Researchers have discovered that you can wake up each morning without feeling sluggish by paying attention to three key factors: sleep, exercise, and breakfast.
Do you feel groggy until you’ve had your morning joe? Do you battle sleepiness throughout the workday?
You’re not alone. Many people struggle with morning alertness, but the new study demonstrates that awaking refreshed each day is not just something a lucky few are born with.
From car crashes to work-related accidents, the cost of sleepiness is deadly.
The findings come from a detailed analysis of the behavior of 833 people who, over a two-week period, were given a variety of breakfast meals; wore wristwatches to record their physical activity and sleep quantity, quality, timing, and regularity; kept diaries of their food intake; and recorded their alertness levels from the moment they woke up and throughout the day.
The researchers included twins—identical and fraternal—in the study to disentangle the influence of genes from environment and behavior.
The researchers found that the secret to alertness is a three-part prescription requiring substantial exercise the previous day, sleeping longer and later into the morning, and eating a breakfast high in complex carbohydrates, with limited sugar.
The researchers also discovered that a healthy controlled blood glucose response after eating breakfast is key to waking up more effectively.
“All of these have a unique and independent effect,” says Raphael Vallat a postdoctoral fellow at the University of California, Berkeley and first author of the study. “If you sleep longer or later, you’re going to see an increase in your alertness. If you do more physical activity on the day before, you’re going to see an increase. You can see improvements with each and every one of these factors.”
Morning grogginess is more than just an annoyance. It has major societal consequences: Many auto accidents, job injuries, and large-scale disasters are caused by people who cannot shake off sleepiness. The Exxon Valdez oil spill in Alaska, the Three Mile Island nuclear meltdown in Pennsylvania, and an even worse nuclear accident in Chernobyl, Ukraine, are well-known examples.
“Many of us think that morning sleepiness is a benign annoyance. However, it costs developed nations billions of dollars every year through loss of productivity, increased health care utilization, work absenteeism. More impactful, however, is that it costs lives—it is deadly,” says senior author Matthew Walker, professor of neuroscience and psychology and author of Why We Sleep (Simon & Schuster, 2018).
“From car crashes to work-related accidents, the cost of sleepiness is deadly. As scientists, we must understand how to help society wake up better and help reduce the mortal cost to society’s current struggle to wake up effectively each day.”
Walker and Vallat teamed up with researchers in the United Kingdom, the US, and Sweden to analyze data acquired by a UK company, Zoe Ltd., that has followed hundreds of people for two-week periods in order to learn how to predict individualized metabolic responses to foods based on a person’s biological characteristics, lifestyle factors, and the foods’ nutritional composition.
The researchers gave participants preprepared meals, with different proportions of nutrients incorporated into muffins, for the entire two weeks to see how they responded to different diets upon waking. A standardized breakfast, with moderate amounts of fat and carbohydrates, was compared to a high protein (muffins plus a milkshake), high carbohydrate, or high sugar (glucose drink) breakfast. The subjects also wore continuous glucose monitors to measure blood glucose levels throughout the day.
…there are still some basic, modifiable, yet powerful ingredients to the awakening equation that people can focus on…
The worst type of breakfast, on average, contained high amounts of simple sugar; it was associated with an inability to wake up effectively and maintain alertness. When given this sugar-infused breakfast, participants struggled with sleepiness.
In contrast, the high carbohydrate breakfast—which contained large amounts of carbohydrates, as opposed to simple sugar, and only a modest amount of protein—was linked to individuals revving up their alertness quickly in the morning and sustaining that alert state.
“A breakfast rich in carbohydrates can increase alertness, so long as your body is healthy and capable of efficiently disposing of the glucose from that meal, preventing a sustained spike in blood sugar that otherwise blunts your brain’s alertness,” Vallat says
“We have known for some time that a diet high in sugar is harmful to sleep, not to mention being toxic for the cells in your brain and body,” Walker adds. “However, what we have discovered is that, beyond these harmful effects on sleep, consuming high amounts of sugar in your breakfast, and having a spike in blood sugar following any type of breakfast meal, markedly blunts your brain’s ability to return to waking consciousness following sleep.”
It wasn’t all about food, however. Sleep mattered significantly. In particular, Vallat and Walker discovered that sleeping longer than you usually do, and/or sleeping later than usual, resulted in individuals ramping up their alertness very quickly after awakening from sleep.
According to Walker, between seven and nine hours of sleep is ideal for ridding the body of “sleep inertia,” the inability to transition effectively to a state of functional cognitive alertness upon awakening. Most people need this amount of sleep to remove a chemical called adenosine that accumulates in the body throughout the day and brings on sleepiness in the evening, something known as sleep pressure.
“Considering that the majority of individuals in society are not getting enough sleep during the week, sleeping longer on a given day can help clear some of the adenosine sleepiness debt they are carrying,” Walker speculates.
“In addition, sleeping later can help with alertness for a second reason,” he says. “When you wake up later, you are rising at a higher point on the upswing of your 24-hour circadian rhythm, which ramps up throughout the morning and boosts alertness.”
It’s unclear, however, what physical activity does to improve alertness the following day.
“It is well known that physical activity, in general, improves your alertness and also your mood level, and we did find a high correlation in this study between participants’ mood and their alertness levels,” Vallat says. “Participants that, on average, are happier also feel more alert.”
But Vallat also notes that exercise is generally associated with better sleep and a happier mood.
“It may be that exercise-induced better sleep is part of the reason exercise the day before, by helping sleep that night, leads to superior alertness throughout the next day,” Vallat says.
Walker notes that the restoration of consciousness from non-consciousness—from sleep to wake—is unlikely to be a simple biological process.
“If you pause to think, it is a non-trivial accomplishment to go from being nonconscious, recumbent, and immobile to being a thoughtful, conscious, attentive, and productive human being, active, awake, and mobile. It’s unlikely that such a radical, fundamental change is simply going to be explained by tweaking one single thing,” he says. “However, we have discovered that there are still some basic, modifiable, yet powerful ingredients to the awakening equation that people can focus on—a relatively simple prescription for how best to wake up each day.”
