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Mutations in the KRAS gene are the major driver of pancreatic cancer. The resulting protein controls multiple signaling pathways involved in cell growth and survival. In cancer, the gene is mutated to be permanently “on,” driving cells to excessively multiply and form tumors.
New drugs have recently been developed to inhibit KRAS and appear to be therapeutically promising. However, pancreatic cancer is especially prone to drug resistance. Most drugs only work for a short period of time before the cancer finds its way around them.
Previous experiments revealed a potential reason why: a group of genes upstream of KRAS, called ERBB, appears to become upregulated in response to KRAS inhibition. In other words, when KRAS goes down, ERBB goes up and drives KRAS and other related genes back up again.
To try to beat this potential source of drug resistance, researchers at University of California San Diego School of Medicine tested a novel combination of KRAS and ERBB drug inhibitors. The findings, published on June 28 in Cancer Research, a journal of the American Association for Cancer Research, reveal the combination of drugs to be dramatically more effective and less prone to resistance than treatment with the KRAS inhibitor alone. The authors now recommend the drug combination be tested in clinical trials for human cancer patients.
“KRAS inhibitors have the potential to completely change the landscape of treating pancreatic cancer,” said co-senior author Herve Tiriac, PhD, assistant research scientist in the Department of Surgery at UC San Diego School of Medicine and Moores Cancer Center at UC San Diego Health. “However, we need to do a lot of upfront testing to optimize KRAS therapy, or clinical trials might get a lot of negative data.”
The study was the first to confirm that human pancreatic cells treated with the KRAS inhibitor MRTX1133 (Mirati Therapeutics) do indeed develop drug resistance and increase their expression of ERBB. But this resistance could be overcome by combining the drug with the FDA-approved pan-ERBB inhibitor Afatinib.
The combination of MRTX1133 and Afatinib also reduced the number of surviving cancer cells more than MRTX1133 alone. This pairing was more effective than combining MRTX1133 with EGFR inhibitors or drugs targeting different molecules downstream of KRAS.
Pancreatic cancer cells were so “exquisitely vulnerable” to MRTX1133 and Afatinib that the drugs showed a synergistic interaction, meaning the benefits of using the two drugs together were even larger than the sum of each one’s individual effect. In other words, the drug pairing was greater than the sum of its parts.
The researchers also tested the drugs in a live mouse model of pancreatic cancer and found that mice treated with both drugs survived significantly longer than those treated with either drug alone. The use of both human and mouse models of pancreatic cancer, 2D cell cultures and 3D organoids and in vitro and in vivo measurements is a major strength of the study.
“The synergy between MRTX1133 and Afatinib was remarkable, and we strongly encourage the clinical testing of this drug combination for patients with pancreatic cancer,” said co-senior author Andrew Lowy, MD, professor in the Department of Surgery and chief of the Division of Surgical Oncology at UC San Diego School of Medicine and clinical director for Cancer Surgery at Moores Cancer Center.
Co-authors of the study include: Kevin Christian Montecillo Gulay, Xinlian Zhang, Jay Patel, Edgar Esparza, Deepa Sheik Pran Babu, Jonathan Weitz, Isabella Ng, Evangeline S. Mose and Minya Pu, all at UC San Diego, as well as Vasiliki Pantazopoulou, Satoshi Ogawa and Dannielle D. Engle at the Salk Institute.

Scientists have developed a new approach to produce life-saving oligonucleotide therapeutics on a large scale, in high purity, and with minimal environmental impacts.
Therapeutic oligonucleotides are an emerging class of drug molecules that have the potential to treat a wide range of diseases.
The finding, by The University of Manchester, will facilitate large-scale production of oligonucleotides to ensure the widest possible access of these drugs for patients.
Oligonucleotides are short sequences of DNA that can modulate or control gene expression. In this way, they have the potential to address the underlying causes of various diseases such as heart disease, cancer, and muscular dystrophy.
Over recent years, there has been an increasing number of approved oligonucleotide-based therapies, but widespread use of the drug has been limited in part because of difficulties in its manufacturing process.
Current methods rely on chemical synthesis that requires large amounts of solvent, generates substantial waste, and delivers final products with low yield and modest purity. Reactions are performed on solid supports or columns, which limits scalability, making them suitable only for producing oligonucleotides in small batches.
The new research, published in the journal Science, presents a sustainable and scalable approach to oligonucleotide production, addressing the challenges associated with current methods.
The findings could have major implications for the pharmaceutical industry.
Sarah Lovelock, Senior Lecturer at the Manchester Institute of Biotechnology at The University of Manchester, said: “Therapeutic oligonucleotides are an exciting new drug modality with huge potential to treat a wide range of diseases, including genetic disorders and viral infections.
