Cause of aggressive liver cancer discovered: molecular staple' that helps repair broken DNA

 Error-correcting mechanisms are very important for cells, because with all the cellular activity constantly going on, malfunctions arise all the time. But when it comes to killing cancer cells, it is in the cells' best interest to induce errors. Radiotherapy and chemotherapy can cause cellular defects by breaking the DNA of the cells. However, some tumor cells have an exceptionally efficient DNA repair machinery that allows them to evade cancer treatment.

In a paper published in Cell Reports, Óscar Llorca of the CNIO, Fernando Moreno-Herrero of the CNB and Puri Fortes of the CIMA-University of Navarra have now revealed the workings of one of these extraordinary repair systems: a molecular staple that has been shown in action for the first time using a new nanotechnology technique.

In liver cancer with the worst prognosis

A few years ago, a team led by Puri Fortes team discovered that about half of patients with hepatocellular carcinoma (the most common type of liver cancer) produce an RNA molecule called NIHCOLE, which is found mainly in the most aggressive tumors and is associated with a poor prognosis. Fortes, Llorca and Moreno-Herrero concluded that NIHCOLE is very effective at helping repair broken DNA, which is why radiotherapy is less effective in tumors where it is present. By eliminating NIHCOLE, cancer cells treated with radiotherapy die more easily.

However, the molecular mechanism by which NIHCOLE facilitates the repair of DNA breaks was not known. The paper just published in Cell Reports explains this: NIHCOLE forms a bridge that binds the broken DNA fragments together.

"NIHCOLE interacts simultaneously with proteins that recognize the two ends of a fragmented DNA, as if stapling them together," explain Llorca and Moreno-Herrero.

Understanding this mechanism may help in the development of strategies to combat liver cancers with the worst prognosis. "The use of NIHCOLE inhibitor drugs may represent a new therapy for the most common form of liver cancer," the researchers say.

Magnetic nano-tweezers for stretching DNA

To understand how NIHCOLE works, Fernando Moreno-Herrero's group has used magnetic tweezers, a nanotechnology technique that allows the physical properties of individual molecules to be studied.

Researchers have designed a DNA molecule that mimics broken DNA, allowing them to detect the junction between the two fragmented ends. First, they attach a tiny magnetic bead, on the scale of a thousandth of a millimeter, to one end of the DNA, and then use magnetic nano-tweezers to pull on that end. The length of the stretched DNA indicates whether it is a reconstituted DNA molecule, in which the broken ends of the DNA have been joined together, or whether it is still broken.

For the authors of the Cell Reports paper, these data show that NIHCOLE "confers advantages on tumor cells by helping them to repair DNA breaks, thereby sustaining the malignant proliferation of cancer cells despite the accumulation of DNA damage resulting from the stress of cell division itself."

'Junk DNA' that is no longer junk

NIHCOLE is not a protein synthesized by a gene, but an RNA molecule. It is part of what biologists dubbed junk DNA two decades ago when the human genome was being sequenced. At the time, they mistakenly believed that this DNA was useless.

Llorca explains, "One of the central dogmas of biology is that the information contained in each gene, in DNA, is translated into proteins. So scientists were stunned when they discovered that only 2% of our DNA contained genes; what was the rest of our genome for? It is unthinkable that 98% of the genome is junk, useless DNA. In the last decade it has been shown that part of this dark genome produces very long RNA molecules, some of which have a prevalent function in cancer."

NIHCOLE is one of these long RNA molecules, the existence and function of which have only recently been discovered to such an extent that biologists are still amazed. It is also surprising that only a small piece of NIHCOLE is required for it to act as a molecular staple.

"This would allow the development of drugs that block or distort this structure, and thus improve the efficacy of radiotherapy or chemotherapy in cancer patients," say the authors of the paper.

More information: Sara De Bragança et al, APLF and long non-coding RNA NIHCOLE promote stable DNA synapsis in non-homologous end joining, Cell Reports (2022). DOI: 10.1016/j.celrep.2022.111917

https://medicalxpress.com/news/2023-01-aggressive-liver-cancer-molecular-staple.html

Mapping effects of dietary nutrients on disease

 Researchers at the Francis Crick Institute and King's College London have created a tool to predict the effects of different diets on both cancerous cells and healthy cells.

