Using artificial intelligence technology to identify patterns of DNA fragments associated with lung cancer, researchers from the Johns Hopkins Kimmel Cancer Center and other institutions have developed and validated a liquid biopsy that may help identify lung cancer earlier.
In a prospective study published June 3 in Cancer Discovery, the team demonstrated that artificial intelligence technology could identify people more likely to have lung cancer based on DNA fragment patterns in the blood. The study enrolled about 1,000 participants with and without cancer who met the criteria for traditional lung cancer screening with low-dose computed tomography (CT). Individuals were recruited to participate at 47 centers in 23 U.S. states. By helping to identify patients most at risk and who would benefit from follow-up CT screening, this new blood test could potentially boost lung cancer screening and reduce death rates, according to computer modeling by the team.
“We have a simple blood test that could be done in a doctor’s office that would tell patients whether they have potential signs of lung cancer and should get a follow-up CT scan,” says the study’s corresponding author, Victor E. Velculescu, M.D., Ph.D., professor of oncology and co-director of the Cancer Genetics and Epigenetics program at the Johns Hopkins Kimmel Cancer Center.Lung cancer is the deadliest cancer in the United States, according to the National Cancer Institute, and worldwide, according to the World Health Organization. Yearly screening with CT scans in high-risk patients can help detect lung cancers early, when they are most treatable, and help avert lung cancer deaths. Screening is recommended by the U.S. Preventive Services Task Force for 15 million people nationally who are between ages 50 and 80 and have a smoking history, yet only about 6%-10% of eligible individuals are screened each year. People may be reticent to follow through on screening, Velculescu explains, due to the time it takes to arrange and go to an appointment, and the low doses of radiation they are exposed to from the scan.
To help overcome some of these hurdles, Velculescu and his colleagues developed a test over the past five years that uses artificial intelligence to detect patterns of DNA fragments found in patients with lung cancer. It takes advantage of differences in how DNA is packaged in normal and cancer cells. DNA is neatly and consistently folded up in healthy cells, almost like a rolled-up ball of yarn, but DNA in cancer cells is more disorganized. When both types of cells die, fragments of DNA end up in the blood. The DNA fragments in patients with cancer tend to be more chaotic and irregular than the DNA fragments found in individuals who do not have cancer.
The team trained artificial intelligence software to identify the specific patterns of DNA fragments seen in the blood of 576 people with or without lung cancer. Then, they verified that the method worked in a second group of 382 people with and without cancer. Based on their analyses, the test has a negative predictive value of 99.8%, meaning that only 2 in 1,000 individuals tested may be missed and have lung cancer.
The group’s computer simulations showed that if the test boosted the rate of lung cancer screening to 50% within five years, it could quadruple the number of lung cancers detected and increase the proportion of cancers detected early — when they are most treatable — by about 10%. That could prevent about 14,000 cancer deaths over five years.
“The test is inexpensive and could be done at a very large scale,” Velculescu says. “We believe it will make lung cancer screening more accessible and help many more people get screened. This will lead to more cancers being detected and treated early.”
The test is currently available through DELFI Diagnostics for use as a laboratory-based test under the Clinical Laboratory Improvement Amendments. However, the team plans to seek approval from the U.S. Food and Drug Administration for lung cancer screening. Velculescu colleagues also plan to study whether a similar approach could be used to detect other types of cancer.

Robert B. Scharpf of Johns Hopkins co-authored the study. Additional co-authors were from the Cleveland Clinic, DELFI Diagnostics, Medicus Economics LLC, Miami Cancer Institute, the Pan American Center for Oncology, Washington University, Centura Health, Vanderbilt Health, Stratevi, Massachusetts General Hospital, the Medical University of South Carolina, the Department of Veterans Affairs, the Perelman School of Medicine at the University of Pennsylvania, New York University Langone Health, Allegheny Health Network and Memorial Sloan Kettering Cancer Center.
The work was supported in part by DELFI Diagnostics, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant, Stand Up To Cancer-DCS International Translational Cancer Research Dream Team Grant, the Gray Foundation, The Honorable Tina Brozman Foundation, the Commonwealth Foundation, the Cole Foundation and the National Institutes of Health.
Velculescu and Scharpf are inventors on patent applications submitted by The Johns Hopkins University related to cell-free DNA for cancer detection that have been licensed to DELFI Diagnostics, LabCorp, Qiagen, Sysmex, Agios, Genzyme, Esoterix, Ventana and ManaT Bio. Velculescu divested his equity in Personal Genome Diagnostics (PGDx) to LabCorp in February 2022. Velculescu is a founder of DELFI Diagnostics, serves on the board of directors, and owns DELFI Diagnostics stock. Scharpf is a founder and consultant of DELFI Diagnostics and owns DELFI Diagnostics stock. Velculescu, Scharpf and Johns Hopkins receive royalties and fees from the company. The Johns Hopkins University also owns equity in DELFI Diagnostics. Velculescu is an adviser to Viron Therapeutics and Epitope. These relationships are managed by Johns Hopkins in accordance with its conflict-of-interest policies.

