Institute of Advanced Research

A group has discovered previously unidentified ovarian cancer-specific membrane proteins. Their findings suggest a new strategy to diagnose ovarian cancer. A study led by Nagoya University in Japan has identified three previously unknown membrane proteins in ovarian cancer. Using a unique technology consisting of nanowires with a polyketone coating, the group succeeded in capturing the proteins, demonstrating a new detection method for identification of ovarian cancer. The discovery of new biomarkers is important for detecting ovarian cancer, as the disease is difficult to detect in its early stages where it can most easily be treated. One approach to detecting cancer is to look for extracellular vesicles (EVs), especially small proteins released from the tumor called exosomes. As these proteins are found outside the cancer cell, they can be isolated from body fluids, such as blood, urine, and saliva. However, the use of these biomarkers is hindered by the lack of reliable ones for the detection of ovarian cancer. A research group led by Akira Yokoi (he, him) of the Nagoya University Graduate School of Medicine and Mayu Ukai (she, her) at the Institute for Advanced Research extracted both small and medium/large EVs from high-grade serous carcinoma (HGSC), the most common type of ovarian cancer, and analyzed them using liquid chromatography-mass spectrometry to analyze the proteins. Initially their research was challenging. "The validation steps for the identified proteins were tough because we had to try a lot of antibodies before we found a good target," said Yokoi. "As a result, it became clear that the small and medium/large EVs are loaded with clearly different molecules. Further investigation revealed that small EVs are more suitable biomarkers than the medium and large type. We identified the membrane proteins FRα, Claudin-3, and TACSTD2 in the small EVs associated with HGSC." Now that the group had identified the proteins, they investigated whether they could capture EVs in a way that would allow for the identification of the presence of cancer. To do this, they turned to nanowire specialist Takao Yasui of the Graduate School of Engineering at Nagoya University who combined his research with that of Dr. Inokuma at the Japan Science and Technology Agency to create polyketone chain-coated nanowires (pNWs). This technology was ideal for separating exosomes from blood samples. "pNW creation was tough," Yokoi said. "We must have tried 3-4 different coatings on the nanowires. Although polyketones are a completely new material to use to coat this type of nanowire, in the end, they were such a good fit." "Our findings showed that each of the three identified proteins is useful as a biomarker for HGSCs," said Yokoi. "The results of this research suggest that these diagnostic biomarkers can be used as predictive markers for specific therapies. Our results allow doctors to optimize their therapeutic strategy for ovarian cancer, therefore, they may be useful for realizing personalized medicine."

What does the inside of a carbon atom's nucleus look like? A new study provides a comprehensive answer to this question. In the study, the researchers simulated all known energy states of the nucleus. These include the puzzling Hoyle state. If it did not exist, carbon and oxygen would only be present in the universe in tiny traces. Ultimately, we therefore also owe it our own existence. What does the inside of a carbon atom's nucleus look like? A new study by Forschungszentrum Jülich, Michigan State University (USA) and the University of Bonn provides the first comprehensive answer to this question. In the study, the researchers simulated all known energy states of the nucleus. These include the puzzling Hoyle state. If it did not exist, carbon and oxygen would only be present in the universe in tiny traces. Ultimately, we therefore also owe it our own existence. The study has now been published in the journal Nature Communications. The nucleus of a carbon atom normally consists of six protons and six neutrons. But how exactly are they arranged? And how does their configuration change when the nucleus is bombarded with high-energy radiation? For decades, science has been searching for answers to these questions. Not least because they could provide the key to a mystery that has long puzzled physicists: Why is there a significant amount of carbon in space at all -- an atom without which there would be no life on Earth? After all, shortly after the Big Bang, there was only hydrogen and helium. The hydrogen nucleus consists of a single proton, that of helium of two protons and two neutrons. All heavier elements were only created many billions of years later by aging stars. In them, helium nuclei fused into carbon nuclei at immense pressure and extremely high temperatures. This requires three helium nuclei to fuse together. "But it's actually very unlikely for this to happen," explains Prof. Dr. Ulf Meißner of the Helmholtz Institute of Radiation and Nuclear Physics at the University of Bonn and the Institute for Advanced Simulation at Forschungszentrum Jülich. The reason: The helium nuclei together have a much higher energy than a carbon nucleus. However, this does not mean that they fuse particularly readily -- on the contrary: It is as if three people wanted to jump onto a merry-go-round. But since they run much faster than the merry-go-round turns, they do not succeed. Simulation on the supercomputer As early as the 1950s, the British astronomer Fred Hoyle therefore postulated that the three helium nuclei first come together to form a kind of transition state. This "Hoyle state" has a very similar energy to the helium nuclei. To stay in the picture: It is a faster-spinning version of the merry-go-round, which the three passengers can therefore easily jump onto. When that happens, the carousel slows down to its normal speed. "Only by taking a detour via the Hoyle state can stars create carbon at all in any appreciable quantity," says Meißner, who is also a member of the Transdisciplinary Research Areas "Modeling" and "Matter" of the University of Bonn. About ten years ago, together with colleagues from the USA, Forschungszentrum Jülich and Ruhr-Universität Bochum, he succeeded in simulating this Hoyle state for the first time. "We already had an idea then of how the protons and neutrons of the carbon nucleus are arranged in this state," he explains. "However, we were not able to prove with certainty that this assumption was true." With the help of an advanced method, the researchers have now succeeded. This is essentially based on confinement: In reality, the protons and neutrons -- the nucleons -- can be located anywhere in space. For their calculations, however, the team restricted this freedom: "We arranged our nuclear particles on the nodes of a three-dimensional lattice," Meißner explains. "So we allowed them only certain strictly defined positions." Computing time: five million processor hours Thanks to this restriction, it was possible to calculate the motion of nucleons. Since nuclear particles affect each other differently depending on their distance from each other, this task is very complex. The researchers also ran their simulation several million times with slightly different starting conditions. This allowed them to see where the protons and neutrons were most likely to be. "We performed these calculations for all known energy states of the carbon nucleus," Meißner says. The calculations were performed on the JEWELS supercomputer at Forschungszentrum Jülich. They required a total of about five million processor hours, with many thousands of processors working simultaneously. The results effectively provide images from the carbon nucleus. They prove that the nuclear particles do not exist independently of each other. "Instead, they are clustered into groups of two neutrons and two protons each," the physicist explains. This means that the three helium nuclei can still be detected after they have fused to form the carbon nucleus. Depending on the energy state, they are present in different spatial formations -- either arranged into an isosceles triangle or like a slightly bent arm, with the shoulder, elbow joint and wrist each occupied by a cluster. The study not only allows researchers to better understand the physics of the carbon nucleus. Meißner: "The methods we have developed can easily be used to simulate other nuclei and will certainly lead to entirely new insights." Participating institutions and funding: Forschungszentrum Jülich, Michigan State University (USA), the China Academy of Engineering Physics and the University of Bonn were involved in the study. The work was made possible by funding from the German Research Foundation, the National Natural Science Foundation of China, the Chinese Academy of Sciences (CAS), the Volkswagen Foundation, the European Research Council (ERC), the U.S. Department of Energy, the Nuclear Computational Low-Energy Initiative (NUCLEI), and the Gauss Center for Supercomputing e.V.