Comparisons of data between pairs of identical and non-identical twins showed that genetics plays only a minor and insignificant role in next-day alertness, explaining only about 25% of the differences across individuals.
“We know there are people who always seem to be bright-eyed and bushy-tailed when they first wake up,” Walker says. “But if you’re not like that, you tend to think, ‘Well, I guess it’s just my genetic fate that I’m slow to wake up. There’s really nothing I can do about it, short of using the stimulant chemical caffeine, which can harm sleep.
“But our new findings offer a different and more optimistic message. How you wake up each day is very much under your own control, based on how you structure your life and your sleep. You don’t need to feel resigned to any fate, throwing your hands up in disappointment because, ‘…it’s my genes, and I can’t change my genes.’ There are some very basic and achievable things you can start doing today, and tonight, to change how you awake each morning, feeling alert and free of that grogginess.”
Walker, Vallat, and their colleagues continue their collaboration with the Zoe team, examining novel scientific questions about how sleep, diet, and physical exercise change people’s brain and body health, steering them away from disease and sickness.
Surprising treatment breakthroughs in recent years
There have been surprising breakthroughs in the treatment of leukemia in recent years. (Shutterstock)
Leukemia is a term that scares many people. It is commonly known as blood cancer and is a malignant disease involving the blood system. But is leukemia truly incurable and fatal? How has leukemia’s treatment method and its effectiveness progressed in recent years?
The Epoch Times interviewed Michael Andreeff, a professor of medicine in the Department of Leukemia, Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center in Houston, Texas, regarding the above questions. This article is written and organized based on the content of the interview.
Leukemia can be divided into two groups, chronic and acute, and it can be further divided into lymphocytic leukemia and myelogenous leukemia according to its cell of origin.
Therefore, in general, there are four main types of leukemia: chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and acute myelogenous leukemia (AML).
The causes and gene mutations of these four types of leukemia are all different—they are not related to one another and have great differences, and their treatment and prognosis are also completely different.
The symptoms of leukemia are not distinct. Patients may feel tired or bleed for no apparent reason. It may not be discovered until a doctor checks the blood counts and finds that they are not normal.
A blood count measures the number of three types of cells in the blood: red blood cells (which contain hemoglobin) that carry oxygen, white blood cells that protect against infection, and platelets that stop bleeding.
Leukemia patients may have at least three or four abnormalities in their blood count.
For example, their hemoglobin levels may be low, which can cause the patients to feel tired because there is not enough oxygen in the blood.
Their white blood cell count may also be too low or too high. Low white blood cell counts indicate that patients do not have enough cells to fight infection and are prone to fevers, which require prompt treatment and can be fatal. On the other hand, an influx of abnormal leukemia cells produced by the bone marrow and released into the blood can cause a high white blood cell count.
The platelet count may also be low. Some patients have very low platelet levels, leading to spontaneous bleeding without trauma.
Blood count results alone are not enough to diagnose leukemia; a bone marrow test is also needed. Bone marrow tests can only determine the type of leukemia, but special tests (such as ones that look for mutated genes and abnormal chromosomes, immunophenotyping, etcetera) can also be performed. These special tests are conducted because there are many immunotherapies and gene-targeted therapies for leukemia.
Because we know so little about its causes, there is currently no feasible or complete way to prevent it, but we do know some of the risk factors that may lead to leukemia.
These days, most cancer patients are treated with chemotherapy. A study found that patients who received chemotherapy for other cancers had a higher chance of developing leukemia in the future, and this is related to Clonal Hematopoiesis of Indeterminate Significance, or CHIP cells.
As people age, a small number of cells in the blood begin to turn abnormal and develop genetic mutations, but these cells are not abnormal enough to cause leukemia or other cancers. These are called CHIP cells.
In such context, chemotherapy treatments for breast, ovarian, lung, and other cancers may transform CHIP cells into a preleukemic state, which may develop into leukemia in the future.
For instance, myelodysplastic syndrome (MDS) is a precursor to acute myelogenous leukemia (AML), and MDS is often seen in patients receiving chemotherapy for solid tumors.
As it seems patients who received chemotherapy for other cancers also have an increased risk of developing leukemia in the future, the current research trend is to replace chemotherapy with other methods, such as immunotherapy.
Exposure to benzene has also been linked to acute myelogenous leukemia. Found in solvents used to wash and degrease machine parts, as well as in some glues used to treat such parts, benzene has been associated with a risk of leukemia.
Radiation can also cause leukemia. Eight years after the atomic bombing of Hiroshima, the number of confirmed cases of chronic myelogenous leukemia in the Hiroshima area reached its peak. It can be inferred that radiation-induced leukemia may take eight years or even longer to develop.
X-rays and radiation used for medical diagnosis can also be a problem. Hence, while CT scans are useful, they should only be done when necessary.
Additionally, certain lawn fertilizers have been linked to the development of chronic lymphocytic leukemia or lymphoma.
Among the four types of leukemia mentioned above, chronic myelogenous leukemia (CML) has made the most progress and has the best treatment effectiveness.
Chromosomal abnormalities have long been noted in the leukemia cells of most CML patients. Such abnormalities were first discovered in Philadelphia, Pennsylvania, hence the name the “Philadelphia chromosome.”
It was not until 1982 that the gene mutation caused by the Philadelphia chromosome was discovered, and the mutation was confirmed to be a single-gene mutation. The first-generation drug targeting the abnormal gene was introduced in 2001 after extensive scientific research and clinical trials, and it instantly changed the three-and-a-half-year average life expectancy of CML patients at the time.
Since then, the survival rate of CML patients has greatly increased, and today, the treatment success rate of the targeted therapy is almost 100 percent, which is simply a dream result.
Gene mutations caused by the Philadelphia chromosome also exist in the leukemia cells of some ALL patients. The treatment success rate of such patients after receiving the targeted therapy is also very high.
Another type of leukemia with a long survival period is chronic lymphocytic leukemia (CLL), which is mainly seen in the elderly, with the average age of patients being 70 years old. It is more common in Western countries and less common in Asian countries.
Symptoms of CLL include swollen lymph nodes in the neck, armpit, or groin, and an enlarged spleen. In addition, patients may have very high white blood cell counts. Doctors generally do not start treatment as long as the patient is in good condition.
