Month: March 2024

Categories : CancerTags :

In the Breast Cancer Fight, the Next Battleground is Malignancy Hibernation

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Photo by Michelle Leman on Pexels

There is a surprising dearth of research about how breast cancer cells can go dormant, spread and then resurface years or even decades later, according to a new review of in vitro breast cancer studies conducted by researchers at the University of Massachusetts Amherst.

“[Our review found that] less than 1% of all these studies that combine cells with designer environments look at dormancy,” says Shelly Peyton, Provost Professor of Chemical Engineering. “It’s not enough. We just don’t understand what’s happening – and it’s killing patients.”

Breast cancer dormancy is a phenomenon in which breast cancer cells metastasise (typically to the liver, lungs, brain or bones) but don’t grow. “They’re not detectable or symptomatic tumours,” Peyton explains. “A patient will have their primary tumour removed and appear to be disease-free for months, years, even decades. And for reasons we don’t understand, something changes about the environment that causes those cells to start regrowing, and then you have a deadly metastasis.”

Patients with metastatic breast cancer have a 30% five-year survival rate, compared to a 99% survival rate for localised breast cancer. “Early detection is key, particularly in the Western world,” says Peyton. “You can have lumpectomies, radiation, small surgeries. And women can survive. It’s when that cancer has spread that it becomes much harder to treat.”

This relapse in distant organs impacts 40% of early-stage breast cancer patients, and breast cancer dormancy is a contributing factor. But while metastasis has known biomarkers, dormant cancer cells are very hard to identify. 

“When you have a single dormant breast cancer cell that’s hiding in a distant tissue, it’s really hard to detect that,” says Nate Richbourg, lead author on the paper and postdoctoral researcher in the Peyton Lab. “And you don’t want to do an invasive biopsy or prescribe toxic chemotherapy for something that might not be a problem.”

With these challenges in mind, the review, published in Science Advances, aimed to identify gaps in the research, particularly focusing on in vitro studies, or research using benchtop-model environments instead of animal models or humans. In vitro studies allow for the precise control of the environment, which Peyton’s research group says may play a deciding role in whether a cell remains dormant or reactivates into a deadly metastatic tumor. 

“What can we control in these artificial environments that will give us insight into how breast cancer dormancy happens, and what we can do to treat it as well?” Richbourg asks, describing the importance of in vitro modelling. “When we create this artificial dormancy, we can see how many of those cells could turn back into proliferating and potentially deadly cells.”

Their review highlights just how complex the role of the environment is. “If you have a [breast cancer] cell somewhere in the bone marrow, you’re going to have other cells there, the physical factors in your environment, and the biochemical factors,” Richbourg gives as an example. “We try to use reductive models to separate the thing that is influencing this behaviour. But what we’re seeing is that everything works together to create this breast cancer dormancy effect. The better we can create models that capture all that nuance, the better we’re going to be able to understand it.”

For Peyton, their work is also a call to action. “The paper is calling out to the field that we need to do more,” she says. This includes being more creative with the materials that already exist and developing new materials; identifying ways to model the decades-long progression of dormancy that is impossible to recreate in a single study; and expanding the diversity of cell lines used for research (Richbourg points out that many of the studies they reviewed used the same cell line, MDA-MB-231, derived from one 40-to-50-year-old white woman).

Finally, the researchers have an eye to the ultimate goal: better treatments to save patients. “We see that that there are some clinical trials that are happening that are derived from some of those in vitro models,” says Ninette Irakoze, graduate student in the Peyton Lab. “The paper gives hope that, with more development of these in vitro models, eventually we could find treatments to eradicate dormant cancer.”

Source: University of Massachusetts Amherst

Categories : IT in Healthcare Lab Tests and ImagingTags :

Is AI a Help or Hindrance to Radiologists? It’s Down to the Doctor

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New research shows AI isn’t always a help for radiologists

Photo by Anna Shvets

One of the most touted promises of medical artificial intelligence tools is their ability to augment human clinicians’ performance by helping them interpret images such as X-rays and CT scans with greater precision to make more accurate diagnoses.

But the benefits of using AI tools on image interpretation appear to vary from clinician to clinician, according to new research led by investigators at Harvard Medical School, working with colleagues at MIT and Stanford.