“Many pharmaceutical companies have therapeutic oligonucleotide candidates in their pipelines, including those for common diseases. The development of more scalable and sustainable approaches to oligonucleotide production will be key to ensuring the widest possible access to this powerful class of therapeutics.”
In nature, DNA can be copied or amplified using enzymes called polymerases. The new approach uses these polymerases to amplify a catalytic DNA template to make a high volume of therapeutic oligonucleotides in a single step. This contrasts the iterative rounds of chain extension, capping, oxidation and deprotection associated with established methods.
Researchers at the University of Manchester are now working in a collaborative partnership with technology innovation catalyst CPI, AstraZeneca, and Novartis to scale up the approach presented within this research.

Published13 minutes agoShareclose panelShare pageCopy linkAbout sharingImage source, ReutersBy James GallagherHealth and science correspondentA key defence that blocks nearly all bird flu when it attempts to invade our body has been discovered by scientists. Bird flus have been involved in four pandemics since 1918 – killing millions of people.The research, led by the University of Glasgow, showed those pandemics and normal winter flus had evolved ways of getting round this “powerful barrier”. The team think we will soon be able to predict which of the flus currently in birds pose the biggest risk.The scientists were investigating spillover events. These are the moments a person catches an infection from an animal. This jump across species is a critical step in the start of a new pandemic. Listen: The Jump on BBC SoundsIn laboratory experiments, researchers uncovered a section of our genetic code – our DNA – that becomes activated in response to an infection. It is called BTN3A3 (although even the researchers admit “we’re stuck” with a clunky name). The data, published in the journal Nature, showed BTN3A3 became active in our nose, throat and lungs and that it reduced the ability of bird flus to replicate. Researcher Dr Rute Maria Pinto said “nearly all” bird flus are unable to bypass this protection so “these are normally blocked by it, so they don’t jump”.She added: “The big majority of human viruses and in fact all pandemic viruses so far, have [resistance to BTN3A3] so they overcome this block and therefore infect.”There is a constant chance of bird flus making the jump into people. There is a variety of flu viruses in wild birds, and poultry poses a high risk because of the sheer number of farmed animals and their close proximity to people. The 1918 flu pandemic is thought to have started in birds and is estimated to have killed 50 million people. The researchers showed a form of bird flu called H7N9 developed higher levels of resistance to BTN3A3 in 2011 and 2012 before the first human cases emerged in 2013.Evolving ways of bypassing BTN3A3 is one of the steps a bird flu can take to successfully infect us. The researchers’ vision is to routinely analyse – or sequence – the genetic code of flus that are currently circulating in birds, identify the dangerous ones and tackle them. Image source, PA MediaProf Massimo Palmarini, director of the Centre for Virus Research in Glasgow, told me: “In the not so distant future we’ll be able to put together all the pieces of the puzzle.”From a sequence of a virus, we’ll be able to say this has a 90% chance to cross over to humans, this virus has only a 10% chance.”Then targeted measures could be introduced to help control viruses that do have a high risk of making the jump.The current outbreak?The world’s bird populations have been hit by the largest bird – or avian – flu outbreak ever recorded. Bird flu outbreak: What is it and what’s behind it?Bird flu: Brazil declares animal health emergencyThe virus – H5N1 – has occasionally jumped into people coming into close contact with infected animals, but it has not spread from one person to another. Prof Palmarini said “a bit more than 50%” of virus samples from birds and “all seven” cases detected in people this year had resistance to BTN3A3.”That is one layer of concern, the other is the virus has spread as never before,” he told me. However, the ability to bypass BTN3A3 is only one aspect of the virus’s threat to human health.Dr Stephen Oakeshott, the head of infections and immunity at the Medical Research Council, said: “This interesting study illustrates an important piece of the very complex puzzle underpinning viral transmission between species.”This type of mechanistic scientific insight, coupled with genetic surveillance, can offer a window into future disease risks to inform public health planning.”Follow James on Twitter.