However, the approach is changing, and more doctors are considering early intervention for CLL. This is because the longer the waiting period, the more chromosomal and other molecular abnormalities become present in the patient’s leukemia cells.
Currently, CLL can be treated with methods like chemotherapy and gene-targeted therapy. Chemotherapy has significantly improved the survival rate of patients, while gene-targeted therapy is effective for almost all CLL patients.
It takes a longer observation period to determine whether a patient is completely cured, as CLL is inherently a slow-evolving chronic disease.
Doctors tend to be conservative and will not claim that a patient is completely cured. However, CLL patients are expected to have a long life expectancy. Most CLL patients can stay in a leukemia-free remission state, and many of them will recover. Relapsed patients now have access to alternative medicines, which were not available 10 years ago.
There is an extremely critical and dangerous subtype of acute myelogenous leukemia (AML) called acute promyelocytic leukemia (APL).
In addition to abnormal white blood cells in the body, APL patients also have coagulation disorders. If left untreated, the patient usually bleeds to death within a few weeks, or even overnight.
As a result, the early mortality rate of APL patients was up to 30 percent, and the overall survival rate was only 30 percent. This type of leukemia is also the most difficult to treat.
Worse, these patients do not experience early warning symptoms, and they often say, “I’ve never been sick.” However, the leukemia had been developing in their body for years; it simply did not cause symptoms until later on.
Surprisingly, the drugs developed (pdf) to save the lives of APL patients are a form of the vitamin, all-trans retinoic acid (ATRA), and the highly toxic substance arsenic trioxide (commonly known as arsenic).
After clinical verification, all-trans retinoic acid and arsenic have become the standard drugs for treating APL all over the world, and they have indeed achieved the effect of stopping bleeding and saving patients’ lives.
The cure rate of APL has reached 80 to 90 percent worldwide, and the effectiveness of the disease’s treatment can only be described as miraculous.
APL only accounts for 15 percent of the total number of AML patients, and great progress has been made in the treatment of the remaining AML patients.
Different AML patients have mainly relied on two kinds of drug treatment for more than 50 years, and the cure rate is only about 20 to 25 percent. However, 10 new drugs have been approved by the FDA in the past three years, and the response rate of elderly AML patients to treatment has reached nearly 90 percent. Many patients are expected to be cured, though the exact results are still being observed.
The treatment of acute lymphocytic leukemia (ALL) still requires many sessions of chemotherapy, but it can be tolerated by children’s bodies and the cure rate is close to 90 percent, which is amazing.
Treatment outcomes in adults with ALL are significantly worse than in children, but high remission rates can still be achieved. Patients in remission usually remain in good health, and there is no trace of leukemia on microscopic or molecular testing.
In addition to chemotherapy, immunotherapy is an essential treatment method for ALL. One of the commonly used immune drugs is a monoclonal antibody that can be mass-produced. The antibody recognizes and binds to protein antigens on the cell surface, ultimately destroying the leukemia cells. Immunotherapy has significantly reduced the relapse and mortality rate of ALL patients.
Another emerging cancer treatment involves collecting a patient’s normal white blood cells, genetically modifying them, and then returning them to the patient. These cells, called CAR-T cells, kill leukemia cells.
This treatment method for ALL has been approved by the FDA. It has been clinically proven that CAR-T cell therapy is effective in about half of ALL patients who do not respond to any other treatment, which is a huge improvement.
Generally speaking, the cure rate of leukemia patients is increasing year by year, and a significant change in the survival curve can be seen every five years; some types of leukemia even reach a 90 percent cure rate. However, it is undeniable that the cure rate for some types of leukemia remains extremely low.
For example, a type of leukemia with a mutation in the P53 gene barely responds to any current treatments.
Even with drugs available, there is one big problem in leukemia treatment, and that is high drug prices. For example, a targeted drug for CML costs $100,000 per year in the United States.
It takes an average of 20 years and a huge amount of capital for a drug to go from development to animal testing, to three phases of clinical trials, and eventually to FDA approval. Most people cannot afford such expensive drugs. Some patients have no choice but to travel to other countries in search of cheap generic drugs.
However, it is possible to access free medicine in the United States.
During the clinical trial phase of a drug (which usually lasts several years), patients participating in the trial are given free medication, including other standard drugs used in combination.
Drug companies sometimes also provide free access to many drugs that have been approved by the FDA. While many patients can still obtain free drugs even if their insurance company does not cover their costs, this requires the cooperation of a professional team to fight for the patients’ access.
Many people think that participating in clinical trials and using new drugs that have not been approved by the FDA is tantamount to treating themselves as guinea pigs, but this is not the case.
“Patients will not die from the use of new drugs, only from cancer,” Andreeff said.
A lot of preliminary work is required before any new drug can enter large-scale clinical trials. A team of experts consisting of chemists, pharmaceutical chemists, and doctors works in the laboratory for years prior to a drug receiving approval. Every new clinical trial needs to be approved by the FDA before it can start, and there are many safeguards under the supervision of the FDA.
Furthermore, doctors recommend experimental new drugs only when they think patients will benefit from them.
Even if patients do not experience substantial therapeutic responses after participating in clinical trials, or the experimental new drug is not approved by the FDA in the end, participating in such clinical trials may prolong patients’ lives.
Statistics have shown that patients participating in clinical trials live longer than those receiving standard treatment elsewhere.
In specialized cancer centers with abundant information and resources, some cancer specialists have access to information about new drugs, and they already know the effectiveness of those drugs long before the FDA approves them. Even after new drugs are approved by the FDA, it may take a while before oncologists can start using them.
As a doctor who works at a large specialized cancer center, Andreeff believes that it is best for patients to start treatment at one of these cancer centers, or at least consult the specialists there for a second opinion, so as not to miss out on treatment options that may be right for them.
It is more appropriate to use BMI as the determinant for metabolic and bariatric surgery in treatment of type 2 diabetes.
The 1991 NIH consensus statement on metabolic and bariatric surgery was recently updated by the American Society for Metabolic and Bariatric Surgery (ASMBS) and the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO), reflecting our enhanced understanding that surgery is a safe and effective tool for treating obesity and adiposity-related comorbidities, and people will benefit from bariatric surgery at lower BMI than proposed in the older guidelines.