The study findings suggest that individual clinician differences shape the interaction between human and machine in critical ways that researchers do not yet fully understand. The analysis, published in Nature Medicine, is based on data from an earlier working paper by the same research group released by the National Bureau of Economic Research.

In some instances, the research showed, use of AI can interfere with a radiologist’s performance and interfere with the accuracy of their interpretation.

“We find that different radiologists, indeed, react differently to AI assistance – some are helped while others are hurt by it,” said co-senior author Pranav Rajpurkar, assistant professor of biomedical informatics in the Blavatnik Institute at HMS.

“What this means is that we should not look at radiologists as a uniform population and consider just the ‘average’ effect of AI on their performance,” he said. “To maximize benefits and minimize harm, we need to personalize assistive AI systems.”

The findings underscore the importance of carefully calibrated implementation of AI into clinical practice, but they should in no way discourage the adoption of AI in radiologists’ offices and clinics, the researchers said.

Instead, the results should signal the need to better understand how humans and AI interact and to design carefully calibrated approaches that boost human performance rather than hurt it.

“Clinicians have different levels of expertise, experience, and decision-making styles, so ensuring that AI reflects this diversity is critical for targeted implementation,” said Feiyang “Kathy” Yu, who conducted the work while at the Rajpurkar lab with co-first author on the paper with Alex Moehring at the MIT Sloan School of Management.

“Individual factors and variation would be key in ensuring that AI advances rather than interferes with performance and, ultimately, with diagnosis,” Yu said.

AI tools affected different radiologists differently

While previous research has shown that AI assistants can, indeed, boost radiologists’ diagnostic performance, these studies have looked at radiologists as a whole without accounting for variability from radiologist to radiologist.

In contrast, the new study looks at how individual clinician factors – area of specialty, years of practice, prior use of AI tools – come into play in human-AI collaboration.

The researchers examined how AI tools affected the performance of 140 radiologists on 15 X-ray diagnostic tasks – how reliably the radiologists were able to spot telltale features on an image and make an accurate diagnosis. The analysis involved 324 patient cases with 15 pathologies: abnormal conditions captured on X-rays of the chest.

To determine how AI affected doctors’ ability to spot and correctly identify problems, the researchers used advanced computational methods that captured the magnitude of change in performance when using AI and when not using it.

The effect of AI assistance was inconsistent and varied across radiologists, with the performance of some radiologists improving with AI and worsening in others.

AI tools influenced human performance unpredictably

AI’s effects on human radiologists’ performance varied in often surprising ways.

For instance, contrary to what the researchers expected, factors such how many years of experience a radiologist had, whether they specialised in thoracic, or chest, radiology, and whether they’d used AI readers before, did not reliably predict how an AI tool would affect a doctor’s performance.

Another finding that challenged the prevailing wisdom: Clinicians who had low performance at baseline did not benefit consistently from AI assistance. Some benefited more, some less, and some none at all. Overall, however, lower-performing radiologists at baseline had lower performance with or without AI. The same was true among radiologists who performed better at baseline. They performed consistently well, overall, with or without AI.

Then came a not-so-surprising finding: More accurate AI tools boosted radiologists’ performance, while poorly performing AI tools diminished the diagnostic accuracy of human clinicians.

While the analysis was not done in a way that allowed researchers to determine why this happened, the finding points to the importance of testing and validating AI tool performance before clinical deployment, the researchers said. Such pre-testing could ensure that inferior AI doesn’t interfere with human clinicians’ performance and, therefore, patient care.

What do these findings mean for the future of AI in the clinic?

The researchers cautioned that their findings do not provide an explanation for why and how AI tools seem to affect performance across human clinicians differently, but note that understanding why would be critical to ensuring that AI radiology tools augment human performance rather than hurt it.

To that end, the team noted, AI developers should work with physicians who use their tools to understand and define the precise factors that come into play in the human-AI interaction.

And, the researchers added, the radiologist-AI interaction should be tested in experimental settings that mimic real-world scenarios and reflect the actual patient population for which the tools are designed.

Apart from improving the accuracy of the AI tools, it’s also important to train radiologists to detect inaccurate AI predictions and to question an AI tool’s diagnostic call, the research team said. To achieve that, AI developers should ensure that they design AI models that can “explain” their decisions.

“Our research reveals the nuanced and complex nature of machine-human interaction,” said study co-senior author Nikhil Agarwal, professor of economics at MIT. “It highlights the need to understand the multitude of factors involved in this interplay and how they influence the ultimate diagnosis and care of patients.”