Their work could help disentangle the subtle metabolic changes associated with different types of nutrients, and improve our understanding of the link between diet and disease.

Metabolism refers to the set of processes that allow an organism to use nutrients from its environment in order to function. Relative amounts of sugars, fats and protein in the diet determine what "fuel" is available for the cells, and also how those cells process the nutrients. Cancer cells, like other diseased cells, change their metabolism to support survival and growth.

As part of the study, published in iScience, the research team at the Center for Host-Microbiome Interactions at King's College London first created a comprehensive map of all metabolic pathways in the mouse. The Crick team then gathered experimental data to put into the model by measuring the levels of gene expression in liver and liver tumors from mice that had been fed either "healthy" diets or "unhealthy" diets, rich in fats and sugars.

They found specific changes in metabolism associated with unhealthy diets, which were seen to promote the production of glycerol and succinate in both cancerous and healthy tissues. They also observed that the differences in metabolism between healthy and cancerous cells were highest in the context of an unhealthy diet, suggesting that tumors are able to better exploit unhealthy diets to promote survival and growth.

Patricia Nunes, Senior Laboratory Research Scientist at the Crick, said, "By using experimental data from the lab, the model allows us to start understanding the complex metabolic changes that happen in tissues due to specific nutrients in the diet."

Dimitrios Anastasiou, head of the Crick's Cancer Metabolism Laboratory, said, "We know that poor diet wreaks havoc in our body's metabolism. It can cause obesity and promote liver disease, which, in turn, can progress to liver cancer. We want to understand which nutrients in our diets, and in what combinations, drive these detrimental outcomes."

The team then modeled the effects of a change in dietary components—from healthy to unhealthy, and unhealthy to healthy—in various combinations. They observed that, although some cancer-specific metabolic functions persisted on healthy diets, they could also reverse many of them, but only when both fats and carbohydrates were limited.

Frederick Clasen, first author and Ph.D. student jointly at the Crick and King's College London, said, "The potential applications of this work are far reaching. We can now see which changes in diet actually impact cell metabolism, and which have very little effect because the cells are already programmed to draw missing nutrients from their surroundings."

Saeed Shoaie, head of the Translational Systems Biology group from the Faculty of Dentistry, Oral & Craniofacial Sciences at King's College London, said, "To further increase the accuracy of our model's predictions, we are now generating more sophisticated models of metabolism, that take into account how different organs exchange metabolites, and how bacteria in the gut influence what nutrients are available to tissues."

Anastasiou concludes, "Our approach can be used to help guide dietary changes that complement treatments for different diseases. But the most effective use of this understanding will be in preventing more disease by helping us select the foods we eat."

More information: Frederick Clasen et al, Systematic diet composition swap in a mouse genome-scale metabolic model reveals determinants of obesogenic diet metabolism in liver cancer, iScience (2023). DOI: 10.1016/j.isci.2023.106040. www.cell.com/iscience/fulltext … 2589-0042(23)00117-7

https://medicalxpress.com/news/2023-01-effects-dietary-nutrients-disease.html

Fresh questions about oxytocin as the 'love hormone' behind pair bonding

 Turning a decades-old dogma on its head, new research from scientists at UC San Francisco and Stanford Medicine shows that the receptor for oxytocin, a hormone considered essential to forming social bonds, may not play the critical role that scientists have assigned to it for the past 30 years.

In the study, appearing Jan. 27, 2023 in Neuron, the team found that prairie voles bred without receptors for oxytocin and showed the same monogamous mating, attachment, and parenting behaviors as regular voles. In addition, females without oxytocin receptors gave birth and produced milk, though in smaller quantities, than ordinary female voles.

The results indicate that the biology underlying pair bonding and parenting isn't purely dictated by the receptors for oxytocin, sometimes referred to as the "love hormone."

"While oxytocin has been considered 'Love Potion #9,' it seems that potions 1 through 8 might be sufficient," said psychiatrist Devanand Manoli, MD, Ph.D., a senior author of the paper and member of the UCSF Weill Institute for Neurosciences. "This study tells us that oxytocin is likely just one part of a much more complex genetic program."

