Rare hormone producing cells in the gut secrete hormones in response to incoming food and play key roles in managing digestion and appetite. Researchers have now developed new tools to identify potential ‘nutrient sensors’ on these hormone producing cells and study their function. This could result in new strategies to interfere with the release of these hormones and provide avenues for the treatment of a variety of metabolic or gut motility disorders.
The intestine acts as a vital barrier. It protects the body from harmful bacteria and highly dynamic pH levels, while allowing nutrients and vitamins to enter the bloodstream. The gut is also home to endocrine cells, which secrete many hormones that regulate bodily functions. These enteroendocrine cells (endocrine cells of the gut) are very rare cells that release hormones in response to various triggers, such as stretching of the stomach, energy levels and nutrients from food. These hormones in turn regulate key aspects of physiology in response to the incoming food, such as digestion and appetite. Thus, enteroendocrine cells are the body’s first responders to incoming food, and instruct and prepare the rest of the body for what is coming.
Understanding hormone release
Medications that mimic gut hormones, most famously GLP-1, are promising for the treatment of multiple metabolic diseases. The ability to directly manipulate endocrine cells to adjust hormone secretion could open up new therapeutic options. However, it has been challenging to understand how gut hormone release can be influenced effectively. Researchers have had trouble identifying the sensors on cells.
Enteroendocrine cells represent less than 1% of cells in the intestinal epithelium. In addition, the sensors on these cells are expressed in low amounts. Current studies mainly rely on mouse models, but the signals to which mouse cells respond are likely different from those to which human cells respond. Therefore, new models and approaches were required to study these signals.
Enteroendocrine cells in organoids
The Hubrecht team has previously developed methods to derive large quantities of enteroendocrine cells in human organoids. Organoids contain the same cell types of the organ they are derived from. Therefore, they are useful to explore the development and function of cells. Using a special protein, Neurogenin-3, the researchers could generate high numbers of endocrine cells in organoids of the intestine.
Enteroendocrine cells have different sensors and hormone profiles in different regions of the gut. In order to study these rare cells, the researchers needed to make organoids of all these different regions.
Stomach organoids
In the current study, the team managed to enrich enteroendocrine cells in organoids of other parts of the digestive system, including the stomach. Like the real stomach, stomach organoids respond to known inducers of hormone release and secrete large amounts of the hormone Ghrelin. Ghrelin is also called the ‘hunger hormone’ because it plays a key role in signaling hunger to the brain. The Ghrelin production of the stomach organoids confirms that these organoids can be used to study hormone secretion in enteroendocrine cells.
Enteroendocrine cell sensors
Since enteroendocrine cells are rare, researchers have struggled to profile many of these cells. In the current study, the team identified a so-called surface marker, called CD200, on human cells. The researchers used this surface marker to isolate a large number of human enteroendocrine cells from organoids and study their sensors. This revealed numerous receptor proteins that had not yet been identified in enteroendocrine cells.
The team stimulated the organoids with molecules that would activate these receptors and identified multiple new sensory receptors that control hormone release. When the researchers inactivated these receptors using CRISPR-based gene editing, hormone secretion was often blocked.
Therapeutic applications
With these data, the researchers can now predict how human enteroendocrine cells respond when certain sensory receptors are activated. Their findings thus pave the way for additional studies to explore the effects of these receptor activations. The enteroendocrine cell-enriched organoids will allow the team to perform larger, unbiased studies to identify new regulators of hormone secretion. These studies may eventually lead to therapies for metabolic diseases and gut motility disorders.
Family physicians undergo an extra four years of training, with an emphasis on clinical governance and knowledge of social factors influencing people’s health. Photo by cottonbro studio
By Chris Bateman
Around twenty years ago, family physicians seemed set to take up roles as critical cogs across South Africa’s public healthcare system, but in the years since, doctors trained in this speciality have largely been underutilised. That is now finally set to change, according to the Department of Health, Chris Bateman reports.
The National Department of Health has signalled that they want to see more family physicians appointed as clinical managers tasked with leading multi-disciplinary district hospital teams. This follows years of lobbying by the South African Academy of Family Physicians (SAAFP) advocating for the greater utilisation of family physicians in the country’s public healthcare system.
The SAAFP has long argued the cost and clinical effectiveness of these “super generalists”, who undergo an extra four years of training, with an emphasis on clinical governance and knowledge of social factors influencing people’s health. And it seems their patience has been rewarded with a five-year district health blueprint from government.
