Rethinking How Cancer Cells Evade Targeted Therapy
Glioblastomas (GBMs) are incurable brain tumors with a prognosis of about one-and-a half years on average. They are highly resistant to treatment and have defied all attempts at precision therapy.
UCSF Researchers Identify the Cellular Source of Recurrent Glioma
Newswise — Glioblastomas (GBMs) are incurable brain tumors with a prognosis of about one-and-a half years on average. They are highly resistant to treatment and have defied all attempts at precision therapy.
In their study publishing December 20 in Nature Cancer, first author Lin Wang, PhD and senior author Aaron Diaz, PhD, found that phenotype switching, as opposed to genetic evolution, may be the escape mechanism that explains the failure of precision therapies to date. They found that some cells shift to a mesenchymal, radiation-resistant phenotype (state) as a stress response following standard therapy.
Credit: UCSF Aaron Diaz, PhD, Associate Professor, Neurological Surgery, UCSF Weill Institute for Neurosciences
“We asked if there is another mechanism that explains therapeutic resistance,” said Diaz, associate professor of neurological surgery at the UCSF Weill Institute for Neurosciences. “Our study concludes that, rather than a genetic evolution, there is a phenotypic plasticity or transition which allows these cells to evade therapy.”
To identify what drives treatment resistance to standard therapy, as well as the cellular source of recurrent disease, UCSF researchers used single-nucleus RNA, open-chromatin, spatial profiling to analyze 86 primary-recurrent, patient-matched, paired GBM specimensThis unprecedented cohort represented decades of biobanking at UCSF.
With access to thirty years’ worth of GBM’s, the scientists were able to present novel cell-intrinsic and cell-extrinsic targets as well as a single-cell multi-omics atlas of GBM under therapy. This was the first time that researchers were able to comprehensively map intra-cellular signaling in the tumor-anatomical niches of recurrent GBM and identify novel cell-extrinsic therapeutic targets.
The 86 specimens contained the cellular tumor and adjacent non-malignant tissue from the surgical margin. This unique cohort enabled Diaz and his team to analyze communications between malignant and non-malignant glia. They found that cells in this surgical margin acted as niches of recurrence where non-malignant glia were broadcasting pro-growth signals that influenced the tumor cells to regrow. These paracrine (cell extrinsic) signals stimulated the activator protein (AP1) pathway, leading to mesenchymal transition, therapy resistance and tumor recurrence.
These mesenchymal transitions were apparent in the tumor samples after therapy, along with increased numbers of cycling mesenchymal cells. Pro-growth signals from the tumor microenvironment, as well as the cell-intrinsic response to radiation therapy, drove the mesenchymal shift through a stress-response pathway mediated by AP1.
The researchers were able to combine two techniques to achieve a map of paracrine signals – single-nucleus RNA-sequencing of frozen tissue specimens and spatial transcriptomics profiling of formalin-fixed specimens. From each tumor biopsy, they performed single-nucleus RNA-seq which measures transcriptome-wide gene expression in individual cells, for thousands of cells at a time. They compared the expression of signal receptors to that of their known ligands, between the different cell populations sequenced. They then validated that cells from these populations physically interact and signal in situ, using spatial transcriptomics.
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“This is the first single-cell longitudinal study of this scale in glioma,” said Diaz. “It’s also a study that could be done only at UCSF, because it represents decades of careful biobanking of surgical specimens. Since all the specimens came from UCSF, we know that the treatment histories are homogeneous, in that each patient received only standard-of-care therapy. It’s both this cohort’s scale and treatment uniformity that enable us to see past patient specific effects to the underlying biology of the disease.”
Authors: Other UCSF authors include: Jangham Jung, Husam Babikir, Karin Shamardani, Saket Jain, Xi Feng, Nalin Gupta, Susanna Rosi, Susan Chang, David Raleigh of the UCSF Department of Neurological Surgery; David Solomon of the UCSF Department of Pathology, and Joanna J. Phillips of the UCSF Departments of Neurological Surgery and Pathology.
Funding: This work has been supported by research awards from: NIH/NLM R01LM013897 and UC/CRCC CRN-19-586041 to A.D.; the UCSF Glioma Precision Medicine Program to A.D., S.C., J.J.P., D.S.; NIH/NINDS R01CA246722 to A.D, N.G., and S.R.; UCSF Brain Tumor SPORE Biorepository NIH/NCI 5P50CA097257 to J.J.P.; a gift from the Panattoni family to A.D. and J.J.P.