In lawsuits challenging state abortion bans, lawyers for abortion rights plaintiffs are employing religious liberty arguments the Christian right has used for decades.For years, conservative Christians have used the principle of religious freedom to prevail in legal battles on issues like contraceptive insurance mandates and pandemic restrictions. Now, abortion rights supporters are employing that argument to challenge one of the right’s most prized accomplishments: state bans on abortion.In the year since Roe v. Wade was overturned, clergy and members of various religions, including Christian and Jewish denominations, have filed about 15 lawsuits in eight states, saying abortion bans and restrictions infringe on their faiths.Many of those suing say that according to their religious beliefs, abortion should be allowed in at least some circumstances that the bans prohibit, and that the bans violate religious liberty guarantees and the separation of church and state. The suits, some seeking exemptions and others seeking to overturn the bans, often invoke state religious freedom restoration acts enacted and used by conservatives in some battles over social issues.The lawsuits show “religious liberty doesn’t operate in one direction,” said Elizabeth Sepper, a law professor at University of Texas at Austin.Aaron Kemper, a lawyer representing three Jewish women who are suing to overturn Kentucky’s abortion ban, said he studied and emulated federal and state religious liberty cases that conservatives won.“We were like, it works for them, so we thought we should use sections from those cases,” he said.Though most lawsuits have not yet yielded court rulings, there are signs the arguments may have some legal traction. In Indiana, a judge issued a preliminary injunction blocking the state’s abortion ban, saying it violated the state’s Religious Freedom Restoration Act adopted in 2015 under then-Gov. Mike Pence, an ardent abortion opponent who is now running for president.Recognizing a potential threat, Oklahoma and West Virginia recently amended their religious freedom restoration acts to explicitly prevent challenges to abortion bans under the acts.Some belief systems, including the United Church of Christ’s, support women making their own decisions in pregnancy. Some, including the Episcopal Church and many branches of Judaism have traditions that abortion should be supported in certain cases, especially where pregnancies threaten women’s physical or mental health or involve serious fetal abnormalities. Some faiths do not define life as beginning with conception.The Indiana case was filed by Hoosier Jews for Choice, three Jewish women and a woman with independent spiritual beliefs. Judge Heather Welch of Marion County Superior Court has certified it as a class-action lawsuit on behalf of “all persons in Indiana whose religious beliefs direct them to obtain abortions in situations prohibited by” the ban.The Rev. Dr. Laurie Hafner, a United Church of Christ pastor, is suing the state of Florida over its abortion bans, saying that according to her faith, “women have the ability and wherewithal to make the decision that’s right for them.”Sydney Walsh for The New York Times“The court has concluded that the plaintiffs’ religious exercise is being substantially burdened, that they are suffering irreparable harm,” Judge Welch wrote in blocking the ban.The state has appealed, arguing that “‘abortion access’ is not religious exercise.” Like other states fighting such lawsuits, Indiana said it has a “compelling interest” to prohibit abortions. “Plaintiffs identify no principle that makes abortion a religious act any more than countless other actions that they believe to affect their well-being,” Indiana’s attorney general wrote, adding, “Other acceptable means for plaintiffs to achieve such ends in the context of childbearing include sexual abstinence, contraceptives, IUDs and natural family planning, just to name a few.”Decades ago, some anti-abortion groups warned that religious freedom arguments might be used to bolster abortion rights. When Congress considered what became the 1993 Religious Freedom Restoration Act, the National Right to Life Committee and the U.S. Catholic Conference raised that concern.“The Act, if passed, will be used to seek access to abortions,” the Catholic Conference’s general counsel wrote in 1992.In Florida, lawsuits filed by Episcopal, Buddhist, Unitarian Universalist, Jewish and United Church of Christ clergy say abortion restrictions violate “clerical obligations and faith” and impose “severe barriers” on religious belief, speech and conduct.Mikayla took mifepristone, the first pill in a two-drug regimen to end a pregnancy.Adria Malcolm for The New York Times“We believe God is the source of all life and has caused us to share in the work of creation,” said one plaintiff, the Rev. Dr. Laurie Hafner, senior pastor of Coral Gables Congregational United Church of Christ. “The privileges and responsibilities of being part of co-creating,” she said, mean “women have the ability and wherewithal to make the decision that’s right for them.”Reverend Hafner said she had counseled parishioners deciding whether to terminate pregnancies, including a 14-year-old girl and a woman whose fetus was nonviable. Florida’s six-week abortion ban is currently on hold, but, she said, “what if it gets to that place where I can no longer sit at the bedside or in the living room or in my office with someone out of fear of what might happen?”Within any faith, there may be varying opinions on abortion. But many of those suing say abortion bans embed conservative Christian ideology into state law.One Kentucky plaintiff, Sarah Baron, a 38-year-old mother of two and a board member of a Louisville synagogue, said, “The Torah teaches us that the fetus does not have the same personhood status as the mother until its first breath.”Ms. Baron, who belongs to Judaism’s conservative denomination, said her age and previous fertility struggles raised risks of pregnancy complications or fetal abnormalities.Under Kentucky’s ban, she said, “I would be unable to make that extremely difficult decision of whether to continue carrying a fetus if the pregnancy is causing severe physical or psychological harm to me or the fetus is nonviable.”