Publisher Health

Cancer cells have an innate randomness in their ability to respond to chemotherapy, which is another tool in their arsenal of resisting treatment, new research led by the Garvan Institute of Medical Research shows.
Understanding why some tumour cells become resistant to chemotherapy is a core challenge in cancer research, as chemotherapy is still a frontline treatment for most cancers.
The new research shows that tumour cells from neuroblastoma — cancer that develops in the body’s ‘fight or flight’ sympathetic nervous system — can move between states of responding, or not, to chemotherapy.
“We showed there is ‘noise’ in the process of cell death, which is what happens to cancer cells with chemotherapy treatment — and that this inherent noise, or randomness, in the system of gene expression is an important aspect of chemoresistance,” says Associate Professor David Croucher, Head of the Network Biology Lab at Garvan.
About 15% of people with neuroblastoma don’t respond to chemotherapy treatment.
“Our findings suggest that genetics don’t account for everything; other layers of regulation and other mechanisms of tumour progression can also underpin drug response, so we need to consider them,” says Dr Sharissa Latham, co-lead author on the study.

The team showed that once neuroblastoma cells reach a state of resisting chemotherapy, they can’t go back, suggesting there is a small window where treatment could work on a tumour cell before it’s locked in.
“Combining chemotherapy with drugs that target this noise within tumours may have the best results as a first-line treatment after diagnosis, before tumours lock into a state of resistance,” says Associate Professor Croucher. This flips on its head the typical protocol for clinical trials in cancer where a new treatment is given to patients who have exhausted all other treatment options.
The new study is published in the journal, Science Advances.
Noise in the tumour system
The researchers used mathematical modelling to narrow down the ‘noise’ signals in the pathways of cell death in neuroblastoma tumours. They then applied that to patient cell samples, using cutting-edge imaging to look at single cells, en masse, to visually isolate the cells that didn’t respond to treatment.
The found a marker for resistance — a set of proteins involved in the process of cell death, known as apoptosis.
“We wanted to figure out what underlies that randomness. What is it about those cells and can anything be manipulated to make them respond,” says Dr Latham.
The team identified certain classes of approved drugs that might be combined with chemotherapy to stabilise expression of the genes involved in cell death, or by changing the innate threshold that may tip a tumour cell into a resistant state.
The next step is to start progressing the work to clinical trial.

Researchers at UCL and University of Ghana have successfully predicted whether children have anaemia using only a set of smartphone images.
The study, published in PLOS ONE, brought together researchers and clinicians at UCL Engineering, UCLH and Korle Bu Teaching Hospital, Ghana to investigate a new non-invasive diagnostic technique using smartphone photographs of the eye and face.
The advance could make anaemia screening more widely available for children in Ghana (and other low- and middle-income countries) where there are high rates of the condition due to iron deficiency, as the screening tool is much cheaper than existing options and delivers results in one sitting.
The paper builds on previous successful research undertaken by the same team exploring use of an app – neoSCB – to detect jaundice in newborn babies.
Anaemia is a condition causing a reduced concentration of haemoglobin in the blood, which means oxygen is not transported efficiently around the body.
It affects two billion people globally and can have a significant impact on developmental outcomes in children, increasing their susceptibility to infectious diseases and impairing their cognitive development.

The most common cause of anaemia globally is iron deficiency, but other conditions such as blood loss, malaria and sickle-cell disease also contribute.
First author, PhD candidate Thomas Wemyss (UCL Medical Physics & Biomedical Engineering) said: “Smartphones are globally popular, but research using smartphone imaging to diagnose diseases shows a general trend of experiencing difficulty when transferring results to different groups of people.
“We are excited to see these promising results in a group which is often underrepresented in research into smartphone diagnostics. An affordable and reliable technique to screen for anaemia using a smartphone could drive long-term improvements in quality of life for a large amount of people.”
Traditionally, diagnosis of anaemia requires blood samples to be taken, which can be costly for patients and healthcare systems. It can create inequalities related to the expense of travelling to hospital for a blood test. Often families need to make two trips, to have a blood sample taken and then to collect their results, due to samples being transported between the clinic and the laboratory for analysis.
In the 1980s a handheld device, the HemoCue, was developed to provide more immediate results, but this carries significant upfront and ongoing costs, as well as still needing a finger-prick blood sample.