CRISPR voles pack a surprise

Because prairie voles are one of the few mammalian species known to form lifelong monogamous relationships, researchers study them to better understand the biology of social bonding.

Studies in the 1990s using drugs that prevent oxytocin from binding to its receptor found that voles were unable to pair bond, giving rise to the idea that the hormone is essential to forming such attachments.

The current project emerged from shared interests between Manoli and co-senior author and neurobiologist Nirao Shah, MD, Ph.D., then at UCSF and now at Stanford Medicine. Shah had been interested in the biology of oxytocin and social attachment in prairie voles since teaching about the oxytocin studies decades earlier. Manoli, who wanted to investigate the neurobiology of social bonding, joined Shah's lab in 2007 as a postdoctoral scholar.

For this study, 15 years in the making, the two applied new genetic technologies to confirm if oxytocin binding to its receptor was indeed the factor behind pair bonding. They used CRISPR to generate prairie voles that lack functional oxytocin receptors. Then, they tested the mutant voles to see whether they could form enduring partnerships with other voles.

To the researchers' surprise, the mutant voles formed pair bonds just as readily as normal voles.

"The patterns were indistinguishable," said Manoli. "The major behavioral traits that were thought to be dependent on oxytocin—sexual partners huddling together and rejecting other potential partners as well as parenting by mothers and fathers—appear to be completely intact in the absence of its receptor."

Labor and lactation

Even more surprising for Manoli and Shah than the pair bonding was the fact that a significant percentage of the female voles were able to give birth and provide milk for their pups. Oxytocin is likely to have a role in both birth and lactation, but one that is more nuanced than previously thought, Manoli said. Female voles without receptors proved perfectly capable of giving birth, on the same timeframe and in the same way as the regular animals, even though labor has been thought to rely on oxytocin.

The results help to clear up some of the mystery surrounding the hormone's role in childbirth: Oxytocin is commonly used to induce labor but blocking its activity in mothers who experience premature labor isn't better than other approaches for halting contractions.

When it came to producing milk and feeding pups, however, the researchers were taken aback. Oxytocin binding to its receptor has been considered essential for milk ejection and parental care for many decades, but half of the mutant females were able to nurse and wean their pups successfully, indicating that oxytocin signaling plays a role, but it is less vital than previously thought.

"This overturns conventional wisdom about lactation and oxytocin that's existed for a much longer time than the pair bonding association," said Shah. "It's a standard in medical textbooks that the milk letdown reflex is mediated by the hormone, and here we are saying, 'Wait a second, there's more to it than that.'"

Hope for social connection

Manoli and Shah focused on understanding the neurobiology and molecular mechanisms of pair bonding because it is thought to hold the key to unlocking better treatments for psychiatric conditions, such as autism and schizophrenia, that interfere with a person's ability to form or maintain social bonds.

Over the past decade, much hope was pinned on clinical trials using oxytocin to address those conditions. But those results were mixed, and none has illuminated a clear path to improvement.

The researchers said their study strongly suggests that the current model—a single pathway or molecule being responsible for social attachment –is oversimplified. This conclusion makes sense from an evolutionary perspective, they said, given the importance of attachment to the perpetuation of many social species.

"These behaviors are too important to survival to hinge on this single point of potential failure," said Manoli. "There are likely other pathways or other genetic wiring to allow for that behavior. Oxytocin receptor signaling could be one part of that program, but it's not the be-all end-all."

The discovery points the researchers down new paths to improving the lives of people struggling to find social connection.

"If we can find the key pathway that mediates attachment and bonding behavior," Shah said, "We'll have an eminently druggable target for alleviating symptoms in autism, schizophrenia, many other psychiatric disorders."

More information: Devanand S. Manoli, Oxytocin receptor is not required for social attachment in prairie voles, Neuron (2023). DOI: 10.1016/j.neuron.2022.12.011. www.cell.com/neuron/fulltext/S0896-6273(22)01084-4

https://medicalxpress.com/news/2023-01-fresh-oxytocin-hormone-pair-bonding.html

Drug that ups dopamine can reverse effects of inflammation on brain in depression

 An Emory University study published in Molecular Psychiatry shows levodopa, a drug that increases dopamine in the brain, has potential to reverse the effects of inflammation on brain reward circuitry, ultimately improving symptoms of depression.