“It’s not only cruel,” she said, “but it represents a situation where Jewish law may require the pregnancy to be terminated.”Within Judaism, there are differing views, with some Orthodox Jews supporting only very limited circumstances for abortion. But Mr. Kemper, the Kentucky plaintiffs’ lawyer, said rabbis from every large Kentucky synagogue have supported the lawsuit.Sarah Baron, a Kentucky plaintiff, is a mother of two and a board member of a Louisville synagogue. “The Torah teaches us that the fetus does not have the same personhood status as the mother until its first breath,” she said.Andrew Cenci for The New York TimesThe lawsuits by members of widely known faiths follow a trail blazed by a less conventional religion, the Satanic Temple, which began filing abortion-related lawsuits after the Supreme Court’s 2014 Hobby Lobby decision exempting family-owned corporations from the Affordable Care Act’s mandate that insurance cover contraceptives. The temple, which is recognized by the I.R.S. as a religion and lists 46 American congregations, has lawsuits pending in Idaho, Texas and Indiana, and it recently started the first telemedicine abortion service operated by a religion, with a goal of using it to challenge abortion restrictions.A nontheistic religion that construes Satan not as a New Testament evildoer but as the English literary character who battles oppression, the Satanic Temple often employs a strategy of flamboyant provocation, said Joseph Laycock, a religion scholar at Texas State University and the author of a book about the temple. Its antics make some abortion rights supporters worry that it will stoke anti-abortion sentiment. But some courts have taken its religious freedom claims on various issues seriously, including in a recent preliminary ruling ordering a school district in Hellertown, Pa., to allow its After School Satan Club to meet.Marci Hamilton, a religious freedom expert at the University of Pennsylvania who represents clergy in abortion rights lawsuits in Florida, called the temple’s lawsuits “extremely helpful.”“They are saying, OK, courts, if you’re going to favor the religious right, we’re going to show you a faith whose rights are being violated,” she added.The temple created an abortion ritual, a recitation of tenets about individual control over one’s body and the importance of making decisions based on science. Its general counsel, Matthew Kezhaya, said the ritual strengthens legal claims by linking “abortion and the religion itself” and establishing a practice “interfered with by these particular laws.”The temple’s telemedicine service is currently available in New Mexico, where abortion is legal, but it plans to expand to states with bans and religious freedom laws, temple officials said. It has an intentionally inflammatory name, Samuel Alito’s Mom’s Satanic Abortion Clinic (after the Supreme Court justice who wrote the opinion overturning Roe), but it follows standard medical procedures, employs experienced reproductive health nurses and is listed by a national clearinghouse of legitimate medication abortion services.Mikayla, guided over Zoom by a Satanic Temple minister, participated in the abortion ritual, reciting tenets about autonomy over her body and the importance of science.Adria Malcolm for The New York TimesOne patient, Mikayla, 28, who asked to be identified by her first name to protect her privacy, drove from Texas to an Albuquerque airport hotel to use the service , and allowed The New York Times to observe. During video medical consultations, a nurse practitioner and patient care coordinator discussed effects like cramping and bleeding and urged her to call their 24-hour nurse hotline with questions or concerns.After she received the medication, the process took a different turn. Via Zoom, a minister prompted Mikayla to look in a mirror to reflect on self-empowerment and recite: “One’s body is inviolable, subject to one’s own will alone.” After swallowing the first pill in the two-drug regimen, Mikayla recited a tenet about prioritizing science. The minister advised that after the pregnancy tissue was eventually expelled, Mikayla could recite: “By my body, my blood. By my will, it is done.”Legal experts said some religious freedom lawsuits seeking abortion rights might succeed, given recent Supreme Court decisions that “supported religious exemptions even in cases where there are really strong health and safety issues,” said Elizabeth Reiner Platt, director of the Law, Rights and Religion Project at Columbia University. Arguments for exemptions might also be persuasive because most abortion bans have some exceptions, like rape, experts said.“These should be very strong, compelling cases, but I also acknowledge that this is a highly political issue,” Ms. Platt said.Josh Blackman, a professor at South Texas College of Law Houston who has criticized the lawsuits, questioned the plaintiffs’ legal standing, saying, “A lot of these women are sort of making prospective claims that, One day, I might be pregnant, and one day, I might have this problem and that might require me to have an abortion.”He said some plaintiffs could have religiously sincere “extenuating individual circumstances,” but that allowing widespread exemptions could undermine the law’s larger purpose.Whichever way courts rule could be groundbreaking.“We’re in a completely new landscape,” Ms. Platt said.Adria Malcolm

“It’s Never Too Late” is a series that tells the stories of people who decide to pursue their dreams on their own terms.Joanna Patchett has always had a fear of death, and the dying.“I was terrified of being responsible for people’s lives, and was frightened of the space between life and death,” she said.And yet in July 2020, as coronavirus cases filled up hospitals, Ms. Patchett, who was fresh out of nursing school, found herself caring for extremely ill Covid patients in the intensive care unit at Binghamton General Hospital in upstate New York.“Seeing how sick everyone was — was heartbreaking. It was a life-changing and extremely difficult experience,” said Ms. Patchett, a 39-year-old Binghamton resident. “I didn’t expect to see so many people dying in quick succession, or to be on a floor full of ventilated patients, or intubating people so frequently, or being their primary person to have contact with them when the rest of the world could not.”As the pandemic worsened, Ms. Patchett said, there were many nights where she returned to her empty apartment and cried. Books pictured on her coffee table include “Being Mortal” by Atul Gawande.Lauren Petracca for The New York TimesMs. Patchett had dreamed of becoming an actress, but didn’t have much luck at the profession. In 2019, when she was 35, she went back to school, having been accepted into a one-year accelerated nursing program. Most of her classmates came to nursing straight out of college, and many fondly called her Mom. As the pandemic worsened, she was deeply moved by “how people would open up and be so vulnerable with us.”