Regular cycling can greatly improve mobility in patients with myotonic dystrophy (MD), an inherited genetic disease that causes muscle degeneration, according to research published in The Journal of Clinical Investigation. Professor Mark Tarnopolsky, senior author of the study, said that cycling for 35 minutes three times a week for 12 weeks led to a 32% increase in overall fitness in people with MD.
The participants also saw a 1.6-kilogram increase in their muscle mass and a two percent reduction of body fat. They were also able to walk an extra 47 metres in six minutes, when tested by researchers at the end of the 12-week trial.
The research team recruited 11 patients with MD to examine how effective cycling was in restoring and maintaining their physical health. Researchers also studied the underlying molecular mechanisms through which exercise strengthens the skeletal muscles, which can be severely weakened by MD.
“Exercise really is medicine – we just need to get the message out,” said Prof Tarnopolsky. “Myotonic dystrophy is a progressive condition that will impair your mobility and can put you in a wheelchair. There is no cure for it and only regular exercise helps you achieve better function.”
Prof Tarnopolsky said that some patients with MD are even advised by their doctors not to exercise, for fear of making their condition worse, but that is now proven false.
Prior studies with mouse models showed a range of similar physiological benefits from regular exercise, the researchers said. MD is the most commonly diagnosed type of muscular dystrophy in adults, and the second most prevalent of all muscular dystrophies, noted Prof Tarnopolsky.
MD’s main symptoms include severe skeletal muscle atrophy, general muscle weakness, reduced lung capacity and impaired heart function. Other symptoms may include cataracts, endocrine disorders including diabetes and gastro-intestinal disorders.
“MD itself is really a form of accelerated ageing,” said Prof Tarnopolsky.
The Hershey’s Kisses after which the hormone is named. Photo by Aaron Burden on Unsplash
Kisspeptin, a hormone named for the iconic Hershey’s ‘Kisses’ might be developed as a treatment for non-alcoholic fatty liver disease (NAFLD), according to a new study appearing in the Journal of Clinical Investigation. The hormone also serves to regulate puberty and fertility in humans.
Globally, non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease that affects children and adults and is linked to the rise in obesity and Type 2 diabetes. Largely without symptoms in the early stages, NAFLD begins with the accumulation of fat in the liver, leading to ‘fatty liver’. With disease progression, inflammation sets in, resulting in non-alcoholic steatohepatitis (NASH). This is followed by fibrosis and cirrhosis, and a subset of NASH patients with cirrhosis will also develop liver cancer. There are presently no approved therapeutics to treat NASH.
Study lead investigator, Moshmi Bhattacharya, an associate professor at Rutgers University, has spent over 15 years studying kisspeptin in health and disease. Kisspeptin, encoded by the KISS1 gene, was discovered in a city called Hershey, and named for the iconic Hershey chocolate ‘kisses’. As well as playing key roles in pubertal development and maintaining reproductive function, kisspeptin has also been linked to appetite and, coincidentally given its name, sexual attraction.
In the study, mice fed on a high-fat, high-sugar ‘Western’ diet to induce obesity and NAFLD, were protected from the development of fatty liver, NASH and fibrosis when given kisspeptin. Kisspeptin works by binding its receptor, a protein called KISS1R, which, when deleted from liver cells, prevents kisspeptin from functioning, leading mice on Western diets to develop fatty liver. These experiments uncover a powerful relationship between kisspeptin and the reduction of liver fat and fibrosis. “This work shows the kisspeptin receptor signaling pathway has a potential therapeutic role in NAFLD,” said co-author, Professor Vinod K Rustgi. “It does this by protecting against the development of fat in the liver and reducing inflammation and fibrosis. As such, it has the potential to favorably impact the health and lives of millions of patients around the globe.”
Even though cigarette smoking is by far the main cause of lung cancer, only a minority of smokers develop the disease. A study reported in Nature Genetics suggests that some smokers may have robust mechanisms that protect them from lung cancer by keeping mutations in check. The findings could help identify those smokers who face an increased risk for the disease and therefore warrant especially close monitoring.
“This may prove to be an important step toward the prevention and early detection of lung cancer risk and away from the current herculean efforts needed to battle late-stage disease, where the majority of health expenditures and misery occur,” said Simon Spivack, MD, MPH, a co-senior author of the study.
For a long time, it has been assumed that smoking leads to lung cancer by triggering DNA mutations in normal lung cells. “But that could never be proven until our study, since there was no way to accurately quantify mutations in normal cells,” said Dr Jan Vijg, a study co-senior author. Dr Vijg overcame that obstacle a few years ago by developing an improved method for sequencing the entire genomes of individual cells.