About UCSF Health: UCSF Health is recognized worldwide for its innovative patient care, reflecting the latest medical knowledge, advanced technologies and pioneering research. It includes the flagship UCSF Medical Center, which is ranked among the top 10 hospitals nationwide, as well as UCSF Benioff Children’s Hospitals, with campuses in San Francisco and Oakland, Langley Porter Psychiatric Hospital and Clinics, UCSF Benioff Children’s Physicians and the UCSF Faculty Practice. These hospitals serve as the academic medical center of the University of California, San Francisco, which is world-renowned for its graduate-level health sciences education and biomedical research. UCSF Health has affiliations with hospitals and health organizations throughout the Bay Area. Visit https://ucsfhealth.org. Follow UCSF Health on Facebook or on Twitter.
(Family Features) Many people don’t think much about whether their blood is clotting properly. However, when you have a bleeding disorder, a condition that affects the way your body controls clots, it’s no small matter.
According to the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, abnormal clotting can lead to a host of problems, including excessive bleeding after an injury or during surgery.
About 3 million people in the U.S. have bleeding disorders. Some types, such as hemophilia, are inherited, meaning a person who has it is born with it. Inherited bleeding disorders are caused by certain genes passed down from parents to children. These genes contain instructions for how to make proteins in the blood called clotting factors, which help blood clot. If there is a problem with one of these genes, such as a mutation – a change in the gene’s instructions – the body may make a clotting factor incorrectly or not make it at all.
You can also have what’s called an acquired bleeding disorder, meaning you develop it during your lifetime. Acquired bleeding disorders can be caused by medical conditions, medicines or something unknown. Your risk of developing a bleeding disorder depends on your age, family history, genes, sex, or other medical conditions. If bleeding disorders run in your family, you may have a higher risk of developing or inheriting one.
Symptoms of a bleeding disorder may appear soon after birth or develop later in life and can include:
Excessive bleeding or bruising, such as frequent or long nose bleeds (longer than 15 minutes) or frequent or long menstrual periods
Petechiae, which are tiny purple, red, or brown spots caused by bleeding under the skin
Redness, swelling, stiffness, or pain from bleeding into muscles or joints
Blood in urine or stool
Excessive umbilical stump bleeding
Excessive bleeding during surgery or after trauma
If you believe you, or someone you care for, may have a bleeding disorder, talk to a health care provider. Your provider may make a diagnosis based on symptoms, risk factors, family history, a physical exam, and diagnostic tests. Health care providers typically screen for bleeding disorders only if you have known risk factors or before certain surgeries.
How your bleeding disorder is treated depends on its type. If your disorder causes few or no symptoms, you may not need treatment. If you have symptoms, you may need daily treatment to prevent bleeding episodes, or you may need it only on certain occasions, such as when you have an accident or before a planned surgery.
If you have been diagnosed with a bleeding disorder, it’s important to be proactive about your health and follow your treatment plan. To lower your risk of complications:
A Story of Bravery, Balance, and a Bleeding Disorder
There are lots of things that make Mikey White Jr. special. He’s a dedicated athlete. He’s determined, disciplined, and optimistic. He’s also living with hemophilia, a type of bleeding disorder.
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White was diagnosed with hemophilia at age 3 after experiencing several severe bleeding episodes. He had to give up baseball and basketball, his passions, because of the high risk of injuries, but he found competitive swimming – and he’s been breaking records ever since.
“Competitive swimming is a noncontact sport, so it complements my hemophilia while still being an intense and rigorous sport,” White said.
Being an athlete with hemophilia requires support, White admits. He works with his healthcare team and coaching staff to make sure he safely manages his condition and balances it with his training. He hopes his story encourages others living with bleeding disorders to accept and appreciate their bodies the way they are.
(Family Features) Most people don’t want to think about death – let alone talk about it. When the time comes, families often find themselves overwhelmed, not only by grief but by the many decisions that need to be made quickly.
Funeral directors witness this every day. They see the stress and confusion that can come when there is no plan in place and the peace of mind that comes with thoughtful preparation.
After consulting funeral directors nationwide, the National Funeral Directors Association (NFDA) uncovered five things they wish families knew before a death occurs.