“You could see the humanity, how worthy everyone is of life, and how hard the body fights to live,” she said.Ms. Patchett never imagined her life would turn out this way. After getting a bachelor’s degree in English and drama from Ithaca College, she spent a decade feeling “lost and depressed,” bouncing from one job to another — teaching English and yoga, working in a dental office. She felt behind in life because she didn’t know what she wanted to do. “I knew I had something to give, but didn’t know what that was,” she said.“I was jealous of people who challenged themselves,” Ms. Patchett said. “I never had. If I was going to grow and find myself, I needed to try something scary. I had to take a risk and challenge myself.”It was her mother who cajoled her into nursing, sensing she’d be good in the field, even though Ms. Patchett disagreed. “I didn’t think I was equipped for that experience, or that I could handle it spiritually and emotionally.”As the stress of caring for Covid patients took a mental toll, Ms. Patchett adopted a rescue cat, Tanky. “I wanted something to love,” she said. “Tanky really helped me through Covid.”Lauren Petracca for The New York TimesBut over the past several years, that’s exactly where she found herself, despite the 12-hour shifts, the daily emergencies and the often harrowing emotional work. For Ms. Patchett, who lives alone, it was especially difficult to return to an empty apartment. Though her family lived only five miles away, she couldn’t see her relatives often because of the high risk of contracting the coronavirus, and there was nothing alive and vibrant to come home to. Many nights she returned from work and cried. As the intense stress of being an I.C.U. nurse took a mental toll on her, she adopted a cat, Tanky. “I wanted something to love,” she said. “Tanky really helped me through Covid. He is 15 pounds of furball love and emotional healing.”“To lose patients I’d become close to and have them die in such a devastating way made me question everything,” she said. “But I began to see this work as my duty. It was a war. I wasn’t going to let them die alone.”The following interview has been edited and condensed.Since, on your first nursing job, you unexpectedly found yourself assigned to the I.C.U. floor and caring for Covid patients, did you ever regret your decision to become a nurse?No. I never regretted this work or being here, even though it was terrifying. If anything, I found my calling. I wasn’t afraid to be the person watching someone die, or being with them when they were. I was good at being present as they passed, and I could work under a tremendous amount of stress.How did you find the strength to face your fears?I didn’t have a choice. You can’t run away from this kind of work. I found my ability to be challenged and then I found the strength to stay. I didn’t have the luxury of leaving sick people, nor did I want to. Someone had to be there. I knew it had to be me.Once you were accepted into a nursing program, you realized you were one of the oldest people attending. What was that like?I felt out of place. Most everyone was 20, 25-year-olds, pursuing nursing shortly after getting their first degree. They were bubbly. I didn’t feel part of that excited buzz. But Gen Z is a welcoming group. They didn’t have the judgment that was inside of me. Once we broke into clinical groups, we became very tight and depended on each other. We shared a lot of intense moments that gave me strength because we supported one another.How did it feel to have the younger students call you Mom?It was endearing. I watched out for them and made sure everybody was OK. I would bring food in case somebody hadn’t eaten. I became the person they turned to if they were going through a hard moment. I had experience from being older, something no one else had. And they made me feel I mattered; that made me feel special. I learned from them, too.After fighting to save Covid patients, Ms. Patchett switched to palliative care. “I wanted to help people control their death, rather than watch people die flailing and gasping,” she said.Lauren Petracca for The New York TimesWhat has being a nurse taught you?I’ve never had a job that was so meaningful or made me feel I was serving a purpose. Facing death helped me realize you can’t give up. Through nursing, I’ve learned life is going to be incredibly hard, and it’s going to hurt, but you have to make the choice to keep fighting — that’s part of living. I learned I matter, and I matter to people who are dying and who want me by their side as they are doing it.After 18 months of fighting to save Covid patients, you decided to switch to palliative care. Why?I burned out. I realized I had to move to another part of nursing. On the I.C.U. floor, I’d received a tutelage in death. I wanted to help people control their death, rather than watch people die flailing and gasping. When we seemed out of the woods for Covid, I started helping the elderly and those with terminal illnesses decide how they wanted to die. I’m now a hospice nurse case manager at Lourdes Hospice, an outpatient home end-of-life care provider, in Vestal, N.Y., where I interact with 20 to 30 families a week. And I’m part of deeper discussions that deal with the dignity of dying.What have you learned about yourself as you’ve learned to care for others?I have a voice that carries wisdom. I have a special ability to listen and to see people while being present with them in those very hard moments.What’s the best piece of advice you can offer?When it comes to changing your life, you sometimes have to decide to change. Once you do, almost anything is possible. Everything you do contributes to who you are now. Ironically, my yoga, acting and teaching training gave me the ability to stay grounded, present and in the moment. Not one part of your journey, even if you’re not sure what you’re doing, or where it’s going to lead you, is ever wasted. You’re never late; you’ve simply not arrived yet.