This was confirmed to Spotlight by Dr Luvuyo Bayeni, Chief Director of Human Resources for Health at the National Department of Health.
Advocates for the speciality argue that family physicians have been neglected, with posts thin on the ground and their potential contribution under-estimated. The discipline was registered with the HPCSA in 2007.
Professor Bob Mash, Distinguished Professor at Stellenbosch University where he heads the Division of Family Medicine and Primary Care, describes the specialty as “one of the most underutilised solutions to many of the problems facing district health service delivery”. Mash is the immediate past president of the SAAFP.
Bayeni, a former clinician/administrator in the Eastern Cape, was appointed to lead the health department’s human resource operations in July last year. Since then, he attended the last two annual SAAFP conferences and has been meeting regularly with the academy’s leadership.
With austerity measures being the catch-all rebuttal by provincial heads of department whenever the wisdom of freezing posts is questioned, Bayeni is trying to persuade his provincial counterparts to adopt a policy of appointing family physicians to clinical manager posts as a highly cost-efficient move, citing successes in the Western Cape. The idea is that family physicians are able to quickly diagnose and treat patients while mentoring junior colleagues. They also help design or tweak hospital and referral clinic systems for efficiency and identify preventative health interventions at community level.
Blueprint approved
In a wide-ranging interview with Spotlight, Bayeni said his family medicine oriented blueprint had been approved by the Presidency’s Department of Policy Planning, Monitoring and Evaluation for inclusion in all future health indicators. His plan is to initially get family physicians as clinical managers into all medium to large district hospitals (150 beds and above), before ensuring they are placed in every health district, including at lower level hospitals and community health centres, at all times leading a multi-disciplinary team.
“Instead of waiting for HR plans and organograms, this is going into the mid-term framework for monitoring. It’s a strategic opportunity, where we ask ourselves, ‘how do we define a multi-disciplinary team for a district hospital?’ and then work through and with them. We’ll define and map where our priority district hospitals are, starting with the medium to large district hospitals,” he said.
Bayeni said he met with his provincial counterparts and military health service chiefs last week, (14-18 October), where he said he was going to, “make sure they all know about this. Organograms are all fine and well and necessary, but I want this top of mind when they consider them.”
“Personally, by April next year, (the new financial year), I want to see more family physicians being appointed, either in the district or in the position of clinical managers wherever there are vacancies. I’ll ask the provinces to help me with monitoring and evaluation,” he said.
He said his ambition is to change the mindset of provincial healthcare leaders “wherever necessary” about family physicians being regarded as “just another specialty” when creating and enumerating posts.
Positive responses
Several top family medicine academics and clinicians around the country who have been at the forefront of providing data and lobbying for a more pragmatic healthcare delivery approach, welcomed the renewed focus on family physicians.
Professor Steve Reid, a veteran rural family physician and head of Primary Health Care at the University of Cape Town (UCT), told Spotlight the main problem was what he called a framing issue.
“The way we think about medicine is to just go to the doctor and get it sorted, rather than how a huge number of diseases can be managed and prevented early on – it’s been a major shift over the last fifty years. I mean we now have studies that link pre-natal health to later chronic diseases. The whole idea of social medicine went out of vogue, and the idea that health has far more to do with the social determinants of health than it has to do with the health system had too little purchase,” he said.
Reid observed that no family physician can work in isolation – they made the most difference when they had a multi-disciplinary team around them.
Labelling family physicians “boundary-spanners par excellence”, he said “they join the dots rather than work in silos like other specialties who tend to guard their turf jealously.”
“Brazil is a middle-income country just like South Africa and their simple model of one doctor, a nurse and four to six community health workers per 4 000 population has got 80% of their population covered, including vast urban areas like Sao Paulo and Rio de Janeiro,” he said. In South Africa’s case, having a family physician as the leader will further enhance this model.
‘Around 400 needed’
Mash said South Africa’s previous health policies saw family physicians as a sub-specialty of internal medicine or as specialists who should work at tertiary hospitals and within primary care teams. Currently, chiefly due to the lack of posts, only a third of family medicine graduates were retained in the public sector, with ten percent emigrating and eleven percent giving up medicine altogether. Most were employed in the Western Cape, where the health system had committed to appointing family medicine practitioners at district hospitals and primary care facilities, Mash added.
The SAAFP recommends a mid-term goal of one family physician at every district hospital, community health centre or sub-district.