The American Diabetes Association’s 2022 Standards of Care in Diabetes: Obesity and Weight Management for the Treatment of Type 2 Diabetes proposes surgery for those with type 2 diabetes and BMI of at least 30 kg/m2 or at least 27.5 kg/m2 for Asian American patients. Several randomized controlled trials and many other studies demonstrate the benefits of surgery for diabetes prevention, treatment and possible remission. Beyond this, for those who undergo surgery, there are significant reductions in microvascular complications, cardiovascular events, cancer occurrence and mortality.
Factors that improve chances for remission of type 2 diabetes after surgery include shorter duration of type 2 diabetes, better glycemic control and not requiring insulin therapy. While there are data showing significant postsurgical improvements in glycemic control for those with uncontrolled type 2 diabetes, there is a much greater chance for remission of type 2 diabetes if surgery is performed earlier in the course of disease and with better glycemic control — arguing against using diabetes control as the primary determining factor for metabolic and bariatric surgery.
A postsurgical weight loss of 20% or higher appears to impart the greatest odds of achieving diabetes remission, and procedures that lead to greater weight loss are associated with greater improvements in glycemia and likelihood for diabetes remission. This tracks with what we know about the impact of excess and dysfunctional adiposity on insulin resistance and the pathogenesis of type 2 diabetes.
By performing metabolic and bariatric surgery earlier during type 2 diabetes, or even before insulin resistance and metabolic syndrome have become type 2 diabetes, our patients have greater chances of having adiposity-related complications of obesity into remission. This will, in turn, lead to improvements in morbidity, mortality and quality of life.
Jaime Almandoz, MD, MBA, FTOS, is medical director of the weight wellness program and associate professor of internal medicine in the division of endocrinology at University of Texas Southwestern Medical Center. He can be reached at jaime.almandoz@UTSouthwestern.edu.
Diabetes control is important, but it is not the endgame because diabetes does not come in isolation.
The way obesity affects patients and how it needs to be treated draws the closest analogy to cancer and cancer treatment. For example, patients who develop cancer don’t develop a disease that can be treated with one specialty — they need a multidisciplinary team. Depending on the stage of the cancer, they may need different treatments, and the more delays in treatment, the worse outcomes are. Obesity and diabetes are similar.
Obesity and type 2 diabetes are partners — a patient is diagnosed with one, is often diagnosed with the other, and if one improves then the other improves as well.
The longer a patient has diabetes and the more diabetes goes uncontrolled, the less chance that diabetes improves after bariatric or metabolic surgery. As early referral and treatment for cancer lead to better outcomes, the earlier referral of patients with type 2 diabetes and severe obesity to bariatric or metabolic surgery also yields better diabetes resolution. As patients with obesity gain more weight, their type 2 diabetes gets worse. When the patient has surgery to reduce their weight, the surgery has a metabolic effect before the person loses any weight.
Most patients will have severe obesity and type 2 diabetes together. Many patients also have high blood pressure, high cholesterol and sleep apnea. When we treat type 2 diabetes with specific medications, we are not addressing any of these other problems. With surgery, the improvement is not only to weight and quality of life, but also to diabetes, cardiovascular risk and cancer risk. In addition, today, metabolic and bariatric surgery is as safe as gallbladder surgery and hip replacement when done in appropriate centers of excellence.
Even for patients who are not diabetic and only have obesity, when they undergo metabolic and bariatric surgery, they are 80% less likely to develop diabetes 15 to 20 years later, which has been shown in the Swedish Obese Subjects study.
Diabetes control is important, but it’s not the only goal.
The FDA approved once-weekly semaglutide for the treatment of obesity among adolescents aged 12 to 17 years with an initial BMI in the 95th percentile for age and sex, according to a press release.
The FDA’s new indication for semaglutide (Wegovy, Novo Nordisk) comes a little more than 18 months after the medication was initially approved in June 2021 for chronic weight management in adults with obesity or with overweight plus one weight-related condition. As Healio previously reported, semaglutide was the first drug to be approved for chronic weight management for adults with obesity since 2014.
“The prevalence of teen obesity in the U.S. continues to rise, affecting teens and their families,” Aaron S. Kelly, PhD, co-director of the University of Minnesota Center for Pediatric Obesity Medicine, said in a press release. “Now, more than ever, we need new options to support teens. This FDA approval offers an additional tool to address this serious, chronic, progressive disease.”
As Healio previously reported, semaglutide conferred significant weight loss in a cohort of adolescents with obesity in the STEP TEENS phase 3a clinical trial. In the trial, 201 adolescents with obesity were randomly assigned to once-weekly semaglutide 2.4 mg plus lifestyle intervention (n = 134) or placebo (n = 67) for 68 weeks. At the end of the trial, the semaglutide group had a BMI reduction of 16.1% compared with a BMI increase of 0.6% in the placebo group. Additionally, 73% of adolescents in the semaglutide group lost 5% or more of their body weight compared with 18% of the placebo group.
The adverse events reported in STEP TEENS were similar to those previously reported among adults. The most common adverse events for adolescents were gastrointestinal disorders, reported by 62% of those in the semaglutide group. Adolescents using semaglutide had greater incidences of gallbladder problems, low blood pressure, rash and itching compared with adults using the medication.
Semaglutide is approved for use for adolescents with obesity in conjunction with a reduced calorie meal plan and increased physical activity. Novo Nordisk announced it planned to make all dose strengths of semaglutide available in the U.S. by the end of 2022, according to the press release.
The approval of once-weekly semaglutide for adolescents aged 12 years and older marks another milestone and a big step forward for the treatment of obesity in the pediatric population. Semaglutide has now become the third medication — along with liraglutide and combination phentermine/topiramate extended release — in the past 2 years that the FDA has approved for chronic weight management in this population. Having an option like semaglutide, which resulted in a mean 16.1% reduction in BMI in adolescents with obesity over 68 weeks in the STEP TEENS trial, should be extremely encouraging to providers who treat adolescents with obesity. Never before have we seen this kind of BMI reduction with a weight loss medication in adolescents.