It’s Never Too Early to Start Planning
While everyone knows death and taxes are inevitable, conversations about death are often avoided.
Simply documenting your wishes and discussing your preferences with your family can alleviate the difficult decisions your loved ones will have to make in the future. Speak with a funeral director to explore the many options for planning a meaningful funeral.
Legal and Financial Details Can Cause Unexpected Issues
Families often don’t realize power of attorney ends at death, meaning a designated person can no longer make decisions or access bank accounts once an individual dies.
To avoid complications, consider adding a trusted loved one to your bank account and ensure life insurance beneficiaries are up to date. Too often, deceased individuals leave minor children, deceased spouses or former partners as beneficiaries, leading to legal and financial challenges.
Final Wishes Shouldn’t Be In Your Will
Many people believe the best place to document their final wishes is in their will. However, wills are often not read until after funeral services take place, making them an unreliable way to communicate last requests. Instead, discuss and document your wishes with family members or a trusted funeral professional who can keep your wishes on file until there is a need.
There Are a Variety of Memorialization Options
End-of-life planning offers more choices than many realize. While burial remains a common preference, cremation is an increasingly popular choice and can even include a viewing and funeral service. Additionally, eco-friendly options, such as alkaline hydrolysis, natural burial and natural organic reduction are becoming more widely available for those seeking green memorialization. In fact, according to NFDA’s 2024 Consumer Awareness and Preferences Study, 68% of respondents expressed interest in green funeral options.
Exploring these possibilities with a funeral professional can help ensure your final arrangements reflect your values, traditions and personal wishes.
Funeral Directors Don’t Just Manage Funerals – They’re Trusted Guides In Honoring Life
Funeral directors play a vital role in helping families create meaningful services that reflect their loved one’s life, values and traditions. Whether planning ahead or facing a recent loss, funeral professionals provide expertise, compassionate care and personalized guidance during one of life’s most difficult moments.
Choosing the right funeral director is an important decision and finding someone who understands your needs can make all the difference in honoring your loved one in a personal and meaningful way.
Start the conversation today by talking about end-of-life planning. It isn’t easy, but it’s one of the most important conversations you can have with your loved ones. A little planning today can make a world of difference tomorrow.
Use comprehensive resources like RememberingALife.com, which is designed to guide families through every stage of the journey, including planning, funeral options and grief resources. The site offers valuable tools and support, such as the “Find a Funeral Home” tool to connect families with compassionate, local funeral directors and much more.
Photo courtesy of Shutterstock
SOURCE:National Funeral Directors Association
Workers who are in frequent contact with potentially sick animals are at high risk of bird flu infection.
Costfoto/NurPhoto via Getty ImagesRon Barrett, Macalester College
Disease forecasts are like weather forecasts: We cannot predict the finer details of a particular outbreak or a particular storm, but we can often identify when these threats are emerging and prepare accordingly.
The viruses that cause avian influenza are potential threats to global health. Recent animal outbreaks from a subtype called H5N1 have been especially troubling to scientists. Although human infections from H5N1 have been relatively rare, there have been a little more than 900 known cases globally since 2003 – nearly 50% of these cases have been fatal – a mortality rate about 20 times higher than that of the 1918 flu pandemic. If the worst of these rare infections ever became common among people, the results could be devastating.
Approaching potential disease threats from an anthropological perspective, my colleagues and I recently published a book called “Emerging Infections: Three Epidemiological Transitions from Prehistory to the Present” to examine the ways human behaviors have shaped the evolution of infectious diseases, beginning with their first major emergence in the Neolithic period and continuing for 10,000 years to the present day.
Viewed from this deep time perspective, it becomes evident that H5N1 is displaying a common pattern of stepwise invasion from animal to human populations. Like many emerging viruses, H5N1 is making incremental evolutionary changes that could allow it to transmit between people. The periods between these evolutionary steps present opportunities to slow this process and possibly avert a global disaster.
Spillover and viral chatter
When a disease-causing pathogen such as a flu virus is already adapted to infect a particular animal species, it may eventually evolve the ability to infect a new species, such as humans, through a process called spillover.