Source: Harvard Medical School

Categories : Substance UseTags :

Low Social Status Increases Risk of Health Problems from Alcohol Problems

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People with low income or education levels may benefit from screening for alcohol-related conditions

Photo from Pixabay CC0

Men and women with lower income or education levels are more likely to develop medical conditions related to alcohol abuse compared to similar individuals with a higher socioeconomic status. Alexis Edwards of Virginia Commonwealth University, US, and colleagues report these findings in a new study published March 19th in the open access journal PLOS Medicine.

The World Health Organization estimates that harmful alcohol use accounts for 5.1% of the global burden of disease and injury worldwide, and results in three million deaths each year. Excessive alcohol consumption can also take an economic toll. Previous studies have identified links between a person’s socioeconomic status and alcohol use, but currently it is unclear how an individual’s social class impacts their future risk of acquiring alcohol-related medical conditions, like alcoholic liver disease.

In the new study, researchers used a model that follows people over time to estimate their risk of developing medical conditions from alcohol abuse using two indicators for socioeconomic status: income and education level. The researchers analysed data from more than 2.3 million individuals in a Swedish database to show that both men and women with a lower income or education level were more likely to develop these conditions. The associations held true, even when researchers controlled for other relevant factors, such as marital status, history of psychiatric illness and having a genetic predisposition to abuse alcohol.

The new findings are important for understanding which populations are most likely to suffer from medical conditions resulting from alcohol abuse, and contribute to a growing body of literature on health disparities that stem from socioeconomic factors. The researchers recommend that individuals with lower income or education levels might warrant additional screening by clinicians to evaluate their alcohol consumption and identify related conditions.

The authors add, “Among individuals with an alcohol use disorder, those with lower levels of education or lower incomes are at higher risk for developing an alcohol-related medical condition, such as cirrhosis or alcoholic cardiomyopathy. Additional screening and prevention efforts may be warranted to reduce health disparities.”

Source: PLOS

Categories : Environmental Effects Ethics and LawTags :

Opinion Piece: Ripples of Change toward Building a World of Water Equity and Unity

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By Robert Erasmus, Managing Director at Sanitech

Photo by Hush Naidoo Jade Photography on Unsplash

World Water Day 2024 resonates deeply in South Africa, where access to clean water remains a significant struggle for many. Recent protests sparked by water scarcity highlight the urgency of this issue, reminding us that water is not just a resource, but a fundamental human right.

This year’s theme, “Leveraging Water for Peace,” calls for unity and recognition of water’s universal significance. As we face the reality of inequality, it is important for us to renew our commitment to equitable water access for all, by fostering dialogue and taking action that is deeply rooted in empathy and ubuntu. Every drop should bring not only sustenance, but also the promise of peace and prosperity.

Connecting local struggles to global issues

South Africa’s water challenges mirror broader global concerns. Ranked a worrying fifth in global water risk, we share these strained resources with our neighbours. This interconnectedness cannot be ignored, and neglecting this truth is likely to fuel regional tensions. Instead, by highlighting our shared challenge, we can strengthen our position and emphasise the need for collaborative solutions. The depth of South Africa’s water scarcity isn’t just a domestic issue – it’s a regional one. Our ranking among the world’s worst puts us alongside stressed neighbours, suggesting the potential for cross-border conflict over shared resources.

Internally, competition between formal and informal users already creates friction, amplified by seasonal rainfall and inadequate infrastructure. To make matters worse, poor sanitation further contaminates water sources, escalating the crisis. The Institute for Security Studies’ Public Violence and Protest Monitor shows that in South Africa, community frustrations with water and sanitation delivery failures resulted in 585 cases of public protest between January 2013 and April 2021, of which incidents, 65% escalated into violent protests.

Aligning with the water rights framework

Although South Africa boasts a progressive water rights framework, our efforts must align with this framework, ensuring that the fight for water equity remains central to our pursuit of peace. Empowering communities with access to clean drinking water and sanitation and upholding water rights are essential steps toward conflict prevention.

