reduce swelling, which will help you return to your daily activities much faster than if you had not been operated on. Surgical tourniquet allow the surgeons to perform an increased amount of work in a less invasive way by allowing the wounds to heal without the need for excessive blood transfusions, the use of antibiotics to reduce infection, and the shortening or complete removal of the lymph nodes through coagulation therapy.

Surgical tourniquets are the only device that offers the safe, effective, and comfortable management of post-surgical blood loss, acute trauma, and spinal cord injuries, after cardiopulmonary resuscitation or acute coronary syndromes after a pulmonary artery or heart arrest. They provide significant improvement in patient outcomes, reducing pain, swelling and blood loss/dryness, post-operative weight loss, and mortality. Surgical tournaments have achieved recognition as an advanced life-saving surgical method, used in virtually all areas of medicine. Surgical tourniquets are now routinely conducted for selected operative indications where alternative methods have failed.