Published1 hour agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesBy Kelly Ng & Yuna Kuin Singapore and SeoulSouth Koreans have become a year or two younger as a new law aligns the nation’s two traditional age-counting methods with international standards.The law scraps one traditional system that deemed South Koreans one year old at birth, counting time in the womb.Another counted everyone as ageing by a year every first day of January instead of on their birthdays.The switch to age-counting based on birth date took effect on Wednesday.President Yoon Suk Yeol pushed strongly for the change when he ran for office last year. The traditional age-counting methods created “unnecessary social and economic costs”, he said.For instance, disputes have arisen over insurance pay-outs and determining eligibility for government assistance programmes.Previously, the most widely used calculation method in Korea was the centuries-old “Korean age” system, in which a person turns one at birth and gains a year on 1 January. This means a baby born on 31 December will be two years old the next day.A separate “counting age” system, that was also traditionally used in the country, considers a person zero at birth and adds a year on 1 January. This means that, for example, as of 28 June 2023, a person born on 29 June 2003 is 19 under the international system, 20 under the “counting age” system and 21 under the “Korean age” system.Lawmakers voted to scrap the traditional counting methods last December.Despite the move, many existing statutes that count a person’s age based on the “counting age” calendar year system will remain. For example, South Koreans can buy cigarettes and alcohol from the year – not the day – they turn 19.Three in four South Koreans were also in favour of the standardisation, according to a poll by local firm Hankook Research in January 2022.Some, like Jeongsuk Woo, hope the change will help break down Korea’s hierarchical culture. “There is a subconscious layer of ageism in people’s behaviour. This is evident even in the complex language system based on age… I hope the abolition of ‘Korean age’ system and the adaptation of the international standard get rid of old relics of the past,” said the 28-year-old content creator.Another resident Hyun Jeong Byun said: “I love it, because now I’m two years younger. My birthday is in December, so I always felt like this Korean age system is making me socially older than what I actually am. “Now that Korea is following the global standard, I no longer have to explain my ‘Korean age’ when I go abroad.”The 31-year-old doctor said South Korea’s medical sector has already been adopting the international age system.The traditional age-counting methods were also used by other East Asian countries, but most have dropped it. Japan adopted the international standard in 1950 while North Korea followed suit in the 1980s.More on this storySouth Koreans get younger as age system scrappedPublished8 December 2022Why Koreans could soon become a year youngerPublished20 April 2022

Major depressive disorder (MDD) is not only among the most common mental illnesses, affecting over 8% of Americans, but it is also extremely variable from one person to another. Researchers have recently begun making strides toward understanding the neurophysiology underlying different subtypes of depression, which could speed development of better treatments, but much remains to be discovered. Now, a new study in Biological Psychiatry, published by Elsevier, identifies multiple subtypes of MDD using brain imaging.
John Krystal, MD, Editor of Biological Psychiatry, said of the work, “We have long known that disorders like major depressive disorder are highly heterogeneous. This study in a large sample of depressed patients provides leads that can be pursued in subtyping depression on the basis of functional magnetic resonance imaging (fMRI) tests that measure the degree of coordination across brain regions, also known as ‘functional connectivity.'”
The researchers used resting-state fMRI collected at multiple clinical sites from a large cohort of more than 1,000 MDD patients and over 1,000 healthy controls (HC). The study used the so-called normative model, which uses data from a large reference population to quantify individual deviations, much like the growth charts used by pediatricians. The researchers examined the functional connectivity among brain regions and mapped individual functional deviations in the MDD patients compared to this normative prediction across the lifespan.
Senior author Mingrui Xia, PhD, from Beijing Normal University, said, “This approach led to the identification of two reproducible neurophysiological subtypes exhibiting distinct deviation patterns, depressive item scores, and longitudinal treatment predictability.”
One subtype of patients showed severe positive deviations — indicating increased brain connectivity — in the default mode network, limbic, and subcortical areas, and negative deviations in the sensorimotor and attention areas. The second subtype of patients featured a milder and opposite pattern of deviation, highlighting the heterogeneity of depression at the neurophysiological level. The authors speculate that the altered activity could be related to the tendency to ruminate in people with MDD.