Moreover, the trial also demonstrated an improvement in weight-related quality of life, which has not been seen in other weight-loss medication trials in this age group. While there remain questions about long-term safety in adolescents, there is no question that we will need more tools, like semaglutide, to mitigate the rising rates of pediatric obesity and its associated comorbidities. Let’s be sure we don’t take two steps back and instead work toward expanding access to semaglutide and other medication options for adolescents with obesity.
FDA approves once-weekly Wegovy injection for the treatment of obesity in teens aged 12 years and older. Available at: www.novonordisk-us.com/content/nncorp/us/en_us/media/news-archive/news-details.html?id=151389. Published Dec. 23, 2022. Accessed Jan. 9, 2023.
Daniel S. Hsia, MD
Associate Professor
Clinical Trials Unit
Pennington Biomedical Research Center
Louisiana State University
Disclosures: Hsia reports no relevant financial disclosures.
In December 2020, liraglutide was approved by the FDA for treatment of obesity in adolescents. Phentermine/topiramate extended-release capsules received similar FDA approval in June 2022. Both medications are significant advances compared to the previous options of orlistat and phentermine, with regard to efficacy and tolerability.
The FDA’s approval of once-weekly semaglutide for the treatment of adolescents with obesity will enable health care providers to have another treatment option available for our younger patient population. Just as importantly, this approval provides additional evidence that pharmacologic management of teen obesity is rigorously tested, safe and effective. The maturation of this field of medicine continues and is cause for optimism for patients, their families and their physicians.
Michael W. Lee, MD
Medical Director
Scripps Clinic Center for Weight Management
San Diego, California
Linda H. Malkas, PhD, remembers the day a photograph for a newspaper changed her life.
“I was the Vera Bradley chair for oncology at Indianapolis University School of Medicine, and I was doing breast cancer work,” Malkas, who now serves as dean of translational science and M.T. and B.A. Ahmadinia professor in molecular oncology at City of Hope, told Healio. “I had started out as a biochemist and molecular biologist and was interested in DNA replication and repair. I probably would have kept doing that for the rest of my life. Then I met Steve Healey, who showed up to take my photo for a newspaper article.”
Running a bit late for the photo assignment, Healey explained to Malkas that his daughter, Anna, was at Riley Hospital for Children. At age 8 years, Anna had been living with neuroblastoma for almost half of her life.
“Steve took a beautiful photo of me, and as he packed up his camera and equipment, he said, ‘Dr. Malkas, what is it you do?’ I looked at him and said, ‘Come here,’” Malkas said. “We sat in front of my computer, and for 2 hours, I gave him the only thing I could: my data.”
The two wished each other luck, and that might have been the end of the story. However, Malkas kept tabs on Healey and his family. She learned that Anna died of her disease not long after she and Steve met.
When Healey contacted her sometime later asking to visit Malkas at her laboratory, he wasn’t sure she would remember him.
“I said, ‘Oh, I remember you,’” Malkas said.
Malkas hosted Healey at her laboratory for an afternoon, introducing him to each of her young employees and discussing the group’s work.
“It was a wonderful afternoon,” Malkas recalled. “Each of my employees got up and talked for 5 to 10 minutes about what they do. Then we went down to my lab, and he did something that changed the course of my life.”
Healey handed Malkas a check for $25,000 from himself and his wife, Barbara.
“He said, ‘Dr. Malkas, we know you do all this great work on breast cancer, but if you could do something for neuroblastoma, it would mean the world to Barbara and me,’” she said. “This set the whole thing in motion.”
Malkas spoke with her husband and collaborator, Robert Hickey, PhD, associate professor in City of Hope’s department of cancer and molecular medicine, about what they had learned about DNA replication in cancer cells. The two had identified a protein that is altered in cancer cells and correlates with a change in replication fidelity.
“I asked him, ‘Do you think we could make a drug against this protein, and possibly provide a less toxic treatment to these patients?’ I was completely starry-eyed; I had no training in this. And he said, ‘Sure.’”
Malkas’ next challenge: Find a medicinal chemist to help her make this idea a reality.
She spoke with several laboratories, but none could commit the necessary time and resources. Then she received a phone call from City of Hope, asking to meet with her and discuss the possibility of bringing her to their institution.
“We talked about everything they had done during the prior 8 years,” she said. — “They had set up everything I was looking for — current good manufacturing practices facilities and the people for the regulatory process and drug discovery. They had developed the talent. Everything was there.”
When City of Hope offered Malkas a position as director of translational research, she didn’t hesitate.
“I said yes, and the first people I told were Steve and Barbara Healey,” she said. “When I told Barbara, she started to cry. She said, ‘I know if you go, something wonderful is going to happen.’”
When Malkas began her work at City of Hope in 2011, she did so with a mandate: to develop a molecule that would shut down the protein she and Hickey had identified, proliferating cell nuclear antigen (PCNA).
“I came with a target, one that had never been drugged before,” she said. “This protein interacts with at least 200 partners in the human cell, and those are not just DNA replication repair but apoptosis, transcription and cell cycle regulation. I thought if I could shut down the form of this protein that is expressed in cancer cells, I could block not just one pathway, but a variety of pathways.”
Malkas likened this to an airport hub with multiple planes coming into terminals.
“In Indianapolis, the one way you could shut down U.S. air traffic would be with a good snowstorm,” she said. “I thought if I could make a molecule that was like a snowstorm, I’d be able to block those planes from getting into those terminals.”
Malkas and Hickey developed one molecule that came close but was not successful when put into human serum. All the while, the Healey family was never far from Malkas’ mind.
“All I could think of was that I had made a promise to this family,” she said. “I kept thinking of Anna. I needed to do something.”
When Malkas and Hickey created the molecule, she named it AOH1996, which stands for Anna Olivia Healey, the child’s full name, and 1996, her birth year.
“We sent the molecule to the NIH and when they tested it in their NCI-60 cell line panel, it had activity across the board,” she said. “If I hadn’t come to City of Hope, I don’t think I would have been able to create this drug.”
City of Hope has initiated the phase 1 clinical trial of AOH1996, and the institution has announced that the first patient to receive the drug is doing well.