Single-cell whole-genome sequencing methods can inadvertently introduce sequencing errors difficult to distinguish from true mutations – a major flaw when looking for rare and random mutations. To get around this, Dr Vijg developed a sequencing technique called single-cell multiple displacement amplification (SCMDA).
The researchers used SCMDA to compare the mutational landscape of normal lung epithelial cells from two types of people: 14 never-smokers, ages 11 to 86; and 19 smokers, ages 44 to 81, who had smoked a maximum of 116 pack-years. (One pack-year of smoking equals 1 pack of cigarettes smoked per day for one year.) The cells were collected from patients who were undergoing bronchoscopy for diagnostic tests unrelated to cancer. “These lung cells survive for years, even decades, and thus can accumulate mutations with both age and smoking,” said Dr Spivack. “Of all the lung’s cell types, these are among the most likely to become cancerous.”
The researchers found that mutations accumulated in the lung cells of non-smokers as they age, and significantly more mutations were found in the lung cells of the smokers. “This experimentally confirms that smoking increases lung cancer risk by increasing the frequency of mutations, as previously hypothesised,” said Dr Spivack. “This is likely one reason why so few non-smokers get lung cancer, while 10% to 20% of lifelong smokers do.” The study also revealed that the number of cell mutations detected in lung cells increased in a straight line with the number of pack years of smoking and, presumably, so did the lung cancer risk. However, the cell mutations stopped rising after 23 pack-years of exposure.
“The heaviest smokers did not have the highest mutation burden,” said Dr Spivack. “Our data suggest that these individuals may have survived for so long in spite of their heavy smoking because they managed to suppress further mutation accumulation. This leveling off of mutations could stem from these people having very proficient systems for repairing DNA damage or detoxifying cigarette smoke.”
The finding has led to a new research direction. “We now wish to develop new assays that can measure someone’s capacity for DNA repair or detoxification, which could offer a new way to assess one’s risk for lung cancer,” said Dr Vijg.
In a study published in JAMA Network Open, researchers found that after a visit to the ED, many opioid overdose patients carried naloxone, which helps reverse opioid overdoses, which could save their lives in the event of a future overdose.
About 70% of current overdose deaths in the US involve opioids, which means that many of them could be prevented with naloxone. Naloxone is an opioid antagonist, blocking the effect of opioids in overdoses and able to save lives when used in time. It is easy to carry and use, and studies have demonstrated that laypeople can administer it safely and effectively to reverse overdoses.
However the people most likely to witness an overdose, including opioid users and their friends and relatives, may not be able to easily obtain naloxone. Strategies are needed to increase uptake, carrying, and administration of naloxone, especially among at-risk individuals in the community who may not be engaged in routine health care or with community naloxone distribution efforts.
Many at-risk individuals find themselves in the emergency departments (ED), either because of an overdose or other complications of substance use. The Perelman School of Medicine’s Anish Agarwal, an assistant professor of emergency medicine, and Margaret Lowenstein, an assistant professor of medicine, recently examined the potential for ED visits as a critical, reachable moment to engage high-risk individuals in overdose prevention. The team reached out to at-risk patients prescribed naloxone in the ED to understand whether they had obtained their naloxone during or after their ED visit, whether they were carrying it, and their plans to carry it in the future.
The survey asked patients about their experiences and perceptions following the ED encounter related to accessing, using, and carrying naloxone. Most of the patients did not carry naloxone prior to their ED, yet over a third reported having a personal history of an overdose requiring naloxone, and more than a quarter had used naloxone to reverse an overdose for another person in the past. Approximately half of the patients said that they were carrying naloxone after their ED visit, and two-thirds planned to continue carrying. And of patients not carrying naloxone prior to their ED visit, 54% reported a plan to continue carrying it in the future.
University students who put a lot of pressure on themselves to be the best at everything, known as the ‘superhero ideal’, have been hit especially hard by the pandemic. Recent research has shown that by developing authentic and healthy relationships, young people can fight the depressive symptoms associated with this superhero ideal.
The ‘superhero ideal’ was based off the ‘superwoman ideal‘, which is a construct has its origins in the 1960s feminist movement where women could ‘do it all and have it all’. In an article published in Acta Psychologica, Sally A. Theran, associate professor of psychology at Wellesley College and co-author Halina Dour, explain that internalising the superhero ideal is directly related to an increase in depressive symptoms.
“No matter how much we try to deemphasise achievement and success to college-age students and encourage them to work on their own intrinsic motivation and well-being, kids are internalising this message that they feel pressure to achieve,” said A/Prof Theran, who finds in her day-to-day interactions, in addition to her research, that many of her students feel they “have to be superheroes.”