UCSF scientists discover that multiciliated cells adapt the well-known process of cell division to make hundreds of cilia.
The awe-inspiring process of cell division can turn a fertilized egg into a baby — or a cancerous cell into a malignant tumor. With so much at stake, nature keeps it tightly controlled in a process called the cell cycle that scientists thought they thoroughly understood.
But now it turns out there was more to know. Scientists at UC San Francisco have discovered that cells can also use the cell cycle to control how they sprout hair-like projections called cilia.
“The cell cycle has been studied intensively for decades and here, we’ve found it working in a new way,” said Jeremy Reiter, PhD, UCSF professor of biophysics and biochemistry and senior author of the paper, which appeared in Nature on May 29, 2024. “This old dog — the cell cycle — is capable of more tricks than we realized.”
Breaking a rule that prevents cancer
Multiciliated cells are crucial to human health. In the lungs, their cilia sway back and forth to keep fluids like mucus from collecting. In the reproductive system, they help move eggs through the fallopian tubes and into the uterus. And in the brain, they sweep out cerebrospinal fluid to remove waste. When they malfunction, serious disease follows.
Reiter and his colleagues wanted to understand how these cells develop, so they used a technique called single cell RNA sequencing to see which genes turned on and off in individual multiciliated cells in the lungs.

They captured them at different stages of maturity, hoping to glimpse the genetic instructions it takes to grow cilia and found a pattern that looked like the cell cycle.
Previous studies had found that a few cell cycle proteins, called cyclins, were active during cilia growth, as well as centrioles, which anchor the two sets of chromosomes during cell division.
Yet Reiter’s team found that many cell cycle genes, far beyond just the cyclins, were expressed at high levels in the lung cells, even though the cells weren’t dividing.
“In developing multiciliated cells, we saw the same sequential expression of cell cycle regulators, like cyclins and CDKs, that we’d expect to see in stem cells,” said Semil Choksi, PhD, a researcher in the Reiter lab and first author of the paper.
Clearly, this wasn’t the typical cell cycle. For one, this alternative cell cycle, or “multiciliation cycle,” as the scientists dubbed it, was producing an unusually high number of centrioles, much more than the four centrioles made during cell division.
“If you have something go wrong in the cell cycle, and you make too many centrioles, it can lead to cancer,” Choksi said. “Somehow, this strict cancer-preventing rule, no more than four centrioles per cell, is very specifically broken in multiciliated cells to make hundreds of centrioles.”
The cellular orchestra plays something new

Choksi and Reiter took a closer look at how the multiciliation cycle in lung cells differed from the classic cell cycle in dividing stem cells, gene by gene. A particular gene, called E2F7, stood out. Its expression was middling in stem cells, but notably high in maturing, multiciliated cells.
Indeed, when E2F7 was completely disabled, or knocked out, in an animal model, multiciliated cells failed to develop correctly, leading to problems in the brain.
“We thought one of the knobs that evolution might have turned was by upregulating E2F7, to change the canonical cell cycle into the multiciliation cycle,” said Reiter.
The scientists then found that multiciliated cells that lacked E2F7 started to synthesize new DNA — a hallmark of cell division. And hundreds of centrioles, intended for eventual construction of cilia at the cell surface, got stuck in the cell body.
If the cell cycle were like a particular score played by a molecular orchestra, E2F7 was a new conductor, guiding the same instruments in that orchestra to play a new tune, the multiciliation cycle.
“Evolution clearly has adapted the cell cycle to carry out a variety of cellular projects well beyond cell division,” said Reiter. “It’ll be exciting to see what else it’s capable of.”