The trial, which will test the safety of AOH1996 in people with recurring solid tumors, is expected to continue for the next 2 years. Although originally studied for neuroblastoma, the pill has shown efficacy in preclinical studies treating cells from breast, prostate, brain, ovarian, cervical, skin and lung cancers.
Malkas said she and her colleagues are investigating other potential indications for AOH1996, including as a combination treatment for patients who may have difficulty tolerating cisplatin or other chemotherapy drugs.
“A lot of the time, you have to cut back on some of these drugs, because the patients’ systems just can’t take it,” she said. “So, I am thinking that this is probably where the home for this molecule will be — in combination treatment.”
Malkas praised her colleagues at City of Hope, including the trial’s principal investigator, Vincent Chung, MD, who she said brings a “quiet strength” to his role of leading the phase 1 trial, and Daniel Von Hoff, MD, who is serving as an advisor on the trial.
“The day I got the [FDA] approval, which was maybe 2 days before Christmas, I emailed Dr. Von Hoff about it. I thought of it as my Christmas present,” she said. “He emailed me back, saying, ‘I want you to know what you’ve done,’ and he sent me a chart with 350 steps on it, from the naming of the compound to getting the first patient. I was on something like step 348. I said, ‘Dan, I’m so glad I didn’t see this before.’”
Perhaps even more meaningful — the email response Malkas received from the Healey family when she notified them of the approval.
“They sent the most beautiful comments back, “she said. “I was so moved by this family who has suffered such a loss. They said, ‘Now Anna has a legacy.’”
Himalayan tartary buckwheat is gaining ground in US farms as more people recognize its rich phytochemicals
Dry tartary buckwheat groats in a wooden spoon next to a bouquet of Fagopyrum blossoms.
Himalayan tartary buckwheat (HTB), known for its healing powers since ancient times, is now being cultivated in the United States. Deemed a superfood due to its immense nutritional value, its unique healing compounds derive from the harsh conditions in which it was originally grown.
From its ancient origins in the tartan district of the Himalayan Mountains in China, HTB “has historically been used both as a tea and as a food for its healing powers,” Jeffrey Bland, who holds a doctorate in chemistry from the University of Oregon–Eugene, told The Epoch Times. “Over the millennia of the development of the plant, it developed a very significant immune system to defend itself against its environment.”
Bland, widely known as “the father of functional medicine,” is the author of “The Disease Delusion: Conquering the Causes of Chronic Illness for a Healthier, Longer, and Happier Life,” and the founder of Big Bold Health, which sells the “world’s first-ever commercial, certified organic, U.S.-grown harvest of Himalayan tartary buckwheat.”
Himalayan tartary buckwheat’s immune system, explained Bland, is a result of the plant’s ability to make a series of substances called phytochemicals, specifically polyphenols or flavonoids.
“That portfolio of nutrients is produced in very high levels in tartary buckwheat,” he said.
Despite its name, HTB is not related to wheat at all. “It’s a fruit seed,” explained Bland. “It has no genetic relation to wheat, so it has no gluten.”
Himalayan tartary buckwheat contains:
Himalayan tartary buckwheat was cultivated in ancient China and is mentioned in the “Yellow Emperor’s Classic of Medicine,” one of the original documents in Chinese literature on therapeutic herbs and plants, Bland said. It was brought to the Western world during the age of Marco Polo, and Europeans saw the benefits of cultivating the hardy plant.
When colonists first arrived in what would become the United States, one of the foods they brought with them, along with common buckwheat seeds, was Himalayan tartary buckwheat, “because it was known to be so easy to grow and so hardy,” Bland said.
“This was seen by our colonial ancestors as a really important food product to bring to the new world. For the first 100 years in America, this was an important staple in our colonial diets.”
But the common buckwheat seed—the one that’s more familiar to Americans today—gradually edged out Himalayan tartary buckwheat because the common variety has a higher yield per acre and a milder flavor, Bland said.
So, although Himalayan tartary buckwheat has 50 to 100 times higher levels of immune-active substances than common buckwheat, its cultivation in the U.S. dwindled over the past 100 years.
That began to change when Bland surveyed U.S. farmers about four years ago to determine if anyone was growing Himalayan tartary buckwheat. He found only one farmer who was: Sam Beer, a retired research agriculture professor at Cornell University.
Along with his wife, Lucia, Beer began to grow the crop on his small hobby farm in upstate New York after receiving some seeds from the U.S. Department of Agriculture. “He found that the plant was beautiful,” Bland said, who described it as tall and elegant. “And when he harvested the seeds, he found that, lo and behold, it had these unique nutritional characteristics.”
The Beers milled the seed on their farm and sold it locally. About three years ago, Bland founded Big Bold Health and partnered with the Beers and a cooperative of upstate New York organic farmers to revive Himalayan tartary buckwheat in the United States.
“It’s really been a fun project for us to bring this crop back to America,” Bland said.
“We are not treating tartary buckwheat as a commodity,” Beer said in a video about the superfood. “We care about a host of particular compounds that it has and we also care about the way it’s farmed.”
Using organic methods not only keeps toxic chemicals out of our foods, but it also improves food’s nutrition, Bland said. Using herbicides and pesticides lowers stress on a plant, he said, which means it doesn’t need to mobilize a strong stress response.
Polyphenols and flavonoid levels are lower in plants that have been treated with agricultural chemicals than in those that have had to “make their own way in a hostile world,” he said.
“Food is medicine, right? That’s one of the principles behind it. It’s worth paying more attention to what you eat … it’s worth investing time and money and eating good food because it’s directly related to your health,” says Greg Russo, one of the farmers involved in producing Himalayan tartary buckwheat flour.
(Reprinted with permission from Big Bold Health.)
Ingredients
Preparation
Summary: Hormone replacement therapy (HRT) use was associated with better cognition, memory, and larger brain volume in women who carry the Alzheimer’s associated APOE4 genetic variant.
Source: University of East Anglia
Hormone Replacement Therapy (HRT) could help prevent Alzheimer’s Dementia among women at risk of developing the disease—according to University of East Anglia research.
The study shows that HRT use is associated with better memory, cognition and larger brain volumes in later life among women carrying the APOE4 gene—the strongest risk factor gene for Alzheimer’s disease.