Numerous labs across the world have shown that inflammation causes reduced motivation and anhedonia, a core symptom of depression, by affecting the brain's reward pathways.

Past research conducted by the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine has linked the effects of inflammation on the brain to decreased release of dopamine, a chemical neurotransmitter that regulates motivation and motor activity, in the ventral striatum.

In the study, researchers demonstrated that levodopa reversed the effects of inflammation on the brain's functional connectivity in reward circuitry and anhedonia (inability to feel pleasure) in depressed individuals with higher C-reactive protein (CRP), a blood biomarker produced and released by the liver in response to inflammation.

Levels of inflammation can be easily measured by simple blood tests, like CRP, readily available in clinics and hospitals throughout the U.S.

The study included 40 depressed patients with a range of CRP levels from high to low who underwent functional brain scans on two visits after receiving in random order either placebo or levodopa, a drug often prescribed for disorders like Parkinson's disease.

Levodopa improved functional connectivity in a classic ventral striatum to ventromedial prefrontal cortex reward circuit but only in patients with higher levels of CRP. This improvement in reward circuitry in depressed individuals with higher CRP also correlated with reduced symptoms of anhedonia after levodopa.

"This research demonstrates the translational potential for use of inflammation-related deficits in functional connectivity and could have important implications for the future investigations of precision therapies for psychiatric patients with high inflammation," says principal investigator and senior author Jennifer C. Felger, Ph.D., associate professor of psychiatry and behavioral sciences, Emory School of Medicine.

Felger says the study findings are critical for two reasons. First, they suggest depressed patients with high inflammation may specifically respond to drugs that increase dopamine.

Second, Felger says these findings also provide additional evidence that functional connectivity in reward circuitry may serve as a reliable brain biomarker for the effects of inflammation on the brain.

"Moreover, as the effect of levodopa was specific to depressed patients with higher inflammation, this functional connectivity may be used to assess the responsiveness of the brain to novel treatments that might be targeted to this subtype of depressed patients in future studies and clinical trials," says Felger.

More information: Mandakh Bekhbat et al, Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic targets in depression with high inflammation: evidence from a dopamine challenge study, Molecular Psychiatry (2022). DOI: 10.1038/s41380-022-01715-3

https://medicalxpress.com/news/2023-01-drug-dopamine-reverse-effects-inflammation.html

Sam Bankman-Fried tried to influence witness through Signal, DOJ alleges

 Federal prosecutors are attempting to bar indicted FTX co-founder Sam Bankman-Fried from using encrypted messaging software, citing efforts that may “constitute witness tampering,” according to a letter filed in Manhattan federal court Friday.

Bankman-Fried reached out to the “current General Counsel of FTX US who may be a witness at trial,” prosecutors said. Ryne Miller, who was not identified by name in the government filing, is the current counsel for FTX US, and a former partner at Kirkland & Ellis.

The government claims that Bankman-Fried wrote to Miller via Signal, an encrypted messaging app, on Jan. 15, days after bankruptcy officials at crypto exchange disclosed the recovery of more than $5 billion in FTX assets.

“I would really love to reconnect and see if there’s a way for us to have a constructive relationship, use each other as resources when possible, or at least vet things with each other,” Bankman-Fried allegedly told Miller.

Bankman-Fried has also been in contact with “other current and former FTX employees,” the filing said. Federal prosecutors allege that Bankman-Fried’s request suggests an effort to influence the witness’s testimony, and that Bankman-Fried’s effort to improve his relationship with Miller “may itself constitute witness tampering.”

Miller did not immediately respond to a request for comment.

In restricting Bankman-Fried’s access to Signal and other encrypted messaging platforms, the government cites a need to “prevent obstruction of justice.” Federal prosecutors claim that Bankman-Fried directed Alameda and FTX through Slack and Signal, and ordered his employees set communications to “autodelete after 30 days or less.”

Citing previously undisclosed testimony from ex-Alameda CEO Caroline Ellison, the government claimed that Bankman-Fried indicated “many legal cases turn on documentation and it is more difficult to build a legal case if information is not written down or preserved.” Ellison pled guilty to multiple charges of fraud and has been cooperating with the U.S. Attorney’s efforts to build a case against Bankman-Fried.