One way for students to combat the effects of the superhero ideal is to cultivate authentic relationships with peers, parents, and educators, according to the study authors They define an authentic relationship as one in which a person feels able to be honest about who they are with someone else. That does not necessarily mean acting the same way around everyone they know – a student will act differently around a teacher than a friend – but rather that in each of those interactions the person feels they are being true to themselves.
To gauge the authenticity of a relationship, A/Prof Theran said, students can ask themselves, “Does this person make me feel good? Do I feel like I can be myself around this person?”
A/Prof Theran and her team found that students who had authentic relationships were able to partially mediate the relationship between the superhero ideal and depressive symptoms. Specifically, the link between superhero ideal and depressive symptoms is in part due to the lack of authenticity in these adolescents’ relationships. The more the superhero ideal was internalised, the less the authenticity there was with parents and peers. Lower levels of authenticity with parents and peers were associated with more depressive symptoms. Thus, authenticity in relationships is part of the mechanism for explaining the significant relation between the superhero ideal and depressive symptoms.
“In college you are more able to have a shift of self,” A/Prof Theran said. “‘Is this who I am? Is this what I want?’ And you may end up having an identity crisis, but that’s really healthy, in order to figure out who you are.” A/Prof Theran particularly sees this in students who have recently started at university. They are often trying to work out what they want to put effort into and care about, rather than going along with what parents and teachers wanted. The way out of such a crisis, according to A/Prof Theran, is for them to find people, like peers, teachers, parents, around whom they can be their true selves. Being honest about their achievements, failures, and even confusion is one way to go about building such authentic relationships.
A/Prof Theran uses this skill in her own classroom, telling her students when she has a paper rejected, for example, or doesn’t get a grant for which she had applied. “If you are not robotic with your students, then they will genuinely be themselves, too,” she said, “and then hopefully they are less likely to feel such superhero pressure in class and in other areas.” A/Prof Theran said that awareness of both the external and internal pressures on students to achieve is especially important now as adolescents consume social media even more in the pandemic, often unfavourably comparing their ‘worst’ selves with someone else’s filtered online self. Parents can help, A/Prof Theran said, by pointing out the use of filters and angles, and reminding them that someone is posting one curated minute of their day, not their whole self. “Encourage your teen to consider, how authentic are people being in their online presentation? And when people espouse authenticity online, it does not mean that they are actually being their true self,” she said. “The very nature of social media encourages internalisation of the superhero ideal while discouraging authenticity, but bolstering authenticity and critical thinking skills can help combat the negative repercussions of the superhero ideal.”
A/Prof Theran has studied authenticity in relationships for 20 years. She recently co-authored a paper on the ways authentic and empowered friendships among female university students can act as a buffer between childhood emotional and physical abuse and subsequent traumatic symptoms while in university. Another paper explored the roles of authentic relationships in adolescents’ prosocial experiences, which are positive aspects of being around peers. In adolescents with low levels of secure attachments, prosocial experiences increased as their level of authenticity with peers increased, A/Prof Theran found.
“The pandemic really made clear how much relationships mean to us,” said A/Prof Theran. “We feel empowered by our friendships. Reaching out and connecting with others can improve our well-being so much.”
The risk of developing one of three serious eye conditions increases by 85 percent for regular users of common erectile dysfunction (ED) medications such as the phosphodiesterase 5 (PDE5) inhibitors, sildenafil, tadalafil, vardenafil and avanafil, according to new research.
Previously, two of the three conditions had been linked to ED medications only by anecdotal case studies. Now, these links have been confirmed for the first time by a large, epidemiological study, which appears in JAMA Ophthalmology.
“These are rare conditions, and the risk of developing one remains very low for any individual user. However, the sheer number of prescriptions dispensed each month in the US – about 20 million – means that a significant number of people could be impacted,” said first author Dr Mahyar Etminan. “Regular users of these drugs who find any changes in their vision should take it seriously and seek medical attention.”
The researchers analysed health insurance claim records of 213 000 men in the US without a history of these eye problems in the year before they became regular users of ED medications.
They followed the records to see how many men developed one or more of the three conditions, and how that rate compared to men who didn’t use the medications. After accounting for conditions associated with eye problems, such as hypertension, diabetes and coronary artery disease, they found the increased risk for each to be as follows:
A key limitation was that the study could only show correlation between eye conditions and use of these drugs, and could not prove causation. However, possible explanations can be found in the way ED medications function.