The research team found that HRT was most effective when introduced early in the menopause journey during perimenopause.
Prof Anne-Marie Minihane, from UEA’s Norwich Medical School and director of the Norwich Institute for Healthy Aging at UEA, led the study in collaboration with Prof Craig Ritchie at the University of Edinburgh.
Prof Minihane said, “We know that 25 percent of women in the UK are carriers of the APOE4 gene and that almost two thirds of Alzheimer’s patients are women.
“In addition to living longer, the reason behind the higher female prevalence is thought to be related to the effects of menopause and the impact of the APOE4 genetic risk factor being greater in women.
“We wanted to find out whether HRT could prevent cognitive decline in at-risk APOE4 carriers.”
The research team studied data from 1,178 women participating in the European Prevention of Alzheimer’s Dementia initiative—which was set up to study participants’ brain health over time.
The project spanned 10 countries and tracked participants’ brains from ‘healthy’ to a diagnosis of dementia in some. Participants were included if they were over 50 and dementia-free.
The research team studied their results to analyse the impact of HRT on women carrying the APOE4 genotype.
Dr. Rasha Saleh, also from UEA’s Norwich Medical School, said, “We found that HRT use is associated with better memory and larger brain volumes among at-risk APOE4 gene carriers. The associations were particularly evident when HRT was introduced early—during the transition to menopause, known as perimenopause.
“This is really important because there have been very limited drug options for Alzheimer’s disease for 20 years and there is an urgent need for new treatments.
“The effects of HRT in this observation study, if confirmed in an intervention trial, would equate to a brain age that is several years younger.”
Prof Anne Marie Minihane said, “Our research looked at associations with cognition and brain volumes using MRI scans. We did not look at dementia cases, but cognitive performance and lower brain volumes are predictive of future dementia risk.
Prof Michael Hornberger, from UEA’s Norwich Medical School, said, : “It’s too early to say for sure that HRT reduces dementia risk in women, but our results highlight the potential importance of HRT and personalised medicine in reducing Alzheimer’s risk.
“The next stage of this research will be to carry out an intervention trial to confirm the impact of starting HRT early on cognition and brain health. It will also be important to analyse which types of HRT are most beneficial,” he added.
Prof Craig Ritchie, from the University of Edinburgh, said, “This important finding from the EPAD Cohort highlights the need to challenge many assumptions about early Alzheimer’s disease and its treatment, especially when considering women’s brain health.
“An effect on both cognition and brain changes on MRI supports the notion that HRT has tangible benefit. These initial findings need replication however in other populations.”
Abstract
Hormone Replacement Therapy is associated with improved cognition and larger brain volumes in at risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort
The risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT initiation on the heterogeneity in cognitive response to HRT.
The analysis used baseline data from participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort (total n= 1906, women= 1178, 61.8%). Analysis of covariate (ANCOVA) models were employed to test the independent and interactive impact of APOE genotype and HRT on select cognitive tests, such as MMSE, RBANS, dot counting, Four Mountain Test (FMT), and the supermarket trolley test (SMT), together with volumes of the medial temporal lobe (MTL) regions by MRI. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes.
APOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6–10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively). Earlier introduction of HRT was associated with larger right (standardized β= −0.555, p=0.035) and left hippocampal volumes (standardized β= −0.577, p=0.028) only in APOE4 carriers.
HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup. Confirmation of findings in a fit for purpose RCT with prospective recruitment based on APOE genotype is needed to establish causality.
Summary: Study confirms the role the corpus callosum plays in language lateralization.
Source: HSE
A study by the HSE Centre for Language and Brain has confirmed the role of the corpus callosum in language lateralization, the distribution of language processing functions between the brain’s hemispheres.
The authors came up with an innovative language task for their study subjects and applied advanced neuroimaging methods to the data collected.
A paper on their findings has been published in PLoS ONE.
Functional asymmetry between the two cerebral hemispheres in performing higher-level cognitive functions is a major characteristic of the human brain. For example, the left hemisphere plays a leading role in language processing in most people. However, between 10% and 15% of the human population also use the right hemisphere to varying degrees for the same task.
Traditionally, language lateralization to the right hemisphere was explained by handedness, as it is mainly found in left-handed and ambidextrous (using both hands equally well) individuals. But recent research has demonstrated a genetic difference in the way language is processed by left-handed and ambidextrous people.
In addition to this, some right-handed people also involve their right hemisphere in language functions.
These findings prompted the scientists to consider alternative explanations—in particular, by looking at brain anatomy to find out why language functions can shift to the right hemisphere.
Researchers at the HSE Centre for Language and Brain hypothesized that language lateralization may have something to do with the anatomy of the corpus callosum, the largest commissural tract in the human brain connecting the two cerebral hemispheres.
The researchers asked 50 study participants to perform a sentence completion task. The subjects were instructed to read aloud a visually presented Russian sentence and to complete it with an appropriate final word (e.g., “Teper ministr podpisyvaet vazhnoe…”—”Now the minister is signing an important …”).
At the same time, the participants’ brain activity was recorded using functional magnetic resonance imaging (fMRI). Additionally, the volume of the corpus callosum was measured in each subject.
A comparison between the fMRI data and the corpus callosum measurements revealed that the larger the latter’s volume, the less lateralization of the language function to the right hemisphere was observed.
It can be said that in processing language, the brain tends to use the left hemisphere’s resources efficiently and to suppress, by means of the corpus callosum, any additional involvement of the right hemisphere. The larger a person’s corpus callosum, the less involved their right hemisphere is in language processing (and vice versa).
This finding is consistent with the inhibitory model suggesting that the corpus callosum inhibits the action of one hemisphere while the other is engaged in cognitive tasks.
“The study’s innovative design and use of advanced neuroimaging have made this conclusion possible.
“Brain lateralization in language processing is usually hard to measure accurately, as typical speech tasks used in earlier studies (eg image naming, selecting words that begin with a certain letter or listening to speech) tend to cause activation only in some parts of the brain responsible for language functions but not in others.