The researchers knew that haemoglobin has a very characteristic colour due to the way it absorbs light, so aimed to develop a procedure to take smartphone photographs and use them to predict whether anaemia is present.
They analysed photos taken from 43 children aged under four who were recruited to take part in the study in 2018. The images were of three regions where minimal skin pigmentation occurs in the body (the white of the eye, the lower lip and the lower eyelid).
The team found that when these were evaluated together to predict blood haemoglobin concentration, they were able to successfully detect all cases of individuals with the most severe classification of anaemia, and to detect milder anaemia at rates which are likely to be clinically useful.
Principal investigator Dr Terence Leung (UCL Medical Physics & Biomedical Engineering) said: “Since 2018, we’ve been working with University of Ghana on affordable ways to improve healthcare using smartphones. Following our success in screening neonatal jaundice, we are so excited to see that the smartphone imaging technique can also apply to anaemia screening in young children and infants.”
Senior author Dr Judith Meek (UCLH) added: “Anaemia is a significant problem for infants, especially in low- and middle-income countries, and we hope this sort of technology will lead to earlier detection and treatment in the near future.”
The study was funded by the EPSRC via the UCL Global Challenges Research Fund and UCL Centre for Doctoral Training in Intelligent, Integrated Imaging in Healthcare.

The decision applies to 21 states whose attorneys general threatened Walgreens and other pharmacies with legal action if they dispensed the pill there.A few weeks after Republican attorneys general in 21 states sent letters threatening legal action against retail pharmacy chains if they dispensed the abortion pill mifepristone, Walgreens said it would not distribute the pill in those states.In January, after the Food and Drug Administration said it would allow retail pharmacies to become certified to dispense mifepristone — the tightly regulated medication that is the first pill in the two-drug medication abortion regimen — Walgreens, CVS and other pharmacies said they planned to do so in states where abortion was legal. The American Pharmacists Association said that pharmacies would be very cautious about dispensing in any state where they might risk losing their license or face other penalties.The decision this week by Walgreens reflects that caution. In four of the states — Alaska, Iowa, Kansas and Montana — abortion is technically still legal, but there are efforts to restrict it that would apply to abortion pills.“This is a very complex and in flux area of the law, and we are taking that into account as we seek certification,” said a spokesman for Walgreens, Fraser Engerman.He said that Walgreens told 20 attorneys general, who had jointly signed one letter, and the attorney general of Kansas, who sent a separate letter, that it would not be distributing mifepristone in their states.The decision does not affect the second pill in the medication abortion regimen, misoprostol, which is used for several medical conditions and has long been available by prescription at retail pharmacies nationwide.A spokesman for CVS did not immediately respond to a question about whether the company had also decided not to dispense mifepristone in those 21 states, but in January, a spokeswoman said, “We plan to seek certification to dispense mifepristone where legally permissible.”Politico reported the Walgreens decision on Thursday night. The chain’s decision not to dispense pills in Kansas was announced last month.