Bankman-Fried pled not guilty to eight charges in connection with the collapse of his multi-billion dollar crypto empire, FTX. He is due in federal court in October, after being released on $250 million bond.

https://www.cnbc.com/2023/01/27/sam-bankman-fried-tried-to-influence-witness-through-signal-doj.html

New Cancer Data Spark Outcry From Patient Advocates

 Newly released figures showing a rise in the number of men with advanced prostate cancer have laid bare long-simmering resentment among patient advocates who feel the nation's leading cancer group has largely ignored their concerns for years.

The American Cancer Society this month revealed what it called "alarming" news about prostate cancer: After two decades of decline, the number of men diagnosed with the disease in the United States rose by 15% from 2014 to 2019.

"Most concerning," according to the group's CEO Karen Knudsen, PhD, MBA, is that the increase is being driven by diagnoses of advanced disease.

Dr Karen Knudsen

"Since 2011, the diagnosis of advanced-stage (regional- or distant-stage) prostate cancer has increased by 4%–5% annually and the proportion of men diagnosed with distant-stage disease has doubled," said Knudsen at a press conference this month concerning the figures. "These findings underscore the importance of understanding and reducing this trend."

The increase, which works out to be an additional 99,000 cases of prostate cancer, did not take the ACS by surprise; the group has been predicting a jump in diagnoses of the disease, which is the most common cancer in men after skin cancer, and the second most common cause of cancer death for that group.

The ACS announced a new action plan, "Improving Mortality from Prostate Cancer Together" — or IMPACT — to address the rise, especially in Black men, and to curb the increasing rate of advanced, difficult-to-treat cases.

Dr William Dahut

"We must address these shifts in prostate cancer, especially in the Black community, since the incidence of prostate cancer in Black men is 70% higher than in White men and prostate cancer mortality rates in Black men are approximately two to four times higher than those in every other racial and ethnic group," William Dahut, MD, PhD, chief scientific officer for the ACS, said at the press conference. (A study published this month challenged that claim, finding that, after controlling for socioeconomic factors, race does not appear to be a significant predictor of mortality for prostate cancer.)

Dahut told Medscape Medical News that IMPACT "is still [in the] early days for this initiative and more details will be coming out soon."

Charles Ryan, MD, chief executive officer of the Prostate Cancer Foundation, the world's largest prostate cancer research charity, called IMPACT "extremely important work. Highlighting the disparities can only serve to benefit all men with prostate cancer, especially Black men."

Bold Action…or Passivity?

Overall cancer mortality has dropped 33% since 1991, averting an estimated 3.8 million deaths, according to ACS. But the story for prostate cancer is different.

The society and advocates had warned as recently as 2 years ago that prostate cancer was poised to rise again, especially advanced cases that may be too late to treat.

Leaders in the prostate cancer advocacy community praised the ACS plan for IMPACT, but some expressed frustration over what they said was ACS' passivity in the face of long-anticipated increases in cases of the disease.

"I think prostate cancer was not high on their agenda," said Rick Davis, founder of AnCan, which offers several support groups for patients with prostate cancer.  "It's good to see ACS get back into the prostate cancer game."

Darryl Mitteldorf

Davis and patient advocate Darryl Mitteldorf, LCSW, founder of Malecare, another prostate support organization, said ACS dropped patient services for prostate cancer patients a decade ago and has not been a vocal supporter of screening for levels of prostate-specific antigen (PSA) to detect prostate cancer early.

"Early detection is supposed to be their goal," Davis said.

In 2012, the US Preventive Services Task Force (USPSTF) recommended against PSA screening, giving it a D-rating. The move prompted attacks on the task force from most advocates and many urologists.

Following this criticism, the task force recommended shared decision-making between patient and doctor, while giving PSA screening a C-rating. Now, the ACS recommends men in general at age 50 discuss prostate cancer screening with their doctor and that Black men do the same at age 45.

Mitteldorf said ACS "owes prostate cancer patients an explanation and analysis of its response to the USPTF's downgrade of PSA testing and how that response might be related to death and instance rates."