Raising awareness is essential, but tangible action holds the key to progress. Businesses can play an important role in acknowledging South Africa’s water scarcity and investing in corporate social responsibility (CSR) projects that focus on addressing sanitation and water quality in the communities in which they operate. From an individual perspective, it is important that each citizen does their part to conserve water, while supporting organisations that work on improving water access, and raising awareness of related issues within their communities. At a government level, it is critical to prioritise infrastructure maintenance, address sewage contamination, and collaborate with regional partners and industries on sustainable water management strategies, to prevent civil unrest by addressing water equity issues.

Tapping into Ubuntu and empathy

Ubuntu, the South African philosophy of shared humanity, encourages us to understand and share the experiences of others. Cultivating empathy across communities, businesses, and government fosters inclusive dialogue and collaborative solutions. With the principles of ubuntu in mind, it is critical to address sewage contamination to preserve our scarce water resources. It is essential for municipalities and provincial governments to invest in infrastructure upgrades to reduce water loss and improve delivery.   Businesses operating within the sanitation and water treatment sectors have the potential to empower communities by providing filtration and treatment solutions for local water sources. Moreover, the broader private sector can contribute to corporate social responsibility (CSR) initiatives aimed at enhancing sanitation and water quality in vulnerable communities.

Amplifying voices through collaborative communication

Empowering community voices is vitally important. This can be achieved through increased awareness on water scarcity and its impact, as well as by supporting local initiatives that improve water access and quality. Based on the principles of ubuntu, we must advocate for the facilitation of open communication between communities, businesses, and government. Water advocacy groups such as South African Water Caucus (SAWC), and water project NGOs such as the Mvula Trust must continue to advocate for increased funding for water and sanitation projects, by holding the government accountable for meeting water rights and supporting regional cooperation on water management.

Uniting for peace and prosperity

In this way, individuals, organisations, and governments can turn the promise of World Water Day into tangible progress by working together. In prioritising equitable water access, addressing underlying challenges, and fostering collaboration, we can build a future where every drop flows towards peace, not conflict. Remember, water scarcity and strife does not have to be our inevitable future. Through collective action and commitment, we can ensure that this precious resource serves as a bridge to peace and prosperity for all.

Categories : NeurologyTags :

ADHD Medication Associated with Reduced Mortality

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Photo by Annie Spratt on Unsplash

A Swedish study of more than 140 000 individuals with attention-deficit/hyperactivity disorder (ADHD) found that initiation of ADHD medication was significantly associated with a 21% lower mortality two years after diagnosis, according to results published in JAMA. This reduction was especially pronounced for unnatural-cause mortality. Females and males also saw different reductions in types of mortality.

ADHD is the most prevalent neurodevelopmental condition, affecting 5.9% of youths and 2.5% of adults worldwide, according to the 2021 World Federation of ADHD International Consensus Statement. The disorder is associated with a broad range of psychiatric and physical comorbidities, as well as adverse functional outcomes. Furthermore, individuals with ADHD are at twice the risk of premature death, mainly due to unnatural causes.

Randomised controlled trials have demonstrated that ADHD medications, including stimulant and nonstimulant medications, are effective in reducing core ADHD symptoms for children and adults with ADHS. Pharmacoepidemiological studies have also shown reduced risks of negative outcomes, including injuries, traffic collisions, and criminality, which would be expected to decrease the mortality rate. However, there are concerns regarding the cardiovascular safety of ADHD medications, especially following long-term use, which could increase the mortality rate.

To date, three studies have examined the association between ADHD medication and mortality with mixed results. These studies had significant limitations, such as the absence of a control group. To date, there has been no study on the association in adults with ADHD. There are increasing diagnoses of ADHD among adults, who have a higher prevalence of somatic comorbidities, including cardiovascular diseases and other conditions, compared with children and adolescents.

Using the Swedish national registers, the researchers investigated whether initiation of ADHD medication was associated with mortality, using the target trial emulation approach to avoid key biases in pharmacoepidemiological studies.

They assessed for all 6 medications licensed for ADHD treatment in Sweden (methylphenidate, amphetamine, dexamphetamine, lisdexamfetamine, atomoxetine, and guanfacine) during the 2007-2020 period. Analysis of the data showed that, for a two-year follow-up, lower all-cause (hazard ratio [HR], 0.79) and unnatural-cause (HR, 0.75) mortality for the ADHD medication group, but there was no significant association with natural-cause mortality (HR, 0.86). Under unnatural causes, accidental poisoning mortality was halved (HR, 0.47).