To achieve this, said Mash, another 400 family physicians are needed, but at current training rates this could take up to two decades, (not accounting for the current shortage of posts).
He agreed with Public Health Medicine Specialist Tracey Naledi, that only when there’s wider and stronger investment in primary healthcare across provinces will better deployment of Family Medicine practitioners begin to make a real difference to district level health and wellness. Naledi is Associate Professor in Public Health Medicine and Deputy Dean of Social Accountability and Health Systems at UCT’s Faculty of Health Sciences.
Naledi said that while there are many highly skilled veteran ‘utility’ Medical Officers in the district health system, the greater utility of family medicine is in clinical governance, health systems strengthening initiatives and capacity development. Besides teaching, monitoring, and evaluating healthcare delivery, she said family physicians also more appropriately and timeously refer patients to secondary and tertiary care.
Specialist support
“The family physicians should not just be seeing sixty patients at their door daily. They are specialist support – the Medical Officers should be calling them for advice. If family physicians were optimized, we’d see far less referral to tertiary level services,” she said.
The problem is structural, she believes.
“There are not enough human resources for health in general, so at district level people get pulled into doing what’s needed on the shop floor. There’s not enough time to do the strategic work,” she said.
“You can’t just talk about family medicine without talking about full staff requirements. When a family physician goes on outreach, it should not just be about dealing with difficult cases but building the capacity of the outlying areas. They need to ask themselves what they’re leaving behind. Otherwise, you’re cleaning the floor but not closing the tap,” she added.
Mash agreed that family medicine practitioners are “not the magic bullet – but introducing them into district health services can go quite a way towards strengthening the system”.
“We’ve trained them to work independently, to be the senior clinician with the full spectrum of needed skills, on top of which they provide the confidence for the doctors who are there to practice the skills they have. It’s very reassuring having a senior person to help if things go wrong, so it’s a combination of increased confidence and bringing in additional skills,” he said.
“A primary health nurse and community health worker can provide coverage and connection to the community, but a [family medicine] FM practitioner brings in a level of expertise so the team has both coverage and quality,” he added.
History and training
As Mash tells it, from the nineties into the first decade of the 2000s, no medical schools exposed undergraduates to Family Medicine. However, nearly thirty years on, curricula have completely turned around.
Mash says some twenty to thirty family medicine practitioners graduate from the ten South African campuses every year, among the chief disincentives to the specialisation being the paucity of available posts. He said it’s critical to create more family medicine posts “if we are to attract people into that career path. If managers believe a family physician’s contribution is worthwhile, they can outmanoeuvre these restrictive budgets.”
He said public health was being “hugely damaged” by an austerity mindset.
Professor Shabir Moosa, Family Physician in the Department of Family Medicine at Wits University, suggested offering a two-year distance learning diploma in family medicine to get family medicine practitioners into practice faster and then offering in-service further tuition to a full post-graduate degree. Moosa is a former President of the World Organization of Family Doctor’s Africa region.
“Right now, you have family physicians in community healthcare centres which see a thousand people a day. Their job is capacity building, but they’re stuck with menial tasks. Also, right now qualified Family Medicine practitioners, at Wits at least, have a thirty percent teaching commitment so they’re being pulled in many different directions.”
Like Mash, he said “turnstile leadership” in the provinces wrecked progress while leadership in primary healthcare at district and lower levels was mainly by nurses, who were uncomfortable sharing space with family physicians whom they saw as a “power threat”.
Moosa says most family medicine practitioners in rural South Africa (with the exception of the Western Cape), are foreign qualified doctors who found studying it an “easy entrance route”. He takes issue with the emphasis on training family physicians exclusively for use in rural areas, saying that with accelerating urbanisation, this is short-sighted.
Parallel with clinical associates
Associate Professor Tasleem Ras, President of the SAAFP and Postgraduate Programme Director of Family Medicine at UCT, drew a parallel with clinical associates which some provinces had adopted and others not, saying they had no career pathways which has become “a political hot potato”. (Spotlight previously reported under the under-utilisation of clinical associates here and here.)
Ras was alluding to the provincially disparate usage of both categories of healthcare professionals. In the case of family physicians at least, senior medical officer and registrar posts are being creatively used by some provinces to place them, with salary adjustments built in. Clinical associates have no such luxury.