Spillover is a tricky enterprise. To be successful, the pathogen must have the right set of molecular “keys” compatible with the host’s molecular “locks” so it can break in and out of host cells and hijack their replication machinery. Because these locks often vary between species, the pathogen may have to try many different keys before it can infect an entirely new host species. For instance, the keys a virus successfully uses to infect chickens and ducks may not work on cattle and humans. And because new keys can be made only through random mutation, the odds of obtaining all the right ones are very slim.
Given these evolutionary challenges, it is not surprising that pathogens often get stuck partway into the spillover process. A new variant of the pathogen might be transmissible from an animal only to a person who is either more susceptible due to preexisting illness or more likely to be infected because of extended exposure to the pathogen.
Even then, the pathogen might not be able to break out of its human host and transmit to another person. This is the current situation with H5N1. For the past year, there have been many animal outbreaks in a variety of wild and domestic animals, especially among birds and cattle. But there have also been a small number of human cases, most of which have occurred among poultry and dairy workers who worked closely with large numbers of infected animals.
Pathogen transmission can be modeled in three stages. In Stage 1, the pathogen can be transmitted only between nonhuman animals. In stage 2, the pathogen can also be transmitted to humans, but it is not yet adapted for human-to-human transmission. In Stage 3, the pathogen is fully capable of human-to-human transmission.Ron Barrett, CC BY-SA
Epidemiologists call this situation viral chatter: when human infections occur only in small, sporadic outbreaks that appear like the chattering signals of coded radio communications – tiny bursts of unclear information that may add up to a very ominous message. In the case of viral chatter, the message would be a human pandemic.
Sporadic, individual cases of H5N1 among people suggest that human-to-human transmission may likely occur at some point. But even so, no one knows how long or how many steps it would take for this to happen.
Influenza viruses evolve rapidly. This is partly because two or more flu varieties can infect the same host simultaneously, allowing them to reshuffle their genetic material with one another to produce entirely new varieties.
Genetic reshuffling – aka antigenic shift – between a highly pathogenic strain of avian influenza and a strain of human influenza could create a new strain that’s even more infectious among people.Eunsun Yoo/Biomolecules & Therapeutics, CC BY-NC
These reshuffling events are more likely to occur when there is a diverse range of host species. So it is particularly concerning that H5N1 is known to have infected at least 450 different animal species. It may not be long before the viral chatter gives way to larger human epidemics.
Reshaping the trajectory
The good news is that people can take basic measures to slow down the evolution of H5N1 and potentially reduce the lethality of avian influenza should it ever become a common human infection. But governments and businesses will need to act.
People can start by taking better care of food animals. The total weight of the world’s poultry is greater than all wild bird species combined. So it is not surprising that the geography of most H5N1 outbreaks track more closely with large-scale housing and international transfers of live poultry than with the nesting and migration patterns of wild aquatic birds. Reducing these agricultural practices could help curb the evolution and spread of H5N1.
Large-scale commercial transport of domesticated animals is associated with the evolution and spread of new influenza varieties.ben/Flickr, CC BY-SA
People can also take better care of themselves. At the individual level, most people can vaccinate against the common, seasonal influenza viruses that circulate every year. At first glance this practice may not seem connected to the emergence of avian influenza. But in addition to preventing seasonal illness, vaccination against common human varieties of the virus will reduce the odds of it mixing with avian varieties and giving them the traits they need for human-to-human transmission.
At the population level, societies can work together to improve nutrition and sanitation in the world’s poorest populations. History has shown that better nutrition increases overall resistance to new infections, and better sanitation reduces how much and how often people are exposed to new pathogens. And in today’s interconnected world, the disease problems of any society will eventually spread to every society.
For more than 10,000 years, human behaviors have shaped the evolutionary trajectories of infectious diseases. Knowing this, people can reshape these trajectories for the better.Ron Barrett, Professor of Anthropology, Macalester College
This article is republished from The Conversation under a Creative Commons license. Read the original article.
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(Family Features) Most people don’t want to think about death – let alone talk about it. When the time comes, families often find themselves overwhelmed, not only by grief but by the many decisions that need to be made quickly.
Funeral directors witness this every day. They see the stress and confusion that can come when there is no plan in place and the peace of mind that comes with thoughtful preparation.
After consulting funeral directors nationwide, the National Funeral Directors Association (NFDA) uncovered five things they wish families knew before a death occurs.
Ron Barrett, Professor of Anthropology, Macalester College
This article is republished from The Conversation under a Creative Commons license. Read the original article.