Subgroup analysis revealed that for females, the only significant reduction in mortality was for natural causes. The authors noted that this may be due to higher rates of comorbid depression, sleep disorder, atrial fibrillation, and asthma.

When follow-up was extended to five years, associations attenuated save for unnatural-cause mortality (HR, 0.89).

The authors concluded, “ADHD medication may reduce the risk of unnatural-cause mortality by alleviating the core symptoms of ADHD and its psychiatric comorbidities, leading to improved impulse control and decision-making, ultimately reducing the occurrence of fatal events, in particular among those due to accidental poisoning.”

For limitations, the observational nature of the study cannot establish causation, and the authors noted confounding effects such as nonpharmaceutical treatment of ADHD. Potential type I error resulting from multiple comparisons regarding cause-specific mortality and subgroup analyses meant the results are only exploratory. Two more limitations were uncertain adherence to medication and potential misclassification of deaths such as potential cases of suicide being marked as accidental poisoning.

Categories : Cardiovascular DiseaseTags :

Timed Therapy with Intense Light can Benefit Cardiovascular Health

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Photo by Stormseeker on Unsplash

Managing circadian rhythms through intense light and chronologically timed therapy can help prevent or treat a variety of circulatory system conditions including heart disease, according to a new study published in Circulation Research.

“The impact of circadian rhythms on cardiovascular function and disease development is well established,” said the study’s lead author Tobias Eckle, MD, PhD, professor of anaesthesiology at the University of Colorado School of Medicine.

“However, translational preclinical studies targeting the heart’s circadian biology are just now emerging and are leading to the development of a novel field of medicine termed circadian medicine.”

The senior author is Professor Tami A. Martino, PhD, distinguished chair in molecular and cardiovascular research at the University of Guelph in Ontario, Canada.

The study reviews current circadian medicine research, focusing on the use of intense light therapy following surgery, utilizsng light to treat cardiac injury, exploring how cardiovascular disease can differ between men and women and administering drugs at specific times of day to coincide with the body’s internal clock to speed healing.

It also urges more aggressive use of this therapy in humans, rather than relying on mostly animal models.

“There are literally millions of patients who could benefit from this,” Eckle said.

“The treatments are almost all low-risk. Some involve using light boxes and others use drugs that are already on the market.”

Circadian rhythms significantly influence how the cardiovascular system operates. Timing is everything. Blood pressure and heart rates follow distinct patterns, peaking during the day and ebbing at night. When this is disrupted, it leads to worse cardiovascular disease outcomes including myocardial infarction and heart failure. Light is critical in maintaining the proper balance and functioning of the body. Shift employees who may work night hours then day hours often have worse cardiac outcomes.

Eckle, who has studied circadian rhythm and health for years, said intense light can help heal the body after heart surgery while protecting it from injury during surgery, including reducing the chances of cardiac ischemia.

According to the researchers, when light hits the human eye it is transmitted to the suprachiasmatic nucleus, a structure in the brain’s hypothalamus that regulates most circadian rhythms in the body.

Intense light stabilizes the PER2 gene and increases levels of adenosine, which blocks electrical signals in the heart that cause irregular rhythms, making it cardiac protective.

Eckle has used light therapy with patients after surgery and seen positive results including lower levels of troponin, a key protein whose elevation can signal a heart attack or stroke.

Given the mounting evidence that intense light and timed drug treatments are effective, he said, it is time to move forward with more clinical trials.

“Circadian rhythms play a crucial role in cardiovascular health, influencing the timing of onset and severity of cardiovascular events and contributing to the healing process from disease,” Eckle said. “Studies in humans are clearly required. Regarding intense light therapy, chronotherapy and restricted feeding are low-risk strategies that should be tested sooner than later.”

Source: University of Colorado Anschutz Medical Campus

Categories : Neurology PaediatricsTags :

Could a Simple Eye Reflex Test Pick up Autism in Children?

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Photo by Helena Lopes on Unsplash

Scientists at UC San Francisco that they may have discovered a new way to test for autism by measuring how children’s eyes move when they turn their heads. They found that children with a variant of a gene that is associated with severe autism are hypersensitive to this motion.

The gene, SCN2A, makes an ion channel that is found throughout the brain, including the region that coordinates movement – the cerebellum. Several variants of this gene are also associated with severe epilepsy and intellectual disability.