“These medications address erectile dysfunction by improving blood flow, but we know that they can also hinder blood flow in other parts of the body,” explained Dr Etminan. “So although our study doesn’t prove cause-and-effect, there is a mechanism by which these medications could conceivably lead to these problems. The totality of the evidence points toward a strong link.”
The potential risk of SRD and RVO is not covered in the information currently provided to patients along with their ED medications, unlike the ION risk which has been demonstrated by previous research.
Dr Etminan hopes his team’s work will change that. Patients who are unaware of all potential side effects might not seek help in time to avoid serious visual consequences.
Scanning Electron Micrograph of a breast cancer cell. Credit: NIH
Researchers have found that bacteria lurking inside tumours promote cancer metastasis. They do so by enhancing the strength of host cells against mechanical stress in the bloodstream, promoting cell survival during tumour progression, researchers report in the journal Cell.
“Our study reveals that the cancer cell’s behaviour is also controlled by the microbes hiding inside tumours, the majority of which were originally thought to be sterile,” said senior author Shang Cai of the Westlake Laboratory of Life Sciences and Biomedicine. “This microbial involvement is distinct from the genetic, epigenetic, and metabolic components that most cancer drugs target.”
“However, our study does not mean that using antibiotics during cancer treatment will benefit patients,” he cautioned. “Therefore, it is still an important scientific question of how to manage the intratumor bacteria to improve cancer treatment in the future.”
It is known that microbes play a critical role in affecting cancer susceptibility and tumour progression, particularly in colorectal cancers. New evidence suggests however that, in a broad range of cancer types, they also form integral components of the tumour tissue itself, such as pancreatic cancer, lung cancer, and breast cancer. Microbial features are linked to cancer risk, prognosis, and treatment responses, yet the biological functions of tumour-resident microbes in tumour progression remain unclear.
Whether these microbes are actually drivers of tumour progression has been an intriguing question. “Tumour cells hijacked by microbes could be more common than previously thought, which underscores the broad clinical value of understanding the exact role of the tumour-resident microbial community in cancer progression,” Cai explained.
To find answers, Cai’s team utilised a mouse model of breast cancer with significant amounts of bacteria inside cells, similar to human breast cancer. The bacteria were found to be capable of travelling through the circulatory system with the cancer cells, playing critical roles in tumour metastasis. These passenger bacteria have the capacity to modulate the cellular actin network, promoting cell survival against mechanical stress in circulation.
“We were surprised initially at the fact that such a low abundance of bacteria could exert such a crucial role in cancer metastasis. What is even more astonishing is that only one shot of bacteria injection into the breast tumour can cause a tumour that originally rarely metastasises to start to metastasise,” Cai said. “Intracellular microbiota could be a potential target for preventing metastasis in broad cancer types at an early stage, which is much better than to have to treat it later on.”
While intratumour bacteria was found to have a clear role in promoting cancer cell metastatic colonisation, the authors did not exclude the possibility that the gut microbiome and immune system may act together with intratumour bacteria to determine cancer progression. Future in-depth analyses of how bacteria invade tumour cells, how intracellular bacteria are integrated into the host cell system, and how bacteria-containing tumor cells interact with the immune system will help inform how to properly deploy antibiotics in cancer treatment.
This normal human skin cell was treated with a growth factor that triggered the formation of specialised protein structures that enable the cell to move. Credit: Torsten Wittmann, University of California, San Francisco
In a finding which could revolutionise regenerative medicine, researchers have found a way to reverse the age of human skin cells by 30 years, reversing genetic ageing measures for cells without losing their specialised function. The function of older cells was partly restored, as well as rejuvenating the molecular measures of biological age. The research was published in the journal eLife.
One of the ways regenerative medicine aims to replace damaged or old cells is by creating ‘induced’ stem cells, which differentiate into specialised cells. Currently the process is not reversible.
The new method, based on stem cell production, overcomes the problem of entirely erasing cell identity by halting reprogramming part of the way through the process. This let researchers find the precise balance between reprogramming cells, making them biologically younger, while still being able to regain their specialised cell function.
Currently, cell reprogramming takes around 50 days using four key molecules called the Yamanaka factors. The new method, called ‘maturation phase transient reprogramming’, exposes cells to Yamanaka factors for just 13 days. At this point, age-related changes are removed and the cells have temporarily lost their identity. The partly reprogrammed cells were given time to grow under normal conditions, to observe whether their specific skin cell function returned. Genome analysis showed that cells had regained markers characteristic of skin cells (fibroblasts), and this was confirmed by observing collagen production in the reprogrammed cells.