Mitteldorf added that male patients lost key support from ACS when the group dismantled its Man to Man group for prostate cancer patients and its Brother to Brother group for Blacks in particular.

Dahut said Man to Man "sunsetted" and was turned over to any local organization that chose to offer it.  He said longtime staff didn't have "a lot of information about [the demise of] Brother to Brother."

For Davis, those smaller cuts add up to a much larger insult.

"Today, in 2023, ACS continues to poke a finger in the eyes of prostate cancer patients," he said. "Since 2010, they have not given us any respect. ACS dumped its support."

He pointed to the group's funding priorities, noting that outlays for prostate cancer have consistently lagged behind those for breast cancer.

The ACS spent $25.3 million on breast cancer research and $6.7 million for prostate cancer in 2018, and in 2023 will designate $126.5 for breast cancer research and $43.9 million for prostate cancer.

ACS has earmarked $62 million this year for lung cancer programs and $61 million for colorectal cancer.

"Parity between breast cancer and prostate cancer would be a good start in sizing the IMPACT program," Davis said. "After all, breast cancer and prostate cancer are hardly different in numbers today."

Dahut denied any gender bias in research funding. He said the group makes funding decisions "based on finding the most impactful science regardless of tumor type. Our mission includes funding every cancer, every day; thus, we generally do not go into our funding cycle with any set-asides for a particular cancer."

Davis also said the ACS data suggest the growing number of prostate cancer cases is even worse than the group has said. Although the society cites a 3% annual increase in prostate cancer diagnoses from 2014–2019, since 2019 the annual increase is a much more dramatic 16%. Meanwhile, the number of new cases of the disease is projected to rise from 175,000 per year in 2019 to 288,000 this year.

Dahut said the society used the 2014–2019 timeframe for technical reasons, separating confirmed cases in the earlier period from estimated cases in recent years.

"We discourage comparing projected cases over time because these cases are model-based and subject to fluctuations," Dahut said.

https://www.medscape.com/viewarticle/987574

Long COVID Affecting More Than One Third of College Students, Faculty

 Almost 36% of students and faculty at George Washington University with a history of COVID-19 reported symptoms consistent with long COVID in a new study. 

With a median age of 23 years, the study is unique for evaluating mostly healthy, young adults and for its rare look at long COVID in a university community. 

The more symptoms during a bout with COVID, the greater the risk for long COVID, the researchers found. That lines up with previous studies. Also, the more vaccinations and booster shots against SARS-CoV-2, the virus that causes COVID, the lower the long COVID risk. 

Women were more likely than men to be affected. Current or prior smoking, seeking medical care for COVID, and receiving antibody treatment also were linked to higher chances for developing long COVID. 

Lead author Megan Landry, DrPH, MPH, and colleagues were already assessing students, staff, and faculty at George Washington University in Washington, DC, who tested positive for COVID. Then they started seeing symptoms that lasted 28 days or more after their 10-day isolation period. 

"We were starting to recognize that individuals ... were still having symptoms longer than the typical isolation period," says Landry. So they developed a questionnaire to figure out the how long these symptoms last and how many people are affected by them. 

The list of potential symptoms was long and included trouble thinking, fatigue, loss of smell or taste, shortness of breath, and more. 

The study was published online Thursday in the CDC's Emerging Infectious Diseases journal. Results are based on records and responses from 1,388 students, faculty, and staff from July 2021 to March 2022.

People had a median of four long COVID symptoms, about 63% were women, and 56% were non-Hispanic white. About three-quarters were students and the remainder were faculty and staff. 

The finding that 36% of people with a history of COVID reported long COVID symptoms did not surprise Landry.

"Based on the literature that's currently out there, it ranges from a 10% to an 80% prevalence of long COVID," she says. "We kind of figured that we would fall somewhere in there."

In contrast, that figure seemed high to Eric Topol, MD, editor-in-chief ofMedscape, WebMD's sister site for health care professionals.

"That's really high," says Topol, who is also founder and director of the Scripps Research Translational Institute in La Jolla, CA. Topol says most studies estimate that about 10% of people with a history of acute infection develop long COVID. 

Even at 10%, which could be an underestimate, that's a lot of affected people globally. 

https://www.medscape.com/viewarticle/987618