The researchers found that children with these variants have an unusual form of the reflex that stabilizes the gaze while the head is moving, called the vestibulo-ocular reflex (VOR). In children with autism, it seems to go overboard, and this can be measured with a simple eye-tracking device.

The discovery, published in the journal Neuron, could help to advance research on autism, which affects 1 out of every 36 children in the United States. And it could help to diagnose kids earlier and faster with a method that only requires them to don a helmet and sit in a chair.

“We can measure it in kids with autism who are non-verbal or can’t or don’t want to follow instructions,” said Kevin Bender, PhD, a professor in the UCSF Weill Institute for Neurosciences and co-senior author of the study. “This could be a game-changer in both the clinic and the lab.”

A telltale sign of autism in an eye reflex

Of the hundreds of gene mutations associated with autism, variants of the SCN2A gene are among the most common.

Since autism affects social communication, ion channel experts like Bender had focused on the frontal lobe of the brain, which governs language and social skills in people. But mice with an autism-associated variant of the SCN2A gene did not display marked behavioral differences associated with this brain region.

Chenyu Wang, a UCSF graduate student in Bender’s lab and first author of the study, decided to look at what the SCN2A variant was doing in the mouse cerebellum. Guy Bouvier, PhD, a cerebellum expert at UCSF and co-senior author of the paper, already had the equipment needed to test behaviors influenced by the cerebellum, like the VOR.

The VOR is easy to provoke. Shake your head and your eyes will stay roughly centered. In mice with the SCN2A variant, however, the researchers discovered that this reflex was unusually sensitive. When these mice were rotated in one direction, their eyes compensated perfectly, rotating in the opposite direction.

But this increased sensitivity came at a cost. Normally, neural circuits in the cerebellum can refine the reflex when needed, for example to enable the eyes to focus on a moving object while the head is also moving. In SCN2A mice, however, these circuits got stuck, making the reflex rigid.

A mouse result translates nearly perfectly to kids with autism

Wang and Bender had uncovered something rare: a behaviour that arose from a variant to the SCN2A gene that was easy to measure in mice. But would it work in people?

They decided to test it with an eye-tracking camera mounted on a helmet. It was a “shot in the dark,” Wang said, given that the two scientists had never conducted a study in humans.

Bender asked several families from the FamilieSCN2A Foundation, the major family advocacy group for children with SCN2A variants in the US, to participate. Five children with SCN2A autism and eleven of their neurotypical siblings volunteered.

Wang and Bender took turns rotating the children to the left and right in an office chair to the beat of a metronome. The VOR was hypersensitive in the children with autism, but not in their neurotypical siblings.

The scientists could tell which children had autism just by measuring how much their eyes moved in response to their head rotation.

A CRISPR cure in mice

The scientists also wanted to see if they could restore the normal eye reflex in the mice with a CRISPR-based technology that restored SCN2A gene expression in the cerebellum.

When they treated 30-day-old SCN2A mice – equivalent to late adolescence in humans – their VOR became less rigid but was still unusually sensitive to body motion. But when they treated 3-day-old SCN2A mice – early childhood in humans – their eye reflexes were completely normal.

“These first results, using this reflex as our proxy for autism, point to an early window for future therapies that get the developing brain back on track,” Wang said.

It’s too early to say whether such an approach might someday be used to directly treat autism. But the eye reflex test, on its own, could clear the way to more expedient autism diagnosis for kids today, saving families from long diagnostic odysseys.

“If this sort of assessment works in our hands, with kids with profound, nonverbal autism, there really is hope it could be more widely adopted,” Bender said.

Source: University of California – San Francisco

Categories : Genetics Metabolic DisordersTags :

Smart Moo-ve for Diabetes Treatment: Insulin Produced in Cow’s Milk

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Photo by Pixabay on Pexels

An unassuming brown bovine from the south of Brazil has made history as the first transgenic cow capable of producing human insulin in her milk. The advancement, led by researchers from the University of Illinois Urbana-Champaign and the Universidade de São Paulo, could herald a new era in insulin production, one day eliminating drug scarcity and high costs for people living with diabetes.

“Mother Nature designed the mammary gland as a factory to make protein really, really efficiently. We can take advantage of that system to produce a protein that can help hundreds of millions of people worldwide,” said Matt Wheeler, professor in the Department of Animal Sciences, part of the College of Agricultural, Consumer and Environmental Sciences (ACES) at U. of I.