Children born via frozen embryo transfer have similar metabolic profiles to those born via fresh embryo transfer, according to a study published June 6 in the open-access journal PLOS Medicine by Linlin Cui and Zi-Jiang Chen from Shandong University, China, and colleagues.
Prior studies have shown inconsistent results on the long-term metabolic health impacts of assisted reproductive technology. Some have shown that children born via frozen embryo transfer have a higher risk of metabolic disorders, such as obesity, and unfavorable lipid profiles. Other studies have failed to find any significant metabolic differences between those born via frozen or fresh embryo transfer.
In this study, researchers compared the glucose and lipid profiles of more than 4,000 children between 2 and 5 years of age — approximately half had been born via fresh embryo transfer and half had been born via frozen embryo transfer.
Researchers followed the children for an average of 3.6 years and assessed metabolic factors often associated with heart disease and diabetes, such as fasting blood glucose, insulin, cholesterol, and triglycerides.
They found no difference in any of the metabolic factors among children born via fresh embryo transfer and those born via frozen embryo transfer.
Given the relatively large number of participants in this study, the researchers were able to conduct subgroup analyses. After dividing the children into groups based on gender, age, embryo transfer state, and method of conception, there were still no differences in metabolic factors among the frozen and fresh embryo transfer groups.
The study provides more information to women and couples weighing the pros and cons of different techniques offered for assisted reproduction, but the researchers noted the need for additional data on the effect of assisted reproductive technology on long-term metabolic health.
The authors add, “Frozen embryo transfer shows no significant adverse effects on metabolic profiles in early childhood, providing crucial evidence for counseling couples undergoing assisted reproductive technology treatment on its safety.”

Researchers at UNC Lineberger Comprehensive Cancer Center and colleagues have established the most comprehensive molecular portrait of the workings of KRAS, a key cancer-causing gene or “oncogene,” and how its activities impact pancreatic cancer outcomes. Their findings could help to better inform treatment options for pancreatic cancer, which is the third leading cause of all cancer deaths in the United States.
The research was published as two separate articles in Science.
“Because less than 40% of pancreatic cancers respond to treatment with KRAS inhibitors, if we can establish molecular markers to predict which patients will respond, we can better provide them with specific treatments, which should improve their outcomes,” said UNC Lineberger’s Channing J. Der, PhD, Sarah Graham Kenan Distinguished Professor at UNC School of Medicine’s Department of Pharmacology and a corresponding author of both articles. “From diagnosis to death, the average pancreatic cancer patient treated with chemotherapy lives 6 to 12 months, so there’s a very limited time to offer a treatment which will work.”
KRAS is one of the most commonly mutated genes in human cancers and it is found in more than 90% of pancreatic cancer tumors. Exactly how it spurs cancer growth, however, is poorly understood. That’s why UNC Lineberger researchers embarked on their extensive efforts to figure out what other genes and proteins make KRAS expression so lethal.
In the most detailed analysis to date, they demonstrated that the molecular pathway most responsible for the cancer-driving functions of KRASis highly dependent on a protein called ERK that has dual functions in regulating which genes are expressed and which proteins are active. While ERK has been one of the most intensively studied cancer pathways, and it is well-established that ERK is among the significant players in KRAS function, its relative importance and precisely how ERK carries out its role have been unclear.
Indeed, a core finding of the Science papers was that activation of the ERK protein alone is the key driver of resistance to drugs that inhibit KRAS. Taking advantage of improved methods to study cellular signaling, the researchers demonstrated that the ERK protein regulates the expression of a remarkably complex array of thousands of genes and changes the activity of thousands of proteins. Excitingly, the researchers confirmed that their findings in cancer models could accurately reflect responses in patients treated with ERK and KRAS therapies for their pancreatic, colorectal and lung cancers.
Currently, two KRAS drugs have been approved for cancer treatment, and many more are currently being evaluated in ongoing clinical trials. In related studies, Der and colleagues contributed to two articles published in Nature in April about a promising anti-KRAS drug that is effective against many different KRAS mutations. They found that the MYC oncogene can cause resistance to KRAS therapies. Closing the circle, the new Science papers established that MYC is a significant component of how KRAS and ERK support cancer growth and a driver of resistance to KRAS and ERK therapies.
“Our next steps are elucidating more aspects of basic and foundational research regarding KRAS,” Der said. “We will continue to mine the growing body of scientific knowledge we have developed, with the ultimate goal of helping advance the clinical development of newer and better KRAS inhibitors.”