A new study found that walking an additional 500 steps, or about one-quarter of a mile, per day was associated with a 14% lower risk of heart disease, stroke or heart failure, according to preliminary research to be presented at the American Heart Association’s Epidemiology, Prevention, Lifestyle & Cardiometabolic Health Scientific Sessions 2023. The meeting will be held in Boston, February 28-March 3, 2023, and offers the latest science on population-based health and wellness and implications for lifestyle and cardiometabolic health.
“Steps are an easy way to measure physical activity, and more daily steps were associated with a lower risk of having a cardiovascular disease-related event in older adults,” said Erin E. Dooley, Ph.D., an assistant professor of epidemiology at the University of Alabama at Birmingham School of Public Health and lead researcher of the study. “However, most studies have focused on early-to-midlife adults with daily goals of 10,000 or more steps, which may not be attainable for older individuals.”
Participants in the current analysis were part of a larger study group of 15,792 adults originally recruited for the ongoing Atherosclerosis Risk in Communities (ARIC) study. The present study evaluated health data collected from ARIC study visit 6 (2016-17) to evaluate the potential association between daily step counts and cardiovascular disease.
Researchers analyzed health data for 452 participants who used an accelerometer device similar to a pedometer, worn at the hip, that measured their daily steps. Participants were an average age of 78 years old; 59% were women; and 20% of participants self-identified as Black adults (70% of whom were women, and 30% of whom were men).
The devices were worn for three or more days, for ten or more hours, and the average step count was about 3,500 steps per day. Over the 3.5-year follow-up period, 7.5% of the participants experienced a cardiovascular disease event, such as coronary heart disease, stroke or heart failure.
The analysis found: Compared to adults who took less than 2,000 steps per day, adults who took approximately 4,500 steps per day had a 77% lower observed risk of experiencing a cardiovascular event. Nearly 12% of older adults with less than 2,000 steps per day had a cardiovascular event, compared to 3.5% of the participants who walked about 4,500 steps per day. Every additional 500 steps taken per day was incrementally associated with a 14% lower risk of cardiovascular disease.”It’s important to maintain physical activity as we age, however, daily step goals should also be attainable. We were surprised to find that every additional quarter of a mile, or 500 steps, of walking had such a strong benefit to heart health,” Dooley said. “While we do not want to diminish the importance of higher intensity physical activity, encouraging small increases in the number of daily steps also has significant cardiovascular benefits. If you are an older adult over the age of 70, start with trying to get 500 more steps per day.”
Additional research is needed to determine if meeting a higher daily count of steps prevents or delays cardiovascular disease, or if lower step counts may be an indicator of underlying disease.
Everyone can improve their cardiovascular health by following the American Heart Association’s Life’s Essential 8: eating healthy food, being physically active, not smoking, getting enough sleep, maintaining a healthy weight, and controlling cholesterol, blood sugar and blood pressure levels. Cardiovascular disease claims more lives each year in the U.S. than all forms of cancer and chronic lower respiratory disease combined, according to the American Heart Association.
The study had limitations. Participants had to enroll in the accelerometer device study, and hip-worn accelerometers are limited in capturing other activity behaviors that may also be important to heart health, such as bicycling and swimming. Study participants were more likely to have had at least some college or above education compared to the overall ARIC sample, and primarily self-identified as white and female, which may limit the study’s generalizability. Additionally, steps were only measured at one single point in time, and the researchers were unable to examine if changes in steps over time impacted CVD event risk.

Modern fabrication tools such as 3D printers can make structural materials in shapes that would have been difficult or impossible using conventional tools. Meanwhile, new generative design systems can take great advantage of this flexibility to create innovative designs for parts of a new building, car, or virtually any other device.
But such “black box” automated systems often fall short of producing designs that are fully optimized for their purpose, such as providing the greatest strength in proportion to weight or minimizing the amount of material needed to support a given load. Fully manual design, on the other hand, is time-consuming and labor-intensive.
Now, researchers at MIT have found a way to achieve some of the best of both of these approaches. They used an automated design system but stopped the process periodically to allow human engineers to evaluate the work in progress and make tweaks or adjustments before letting the computer resume its design process. Introducing a few of these iterations produced results that performed better than those designed by the automated system alone, and the process was completed more quickly compared to the fully manual approach.
The results are reported this week in the journal Structural and Multidisciplinary Optimization, in a paper by MIT doctoral student Dat Ha and assistant professor of civil and environmental engineering Josephine Carstensen.
The basic approach can be applied to a broad range of scales and applications, Carstensen explains, for the design of everything from biomedical devices to nanoscale materials to structural support members of a skyscraper. Already, automated design systems have found many applications. “If we can make things in a better way, if we can make whatever we want, why not make it better?” she asks.
“It’s a way to take advantage of how we can make things in much more complex ways than we could in the past,” says Ha, adding that automated design systems have already begun to be widely used over the last decade in automotive and aerospace industries, where reducing weight while maintaining structural strength is a key need.