Wheeler is lead author on a new Biotechnology Journal study describing the development of the insulin-producing cow, a proof-of-concept achievement that could be scaled up after additional testing and FDA approval.

Precise insertion of DNA

Wheeler’s colleagues in Brazil inserted a segment of human DNA coding for proinsulin – the protein precursor of the active form of insulin – into cell nuclei of 10 cow embryos. These were implanted in the uteruses of normal cows in Brazil, and one transgenic calf was born. Thanks to updated genetic engineering technology, the human DNA was targeted for expression – the process whereby gene sequences are read and translated into protein products – in mammary tissue only.

“In the old days, we used to just slam DNA in and hope it got expressed where you wanted it to,” Wheeler said. “We can be much more strategic and targeted these days. Using a DNA construct specific to mammary tissue means there’s no human insulin circulating in the cow’s blood or other tissues. It also takes advantage of the mammary gland’s capabilities for producing large quantities of protein.”

When the cow reached maturity, the team unsuccessfully attempted to impregnate her using standard artificial insemination techniques. Instead, they stimulated her first lactation using hormones. The lactation yielded milk, but a smaller quantity than would occur after a successful pregnancy. Still, human proinsulin and, surprisingly, insulin were detectable in the milk.

“Our goal was to make proinsulin, purify it out to insulin, and go from there. But the cow basically processed it herself. She makes about three to one biologically active insulin to proinsulin,” Wheeler said. “The mammary gland is a magical thing.”

The insulin and proinsulin, which would need to be extracted and purified for use, were expressed at a few grams per liter in the milk. But because the lactation was induced hormonally and the milk volume was smaller than expected, the team can’t say exactly how much insulin would be made in a typical lactation.

Conservatively, Wheeler says if a cow could make 1 gram of insulin per liter and a typical Holstein makes 40 to 50 litres per day, that’s a lot of insulin. Especially since the typical unit of insulin equals 0.0347 milligrams.

“That means each gram is equivalent to 28,818 units of insulin,” Wheeler said. “And that’s just one liter; Holsteins can produce 50 liters per day. You can do the math.”

The team plans to re-clone the cow, and is optimistic they’ll achieve greater success with pregnancy and full lactation cycles in the next generation. Eventually, they hope to create transgenic bulls to mate with the females, creating transgenic offspring that can be used to establish a purpose-built herd. Wheeler says even a small herd could quickly outcompete existing methods – transgenic yeast and bacteria – for producing insulin, and could do so without having to create highly technical facilities or infrastructure.

“With regard to mass-producing insulin in milk, you’d need specialized, high-health-status facilities for the cattle, but it’s nothing too out of the ordinary for our well-established dairy industry,” Wheeler said. “We know what we’re doing with cows.”

An efficient system to collect and purify insulin products would be needed, as well as FDA approval, before transgenic cows could supply insulin for the world’s diabetics. But Wheeler is confident that day is coming.

“I could see a future where a 100-head herd, equivalent to a small Illinois or Wisconsin dairy, could produce all the insulin needed for the country,” he said. “And a larger herd? You could make the whole world’s supply in a year.

Source: University of Illinois College of Agricultural, Consumer and Environmental Sciences

Categories : AntibioticsTags :

Steroid Drugs Used for HRT could be Repurposed to Combat E. coli and MRSA

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Methicillin resistant Staphylococcus aureus (MRSA) – Credit: CDC

Researchers from the University of Kent’s School of Biosciences have combined computational and microbiology laboratory approaches to identify existing drugs that can be repurposed to combat antibiotic-resistant bacterial infections, instead of developing new ones.

This research, which has been published in the Journal of Infectious Diseases, revealed that a class of steroid drugs currently used in hormone replacement therapy (HRT) can also stop the growth of antibiotic-resistant E. coli and effectively kill MRSA.

These drugs are particularly good at binding to a protein complex, cytochrome bd, which is important for the growth and survival of a range of disease-causing bacterial species. The researchers made an in silico screening for drugs that could inhibit bd activity, and identified quinestrol, ethinyl estradiol and mestranol, then evaluated their effectiveness in vitro.