A genetic disorder leads to an increase in bioactive lipids in the brain, resulting in an imbalance between excitation and inhibition in neural circuits and promoting mental disorders. However, treatment with an enzyme inhibitor that prevents the activation of lipids can restore balance and alleviate symptoms.
Increased levels of bioactive lipids produced naturally in the body, which affect excitatory transmission between brain cells, promote mental disorders. However, this mechanism can be rebalanced by treatment with an inhibitor that prevents the activation of these lipids in the brain. That is the result of a recent study on the correlation between synaptic lipid signals in the brain and mental disorders. The results of the study ‘Altered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders’ have now been published in Molecular Psychiatry and could create new opportunities for the treatment of mental illness.
The teams led by Johannes Vogt (MD) at the Department of Molecular and Translational Neurosciences at the University of Cologne, Robert Nitsch (MD, PhD) at the Institute of Translational Neuroscience at the University of Münster and partners at other universities investigated the role of the enzyme autotaxin and its opponent, the protein PRG-1, in regulating the balance between excitation and inhibition in the brains of humans and mice. The research was carried out within the framework of Collaborative Research Centre 1451 ‘Key Mechanisms of Motor Control in Health and Disease’ (speaker: Professor Dr Gereon Fink, University of Cologne).
The project under the leadership of Vogt and Nitsch within the CRC deals with the balance between excitation and inhibition in the brain and its effect on motor function. This balance plays an important role in mental disorders. In the case of excitation, neural circuits cause information to be passed on and other neurons to be activated; in the case of inhibition, this information transfer is interrupted.
The project groups in Cologne and Münster had already shown in previous studies that the body’s own lipids in the brain are activated by the enzyme autotaxin and stimulate nerve cell activity at the central checkpoint of signal transmission, the cortical synapse. As a result, they alter information processing in the brain’s networks.
In the current study, the researchers analysed the functional consequences of altered signal balance in 25 individuals induced by the antagonist of autotaxin, which reduces the activated lipids at the synapse. Using various methods for measuring brain waves and brain activity as well as psychological tests, they found specific changes that also occur in patients, so-called intermediate phenotypes of mental disorders. This means, for example, that comparable patterns of brain activation can be found in both patients and their clinically healthy relatives.
Additional studies in the mouse model revealed that animals with a similar genetic disorder showed comparable symptoms: increased anxiety, a depressive phenotype and lower stress resilience. Synchronization and information transfer between brain areas was similarly altered in humans and mice. “The study indicates that the regulation of excitation and inhibition by synaptic lipid signals plays a crucial role in the development of mental disorders,” said Professor Vogt.
Autotaxin is the key enzyme of lipid activation in the brains of mice and humans. The increased excitation state of the networks caused by the genetic disorder could be restored by administering specific inhibitors of autotaxin. According to the researchers, these findings open up new perspectives for the diagnosis and treatment of such disorders. “Targeted modulation of synaptic lipid signals using autotaxin inhibitors that can reach the brain could open up possibilities to treat mental disorders,” concluded Professor Nitsch. In future studies, the researchers plan to further investigate these approaches and to test their effectiveness and safety in clinical trials.

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Nuclear pore complexes (NPCs) are channels composed of multiple proteins that ferry molecules in and out of the nucleus, regulating many critical cellular functions, such as gene expression, chromatin organization and RNA processes that influence cell survival, proliferation, and differentiation.
In recent years, new studies, including work by Maximiliano D’Angelo, Ph.D., associate professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys, have noted that NPCs in cancer cells are different, but how these alterations contribute to malignancy and tumor development — or even how NPCs function in normal cells — is poorly understood.
In a new paper, published June 5, 2024 in Science Advances, D’Angelo with first author Valeria Guglielmi, Ph.D., and co-author Davina Lam, uncover Nup358, one of roughly 30 proteins that form the NPCs, as an early player in the development of myeloid cells, blood cells that if not formed or working properly leads to myeloid disorders such as leukemias.
The researchers found that when they eliminated Nup358 in a mouse model, the animals experienced a severe loss of mature myeloid cells, a group of critical immune cells responsible for fighting pathogens that are also responsible for several human diseases including cancer. Notably, Nup358 deficient mice showed an abnormal accumulation of early progenitors of myeloid cells referred as myeloid-primed multipotent progenitors (MPPs).
“MPPs are one of the earliest precursors of blood cells,” said D’Angelo. “They are produced in the bone marrow from hematopoietic stem cells, and they differentiate to generate the different types of blood cells.
“There are different populations of MPPs that are responsible for producing specific blood cells and we found that in the absence of Nup358, the MPPs that generate myeloid cells, which include red blood cells and key components of the immune system, get stuck in the differentiation process.”
Fundamentally, said Gugliemi, Nup358 has a critical function in the early stages of myelopoiesis (the production of myeloid cells). “This is a very important finding because it provides insights into how blood cells develop, and can help to establish how alterations in Nup358 contribute to blood malignancies.”
The findings fit into D’Angelo’s ongoing research to elucidate the critical responsibilities of NPCs in healthy cells and how alterations to them contribute to immune dysfunction and the development and progression of cancer.
“Our long-term goal is to develop novel therapies targeting transport machinery like NPCs,” said D’Angelo, who recently received a two-year, $300,000 Discovery Grant from the American Cancer Society to advance his work.
This research was supported in part by a Research Scholar Grant from the American Cancer Society (RSG-17-148-01), the Department of Defense (grant W81XWH-20-1-0212) and the National Institutes of Health (AI148668).