To show that the cells had been rejuvenated, the researchers looked for changes in ageing indicators. Dr Diljeet Gill, who conducted the work as a PhD student explained: “Our understanding of ageing on a molecular level has progressed over the last decade, giving rise to techniques that allow researchers to measure age-related biological changes in human cells. We were able to apply this to our experiment to determine the extent of reprogramming our new method achieved.”
Cellular ages examined included the epigenetic clock, where chemical tags present throughout the genome indicate age. Another is the transcriptome, all the gene readouts produced by the cell. According to these two measures, the reprogrammed cells matched the profile of cells that were 30 years younger compared to reference data sets.
However, ‘rejuvenated’ cells need to function as if they were younger as well as looking younger. The rejuvenated fibroblasts were able to produce more collagen proteins compared to control cells that did not undergo the reprogramming process. Fibroblasts also move into areas that need repairing. Researchers tested the partially rejuvenated cells in vitro, and the treated fibroblasts moved into the gap faster than older cells – a sign that these could be used to improve wound healing,
The method also had an effect on other genes linked to age-related diseases and symptoms, the researchers saw, indicating possible future therapies. The APBA2 gene, associated with Alzheimer’s disease, and the MAF gene with a role in the development of cataracts, both showed changes towards youthful levels of transcription.
The researchers plan to explore the mechanism behind the successful transient programming, which is not yet completely understood. It is speculated that key areas of the genome involved in shaping cell identity might escape the reprogramming process.
Dr Diljeet concluded: “Our results represent a big step forward in our understanding of cell reprogramming. We have proved that cells can be rejuvenated without losing their function and that rejuvenation looks to restore some function to old cells. The fact that we also saw a reverse of ageing indicators in genes associated with diseases is particularly promising for the future of this work.”
Professor Wolf Reik, a group leader in the Epigenetics research programme who has recently moved to lead the Altos Labs Cambridge Institute, said: “This work has very exciting implications. Eventually, we may be able to identify genes that rejuvenate without reprogramming, and specifically target those to reduce the effects of ageing. This approach holds promise for valuable discoveries that could open up an amazing therapeutic horizon.”
Individuals with inflammatory skin conditions should avoid using skincare products that contain food products such as goat’s milk, according to a series of case studies published in Clinical & Experimental Allergy. Such skincare products have been marketed to those with ‘sensitive skin’.
In children, milk allergy is one of the most common food allergies, but usually resolves in the first years of life. Adult-onset milk allergy is rare. In patients with inflammatory conditions of the skin such as atopic dermatitis, associations between the use of food allergen-containing skin products and systemic sensitisation to that foodstuff has been demonstrated for several foods. This is of concern, as food-containing skin products are commonly promoted as a safer and more ‘natural’ way of managing a variety of skin conditions. These are widely available for unprescribed purchase in pharmacies and supermarkets.
The present study reports on seven patients with inflammatory skin conditions who experienced anaphylaxis after ingesting goat’s or sheep’s milk or cheese products. All of the patients had a history of using goat’s milk skin products to treat their skin conditions prior to the onset of their allergic reaction. Six of them had atopic dermatitis.
“Marketing of skin products derived from goat’s milk is extensive and targeted to patients with ‘sensitive skin’ who commonly have underlying inflammatory skin conditions,” the authors wrote. “Our findings provide novel evidence of the origins of adult-onset milk allergy and adds to the growing body of evidence that use of foodstuffs as therapy for inflammatory skin conditions can lead to the development of new food allergies.”
Researchers evaluating a random selection of clinical trials done in North America found that they neglected to take into account previous or ongoing trials, which may result in researchers conducting redundant or less impactful studies. The findings were published in the journal Med.
Clinical trials are a crucial tool for assessing the safety and efficacy of medical interventions, but sponsors often provide incomplete information for assessing their ethical justification. Incomplete portrayals of supporting evidence hamper the ability of individuals or authorities to evaluate the trials’ risks, benefits, and scientific merit.
To assess the prevalence of such omissions, researchers accessed the ClinicalTrials.gov registry and evaluated 101 randomly chosen clinical trials. Among those where there was at least one previous trial testing the same drug in the same disease, 30% of industry-sponsored trials and 20% of non-industry-funded trials failed to cite related studies. “Clinical trial protocols undercite easily accessible, relevant trials and do not document systematic searches for relevant clinical trials,” the authors wrote.
“Numerous studies suggest that some clinical trials are pursued despite their clinical hypotheses having been resolved prior to study launch,” write the authors. “Failure to provide a complete and impartial account of prior and ongoing research in study protocols may enable clinical research that fails to inform clinical practice.”