“Instead, we developed a unique speech task for fMRI—sentence completion—which reliably activates all language areas of the brain,” says Olga Dragoy, Director of the HSE Centre for Language and Brain.
It is important to add that the authors reconstructed the volume and properties of the corpus callosum from MRI data using an advanced tractography technique: constrained spherical deconvolution (CSD).
This is more suitable than traditional diffusion tensor imaging for modeling crossing fibers in the smallest unit of volume, the voxel (3D pixel), and is therefore more reliable.
Summary: Using cryoEM technology, researchers have decoded the detailed structures of an entire family of opioid receptors bound to their naturally occurring peptides. This new structural framework should help in the development of safer, more effective medications to treat chronic pain.
Source: UNC Chapel Hill
In the continuing effort to improve upon opioid pain relievers, American and Chinese scientists used cryoEM technology to solve the detailed structures of the entire family of opioid receptors bound to their naturally occurring peptides.
Subsequent structure-guided biochemical studies were then performed to better understand the mechanisms of peptide-receptor selectivity and signaling drugs.
This work, published in Cell, provides a comprehensive structural framework that should help drug developers rationally design safer drugs to relieve severe pain.
This work was spearheaded by the lab of Eric Xu, PhD, at the CAS Key Lab of Receptor Research in China, in collaboration with the lab of Bryan L. Roth, MD, PhD, at the UNC School of Medicine, where graduate student Jeff DiBerto led the pharmacological experiments to understand the receptors’ signaling mechanisms.
Opioid drugs relieve pain by mimicking a naturally occurring pain-relief function within our nervous symptoms. They are the best, strongest pain relievers we have. Unfortunately, they come with side effects, some severe such as numbness, addiction, and respiratory depression, leading to overdose deaths.
Scientists have been trying for many years to overcome the side-effect problem in various ways, all involving one or more of four opioid receptors to no avail. One way scientists continue to explore is the creation of peptide or peptide-inspired small molecule drugs.
Peptides are short chains of amino acids; think of them as short proteins. Certain naturally occurring, or endogenous, peptides bind to opioid receptors on the surface of cells to create an analgesic effect, also known as pain relief.
Think of an analgesic like an anesthetic, except that analgesics do not “turn off” the nerves to numb the body or alter consciousness. So, the idea is to create a peptide drug that has a strong analgesic effect, without numbing nerves or altering consciousness or causing digestive, respiratory, or addiction issues.
“The problem in the field is we’ve lacked the molecular understanding of the interplay between opioid peptides and their receptors,” said Roth, co-senior author and the Michael Hooker Distinguished Professor of Pharmacology.
“We’ve needed this understanding in order to try to rationally design potent and safe peptide or peptide-inspired drugs.”
Using cryogenic electron microscopy, or cryoEM, and a battery of biomechanistic experiments in cells, the Xu and Roth labs systematically solved the detailed structures of endogenous peptides bound to all four opioid receptors. These structures revealed details and insights into how specific naturally occurring opioid peptides selectively recognize and activate opioid receptors.
The researchers also used exogenous peptides, or drug-like compounds, in some of their experiments to learn how they activate the receptors.
The cryoEM structures of agonist-bound receptors in complex with their G protein effectors (called their “active state”) represents what these receptors look like when they are signaling in cells, giving a detailed view of peptide-receptor interactions.
The Roth lab used the structures solved by the Xu lab to guide the design of mutant receptors, and then tested these receptors in biochemical assays in cells to determine how they alter receptor signaling.
Understanding these interactions can then be used to design drugs that are selective for opioid receptor subtypes, as well as to produce certain signaling outcomes that may be more beneficial than those of conventional opioids.
“This collaboration revealed conserved, or shared, mechanisms of activation and recognition of all four opioid receptors, as well as differences in peptide recognition that can be exploited for creating subtype-selective drugs,” said DiBerto, first author and PhD candidate in the Roth lab.
“We provide more needed information to keep pushing the field forward, to answer basic science questions we hadn’t been able to answer before now.”
Previous research showed the structure of opioid receptors in their inactive or active-like states, with active state structures only existing for the mu-opioid receptor subtype, the primary target of drugs like fentanyl and morphine.
In the Cell paper, the authors show agonist-bound receptors in in complex with their G protein effectors, made possible through cryoEM technology that did not exist when currently used medications were being developed.
Drugs such as oxycontin, oxycodone, and morphine cause various effects inside cells and throughout the nervous symptom, including pain relief. But they have effects in the digestive and respiratory systems, too, and interact with cells to lead to addiction.
Fentanyl, meanwhile, is another powerful pain reliever, but it binds to opioid receptors in such a way as to cause severe side effects, including the shutdown of the respiratory system.
The thrust behind such research led by Xu and Roth is to home in on the mechanistic reasons for pain relief potency without triggering the cellular mechanisms that lead to severe side effects and overdosing.
“We are attempting to build a better kind of opioid,” Roth says, “We’re never going to get there without these kind of basic molecular insights, wherein we can see why pain is relieved and why side effects occur.”
Co-first authors of the Cell paper are Yue Wang and Youwen Zhuang of the CAS Key Laboratory of Receptor Research and the State Key Laboratory of Drug Research at the Shanghai Institute of Materia Medica in the Chinese Academy of Sciences.
Abstract
Structures of the entire human opioid receptor family
Opioids are effective analgesics, but their use is beset by serious side effects, including addiction and respiratory depression, which contribute to the ongoing opioid crisis.
The human opioid system contains four opioid receptors (μOR, δOR, κOR, and NOPR) and a set of related endogenous opioid peptides (EOPs), which show distinct selectivity toward their respective opioid receptors (ORs).
Despite being key to the development of safer analgesics, the mechanisms of molecular recognition and selectivity of EOPs to ORs remain unclear.
Here, we systematically characterize the binding of EOPs to ORs and present five structures of EOP-OR-Gi complexes, including β-endorphin- and endomorphin-bound μOR, deltorphin-bound δOR, dynorphin-bound κOR, and nociceptin-bound NOPR.
These structures, supported by biochemical results, uncover the specific recognition and selectivity of opioid peptides and the conserved mechanism of opioid receptor activation.
These results provide a structural framework to facilitate rational design of safer opioid drugs for pain relief.
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