The steroid drugs ethinyl estradiol and quinestrol inhibited E. coli bd-I activity. The IC50 of quinestrol for inhibiting oxygen consumption in E. coli bd-I-only membranes as 0.2µg/mL, although residual activity remained at around 20% at higher concentrations Quinestrol exhibited potent bactericidal effects against S. aureus but not E. coli.

It is expected that steroids may provide an alternative to conventional antibiotics that are becoming increasingly ineffective.

Dr Mark Shepherd, Reader in Microbial Biochemistry at Kent and the corresponding author on the paper, said: “These exciting developments will help to advance research into new antimicrobials, and we are enthusiastic to use our powerful experimental approach to discover drugs that can target other bacterial proteins and combat a wide range of antibiotic-resistant infections.”

Source: University of Kent

Categories : NeurologyTags :

Researchers 3D-print Functional Human Brain Tissue

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AI-generated image illustrating 3-D tissue printing

A team of scientists has developed the first 3D-printed brain tissue that can grow and function like typical brain tissue. This has important implications for scientists studying the brain and working on treatments for a broad range of neurological and neurodevelopmental disorders, such as Alzheimer’s and Parkinson’s disease.

“This could be a hugely powerful model to help us understand how brain cells and parts of the brain communicate in humans,” says Su-Chun Zhang, professor of neuroscience and neurology at UW-Madison’s Waisman Center. “It could change the way we look at stem cell biology, neuroscience, and the pathogenesis of many neurological and psychiatric disorders.”

Printing methods have limited the success of previous attempts to print brain tissue, according to Zhang and Yuanwei Yan, a scientist in Zhang’s lab. The group behind the new 3D-printing process described their method today in the journal Cell Stem Cell.

Instead of using the traditional 3D-printing approach, stacking layers vertically, the researchers went horizontally. They situated brain cells, neurons grown from induced pluripotent stem cells, in a softer “bio-ink” gel than previous attempts had employed.

“The tissue still has enough structure to hold together but it is soft enough to allow the neurons to grow into each other and start talking to each other,” Zhang says.

The cells are laid next to each other like pencils laid next to each other on a tabletop.

“Our tissue stays relatively thin and this makes it easy for the neurons to get enough oxygen and enough nutrients from the growth media,” Yan says.

The results speak for themselves – which is to say, the cells can speak to each other. The printed cells reach through the medium to form connections inside each printed layer as well as across layers, forming networks comparable to human brains. The neurons communicate, send signals, interact with each other through neurotransmitters, and even form proper networks with support cells that were added to the printed tissue.

“We printed the cerebral cortex and the striatum and what we found was quite striking,” Zhang says. “Even when we printed different cells belonging to different parts of the brain, they were still able to talk to each other in a very special and specific way.”

The printing technique offers precision – control over the types and arrangement of cells – not found in brain organoids, miniature organs used to study brains. The organoids grow with less organisation and control.

“Our lab is very special in that we are able to produce pretty much any type of neurons at any time. Then we can piece them together at almost any time and in whatever way we like,” Zhang says. “Because we can print the tissue by design, we can have a defined system to look at how our human brain network operates. We can look very specifically at how the nerve cells talk to each other under certain conditions because we can print exactly what we want.”

That specificity provides flexibility. The printed brain tissue could be used to study signaling between cells in Down syndrome, interactions between healthy tissue and neighboring tissue affected by Alzheimer’s, testing new drug candidates, or even watching the brain grow.

“In the past, we have often looked at one thing at a time, which means we often miss some critical components. Our brain operates in networks. We want to print brain tissue this way because cells do not operate by themselves. They talk to each other. This is how our brain works and it has to be studied all together like this to truly understand it,” Zhang says. “Our brain tissue could be used to study almost every major aspect of what many people at the Waisman Center are working on. It can be used to look at the molecular mechanisms underlying brain development, human development, developmental disabilities, neurodegenerative disorders, and more.”

The new printing technique should also be accessible to many labs. It does not require special bio-printing equipment or culturing methods to keep the tissue healthy, and can be studied in depth with microscopes, standard imaging techniques and electrodes already common in the field.

The researchers would like to explore the potential of specialization, though, further improving their bio-ink and refining their equipment to allow for specific orientations of cells within their printed tissue..

“Right now, our printer is a benchtop commercialised one,” Yan says. “We can make some specialised improvements to help us print specific types of brain tissue on-demand.”

Source: University of Wisconsin-Madison