The work is particularly exciting in that it moves the field toward finding biomarkers, or biological markers, of depression, which currently relies on patient-reported clinical symptoms for diagnosis, treatment, and prognostics. Biomarkers could offer a way to improve all these aspects of treatment for MDD.
Dr. Xia went on to say, “These findings shed light on the diverse neurobiological mechanisms from a connectomics perspective underlying the complex clinical heterogeneity observed in individuals with depression. The implications of this research are far-reaching, providing valuable insights into the development of imaging-based candidate biomarkers. These biomarkers have the potential to guide future precise diagnostic and treatment strategies tailored to each patient’s specific neurophysiological subtype.”
Dr. Xia noted, “By embracing the concept of neurophysiological subtypes, we can potentially revolutionize the field of mental health by enabling clinicians to personalize treatments based on an individual’s unique connectome characteristics. This approach opens up new avenues for precision medicine and holds the promise of improving therapeutic interventions for depression.”

Diabetes is a progressive disease that affects one’s ability to control blood sugar levels. For many patients, the condition becomes more severe over time and blood sugar levels grow more difficult to manage. Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, have granted patients more control in lowering of blood sugar.
John Buse, MD, PhD, the Verne S. Caviness Distinguished Professor of Medicine in the Division of Endocrinology and Metabolism, and an international team of researchers have presented new findings about new higher-dose formulations of oral semaglutide. Their study, which was published in The Lancet, found that once-daily oral semaglutide taken at 25 milligrams (mg) and 50 mg did a better job in lowering blood sugar levels and promoting weight loss than the lowest dose of 14 mg.
“Low doses of GLP-1 receptor agonists are really powerful for reducing A1C, or the average glucose in the blood,” said Buse, who is also co-director of the NC Translational and Clinical Sciences Institute. “Whereas, the higher doses that are really good for weight reduction. On average, patients lost eight kilograms (17.5 lbs) at 50 milligrams, which is nearly twice as much weight loss that we saw with the lowest dose.”
The new study is in line with other studies, which are pushing for the use of oral GLP-1 receptor agonists as a treatment for obesity.
In total, 1,606 participants, who were on average male and of 58.2 years of age, participated in the phase three program for regulatory approval. The participants were randomized into three groups and were asked to take oral semaglutide once a day. Each group took a different dosage of semaglutide, either a 14 mg dosage, a 25 mg dosage, or a 50 mg dosage, for 52 weeks.
Blood sugar levels are measured through a percentage, called A1C. According to the American Diabetes Association, most adults with diabetes need to have an A1C that is less than 7% to be considered healthy. All of the participants in the trial had an A1C between 8.0% and 10.5%. Researchers found that those who received the 25 mg and 50 mg doses of oral semaglutide were more likely to reach the A1C target of

While mitochondria play a crucial role in producing the energy our cells need to carry out their various functions, when damaged, they can have profound effects on cellular function and contribute to the development of various diseases.
Broken-down mitochondria are usually removed and recycled through a garbage disposal process known as ‘mitophagy’.
PINK1 and Parkin are two proteins vital to this process, responsible for ‘tagging’ malfunctioning mitochondria for destruction. In Parkinson’s disease, mutations in these proteins can result in the accumulation of damaged mitochondria in the brain, which can lead to motor symptoms such as tremors, stiffness and difficulty with movement.
The new research, published in Molecular Cell, solves a mystery about how the protein Optineurin recognises unhealthy mitochondria ‘tagged’ by PINK1 and Parkin, enabling their delivery to our body’s garbage disposal system.
Associate Professor Michael Lazarou, a Laboratory Head in WEHI’s Ubiquitin Signalling Division, said the discovery filled a vital knowledge gap that would transform our understanding of this cellular pathway.
“Until this study, Optineurin’s precise role in initiating our body’s garbage disposal process was unknown,” Assoc Prof Lazarou, who also holds a co-appointment with Monash University, said.

“While there are many proteins that link damaged cellular materials to the garbage disposal machinery, we found that Optineurin does this in a highly unconventional way that is unlike anything else we’ve seen from similar proteins.
“This finding is significant because the human brain relies on Optineurin to degrade its mitochondria through the garbage disposal system driven by PINK1 and Parkin. “Knowing how Optineurin does this provides us with a framework on how we might be able to target PINK1 and Parkin mitophagy in disease and prevent the build-up of damaged mitochondria in neurons as we age.
“Achieving this would be instrumental to people with Parkinson’s disease — a condition that continues to impact more than 10 million people worldwide, including 80,000 Australians.”
Outlier discovery
PINK1 acts as a ‘watch-house’ inside the mitochondria, responsible for monitoring their health. When it detects problems, it activates Parkin, which tags damaged mitochondria for removal.

They work together to instruct our body to generate cellular ‘garbage bags’ around broken-down mitochondria and enlist the help of Optineurin to initiate this process.