“You can take a lot of weight out of components, and in these two industries, everything is driven by weight,” he says. In some cases, such as internal components that aren’t visible, appearance is irrelevant, but for other structures aesthetics may be important as well. The new system makes it possible to optimize designs for visual as well as mechanical properties, and in such decisions the human touch is essential.
As a demonstration of their process in action, the researchers designed a number of structural load-bearing beams, such as might be used in a building or a bridge. In their iterations, they saw that the design has an area that could fail prematurely, so they selected that feature and required the program to address it. The computer system then revised the design accordingly, removing the highlighted strut and strengthening some other struts to compensate, and leading to an improved final design.
The process, which they call Human-Informed Topology Optimization, begins by setting out the needed specifications — for example, a beam needs to be this length, supported on two points at its ends, and must support this much of a load. “As we’re seeing the structure evolve” on the computer screen in response to initial specification, Carstensen says, “we interrupt the design and ask the user to judge it. The user can select, say, ‘I’m not a fan of this region, I’d like you to beef up or beef down this feature size requirement.’ And then the algorithm takes into account the user input.”
While the result is not as ideal as what might be produced by a fully rigorous yet significantly slower design algorithm that considers the underlying physics, she says it can be much better than a result generated by a rapid automated design system alone. “You don’t get something that’s quite as good, but that was not necessarily the goal. What we can show is that instead of using several hours to get something, we can use 10 minutes and get something much better than where we started off.”
The system can be used to optimize a design based on any desired properties, not just strength and weight. For example, it can be used to minimize fracture or buckling, or to reduce stresses in the material by softening corners.
Carstensen says, “We’re not looking to replace the seven-hour solution. If you have all the time and all the resources in the world, obviously you can run these and it’s going to give you the best solution.” But for many situations, such as designing replacement parts for equipment in a war zone or a disaster-relief area with limited computational power available, “then this kind of solution that catered directly to your needs would prevail.”
Similarly, for smaller companies manufacturing equipment in essentially “mom and pop” businesses, such a simplified system might be just the ticket. The new system they developed is not only simple and efficient to run on smaller computers, but it also requires far less training to produce useful results, Carstensen says. A basic two-dimensional version of the software, suitable for designing basic beams and structural parts, is freely available now online, she says, as the team continues to develop a full 3D version.
“By integrating engineering ‘intuition’ (or engineering ‘judgement’) into a rigorous yet computationally efficient topology optimization process, the human engineer is offered the possibility of guiding the creation of optimal structural configurations in a way that was not available to us before,” he adds. “Her findings have the potential to change the way engineers tackle ‘day-to-day’ design tasks.”

The immune system of pregnant women with anxiety is biologically different from that of pregnant women without anxiety, according to new research from Weill Cornell Medicine, Johns Hopkins University School of Medicine and Columbia University Irving Medical Center investigators.
The study, published Sept. 14 in Brain, Behavior and Immunity, demonstrates that pregnant women with anxiety have higher levels of certain immune cells known as cytotoxic T cells; these cells attack infected or otherwise compromised cells within the body. Women with anxiety also showed differences in the activity of immune markers that circulate in the blood. This is the first known study to evaluate the relationship of anxiety to the trajectory of immune changes over the course of pregnancy and the postpartum period.
“Women with anxiety appear to have an immune system that behaves differently from that of healthy women during pregnancy and after delivery,” said principal investigator Dr. Lauren M. Osborne, vice chair for clinical research for the Department of Obstetrics and Gynecology at Weill Cornell Medicine, who conducted the research while on Johns Hopkins University School of Medicine’s faculty. “During pregnancy, a delicate dance is supposed to occur, in which the immune system changes so that it does not reject the fetus but is still strong enough to keep out foreign pathogens.”
This study could encourage better treatment of anxiety in pregnant patients, said Dr. Osborne, who is also a reproductive psychiatrist at NewYork-Presbyterian/Weill Cornell Medical Center. As a clinician, she finds that women with anxiety may resist taking antianxiety medications because they fear the drugs will hurt the baby, despite evidence that they are compatible with pregnancy.
Anxiety during pregnancy, which is self-reported by more than 20 percent of people, according to the researchers, is already known to be detrimental to the parent and child. For example, it can increase the risk of preterm birth and a lower newborn birth weight.
For this study, Dr. Osborne and her colleagues assessed a group of 107 pregnant women, 56 with anxiety and 51 without anxiety, during their second and third trimesters and at six weeks postpartum. The researchers evaluated blood samples for immune activity and conducted psychological evaluations to detect clinical anxiety.
They found that in the women with anxiety, levels of cytotoxic T cells were elevated during pregnancy and then decreased in the weeks following childbirth. In women without anxiety, the activity of these cells declined in pregnancy and continued to decline after birth.
The researchers also observed that the activity of largely pro-inflammatory cytokines, or substances secreted by cells as part of the immune system response, was suppressed during pregnancy in women with anxiety and then rose after childbirth, while healthy women exhibited the opposite pattern.
“The takeaway is that this is the first clear evidence that immune activity differs for pregnant women depending on their anxiety status. Knowing that there is immune system involvement is a first step toward understanding the biological factors related to anxiety in pregnancy, and a first step toward developing new treatments,” said Dr. Osborne. “We know that anxiety needs to be treated to ensure healthy outcomes for both mother and child.”

A dissolvable plug delivered stem cell therapy with few side effects in patients with single tract perianal fistulas, Mayo Clinic researchers discovered. Perianal fistulas are painful tunnels between the intestine and the skin that often do not go away with standard medical or surgical care. People with Crohn’s disease or other inflammatory bowel conditions are most at risk for this condition.
In a prospective, phase 1 clinical trial, researchers loaded stem cells from a patient’s own fat tissue onto a bioabsorbable plug that was then surgically implanted to close the anal fistula tract. They followed the patients for one year and reported results of their early research in Diseases of the Colon & Rectum.
“In this early study, our team documented healing of single-tract fistulas,” says Eric Dozois, M.D., a colorectal surgeon and first author on the study. “In my 20 years of clinical experience, our fistula research suggests we are getting closer to a care model.”
As many as 26% of people with Crohn’s disease will develop perianal fistulas. Most often, it starts with an infection within the anal gland and often progresses into an abscess that sometimes requires surgery. Left untreated, perianal fistulas leak fecal material and can lead to permanent colostomy and, in some cases, cancer. A colostomy is a surgical opening in the abdomen that bypasses the damaged colon to rid the body of solid waste. Perianal fistulas can cause quality-of-life challenges, such as the need to wear pads to protect clothing and prevent odor.
“Perianal fistulas are a complex medical condition that, even when repaired surgically, can reoccur, causing a lot of suffering for patients,” says William Faubion Jr., M.D., a gastroenterologist and senior author on the study. “Our hope with this research is to advance a cell-based therapy toward daily clinical care that would be easy to implant in the operating room and offer a new option for patients with unmet needs.”
The research
The research team extracted mesenchymal stem cells from adipose (fat) tissue of 20 patients with perianal fistulas who had not responded to standard medical or surgical treatment. Mesenchymal stem cells are adult stem cells with healing potential that have been well studied. After multiplying the stem cells in the lab, the team combined the cells with a plug created from a dissolvable material. They surgically implanted the plug to close the anal fistula tract then monitored the patients seven times within 12 months, with a focus on investigating safety. They also studied whether the treatment intervention led to clinical healing that could be confirmed through deep tissue imaging.
Dr. Dozois’ team documented complete healing of 14 patients at six months and 13 patients at one year. Three patients withdrew for various reasons during the course of the clinical trial.
Four participants reported side effects such as infections that required admission to the hospital or surgical draining of an abscess. Twelve participants experienced reactions considered to be minor, such as redness, fever or nausea.
Based on their findings, Dr. Dozois’ team is recommending further study of the stem cell-coated fistula plug with larger sample sizes and more types of fistulas. If all goes well, it could take two or three years before this procedure is approved for routine clinical care.
Dr. Dozois, Dr. Faubion and Mayo Clinic have financial interests in the regenerative fistula plug technology. Any profits Mayo Clinic realizes from its business ventures are reinvested in research and education initiatives at Mayo.