The new study revealed that Optineurin removes damaged mitochondria by binding to an enzyme known as TBK1. From there, they found that TBK1 goes on to activate a specific cellular machine that is key to generating these garbage bags around unhealthy mitochondria.
First author Dr Thanh Nguyen said: “Other proteins don’t need TBK1 to help them trigger this degradation process, making Optineurin a real outlier when it comes to how our bodies remove mitochondria.
“This has allowed us to look at the features of this pathway involving TBK1 as a potential drug target, which is a significant step forward in our search for new Parkinson’s disease treatments.
“The ultimate goal would be to find a way to boost levels of PINK1/Parkin mitophagy in the body — especially the brain — so that damaged mitochondria can be removed more effectively.
“We also hope to design a molecule that could mimic what Optineurin does, so damaged mitochondria could be removed even without PINK1 or Parkin.”
“Given Optineurin is critical in activating the garbage disposal system in our brains, this could then prevent the accumulation of damaged mitochondria in this region, which is a significant precursor to Parkinson’s disease.”
Dr Nguyen said while clinical application of the research is years away, the discovery had laid the essential foundation needed to understand how Optineurin works and realise the pathway’s potential as a future therapeutic target.
“Our next step is to work with WEHI’s Parkinson’s Disease Centre to validate our findings in neuronal model systems to understand why Optineurin behaves this way, which will provide further insight into how we can target Optineurin and TBK1 to enhance treatment options for people with PINK1/Parkin mutations in the future.”
The research involves a collaboration with Professor Sascha Martens’ lab at the Max Perutz Labs, University of Vienna and was supported by the National Health and Medical Research Council (NHMRC), the Australian Research Council (ARC), the Human Frontiers Science Program and Aligning Science Across Parkinson’s (ASAP) through the Michael J. Fox Foundation for Parkinson’s Research (MJFF).

Taking higher-than-recommended doses of vitamin D for five years reduced the risk of atrial fibrillation in older men and women, according to a new study from the University of Eastern Finland.
Atrial fibrillation is the most common arrhythmia, the risk of which increases with age, and which is associated with an increased risk of stroke, heart failure and mortality. Vitamin D has been shown to have an effect, for example, on the atrial structure and the electrical function of the heart, suggesting that vitamin D might prevent atrial fibrillation.
Conducted at the University of Eastern Finland in 2012-2018, the main objective of the Finnish Vitamin D Trial, FIND, was to explore the associations of vitamin D supplementation with the incidence of cardiovascular diseases and cancers. The five-year study involved 2,495 participants, 60-year-old or older men and 65-year-old or older women, who were randomised into three groups: one placebo group and two vitamin D3 supplementation groups, with one of the groups taking a supplement of 40 micrograms (1600 IU) per day, and the other a supplement of 80 micrograms (3200 IU) per day. All participants were also allowed to take their personal vitamin D supplement, up to 20 micrograms (800 IU) per day, which at the beginning of the study was the recommended dose for this age group. At baseline, study participants had not been diagnosed with cardiovascular disease or cancer, and they completed comprehensive questionnaires, both at the beginning and throughout the study, on their lifestyles and nutrition, as well as on risk factors of diseases and disease occurrence. Data on the occurrence of diseases and deaths were also obtained from Finnish nationwide health registers. Approximately 20 % of participants were randomly selected for more detailed examinations and blood samples.
During the five-year study, 190 participants were diagnosed with atrial fibrillation: 76 in the placebo group, 59 in the 40 micrograms group, and 55 in the 80 micrograms group. The risk of atrial fibrillation was 27% lower in the 40 micrograms group, and 32% lower in the 80 micrograms group, when compared to the placebo group. In the sub-cohort selected for more detailed examinations, the mean baseline serum calcidiol concentration, which is a marker of the body’s vitamin D concentration, was relatively high, 75 nmol/l. After one year, the mean calcidiol concentration was 100 nmol/l in the 40 micrograms group, and 120 nmol/l in the 80 micrograms group. No significant change in the calcidiol concentration was observed in the placebo group.
FIND is the first randomized controlled trial to observe that vitamin D supplementation reduces the risk of atrial fibrillation in generally healthy men and women. Previous research is limited to only two randomized trials, which did not observe an effect when using doses of 10 micrograms (400 IU) or 50 micrograms (2000 IU) per day. Further confirmation of the present results from the FIND study is therefore needed before doses of vitamin D that significantly exceed current recommendations can be recommended for preventing atrial fibrillation. The FIND study has previously published findings showing no association with the incidence of other cardiovascular events or cancers.
The FIND study was supported by funding from the Research Council of Finland, University of Eastern Finland, Juho Vainio Foundation, Finnish Foundation for Cardiovascular Research, Finnish Diabetes Research Foundation, and Finnish Cultural Foundation, and Medicinska Understödsföreningen Liv och Hälsa.