Naledi says she suspects that healthcare delivery leaders in individual provinces have widely differing views on how to use family physicians, with commensurately differing patient care outcomes. She says the grading of healthcare facilities by the Office for Healthcare Standards Compliance eloquently illustrates an overemphasis on curative service-based funding, with lower-level primary healthcare facilities scoring worst, followed by secondary or district hospitals with tertiary hospitals scoring the highest. Unless this changes, she says “we will continue failing to get bang for buck”.
She adds: “If you look at the district health system, it doesn’t have the full cadre of staff. I mean palliative care, mental health, dental services – these are all structural and broader resource issues for me. You can’t look at family medicine in isolation.”
The argument is that building more capacity for prevention and health promotion would begin to dismantle a self-perpetuating cycle of predominantly curative services. Family medicine training, Naledi says, focuses a lot more on the social determinants of health, prevention, rehabilitation, and palliative care. “It’s not just about clinical abilities but about them being family and community doctors,” she adds.
For those of a certain age, Coneheads is an iconic 90s film. But for breakdancers, it seems, developing a cone-shaped head can be an occupational hazard.
According to a 2024 medical case report, a breakdancer who’d been performing for 19 years was treated for “headspin hole”, a condition also known as “breakdancer bulge” that’s unique to breakdancers. It entails a cone shaped mass developing on top of the scalp after repetitive head-spinning. Additional symptoms can include hair loss and sometimes pain around the lump.
Approximately 30% of breakdancers report hair loss and inflammation of their scalp from head-spinning. A headspin hole is caused by the body trying to protect itself. The repeated trauma from head-spinning causes the epicranial aponeurosis – a layer of connective tissue similar to a tendon, running from the back of your head to the front – to thicken along with the layer of fat under the skin on top of the head in an attempt to protect the bones of skull from injury.
The body causes a similar protective reaction to friction on the hands and feet, where callouses form to spread the pressure and protect the underlying tissues from damage. Everyday repetitive activities from holding smartphones or heavy weights through to poorly fitting shoes can result in callouses.
But a cone-shaped head isn’t the only injury to which breakdancers are prone, however. Common issues can include wrist, knee, hip, ankle, foot and elbow injuries, and moves such as the “windmill” and the “backspin” can cause bursitis – inflammation of the fluid filled sacs that protect the vertebrae of the spine. A headspin hole isn’t the worst injury you could sustain from breakdancing either. One dancer broke their neck but thankfully they were lucky enough not to have any major complications.
Others, such as Ukrainian breakdancer Anna Ponomarenko, have experienced pinched nerves that have left them paralysed. Ponomarenko recovered to represent her country in the Paris 2024 Olympics.
As with other sports, it’s unsurprising to hear that the use of protective equipment results in the reduction of injuries in breakdancing too.
But breakdancers aren’t the only ones to develop cone shaped heads.
Newborns
Some babies are born with a conical head after their pliable skull has been squeezed and squashed during the journey through the vaginal canal and the muscular contractions of mother’s uterus.
A misshapen head can also be caused by caput secundum, where fluid collects under the skin, above the skull bones. Usually, this condition resolves itself within a few days. Babies who’ve been delivered using a vacuum assisted cup (known as a Ventouse) – where the cup is applied to the top of the baby’s head to pull them out – can develop a similar fluid lump called a chignon.
Vacuum assisted delivery can also result in a more significant lump and bruising called a cephalohematoma, where blood vessels in the bones of the skull rupture. This is twice as common in boys than in girls and resolves within two weeks to six months.
If you’ve ever seen newborns wearing tiny hats in the first few hours of their life, then one of these conditions may be the reason.
Newborn skulls are made up of lots of small bony plates that aren’t fused together, which enables babies’ brains to grow without restriction. Usually, once the brain reaches a slower growth pace that the bones can keep up with, the plates fuse together. In craniosynostosis, the plates fuse together too early creating differently shaped heads. Surgery can prevent brain growth restriction but is usually unnecessary if the child hasn’t been identified as having an shaped head by six months of age.
Colourised scanning electron micrograph of a breast cancer cell. Credit: NIH
Researchers from Tampere University, Finland, and Izmir Institute of Technology, Turkey, have developed an in vitro cancer model to investigate why breast cancer spreads to bone. Their findings, published in PLOS One, hold promise for advancing the development of preclinical tools to predict breast cancer bone metastasis.
Breast canceris a significant global public health challenge, with 2.3 million new cases and 700 000 deaths every year. Approximately 80% of patients with primary breast cancer can be cured, if they are diagnosed and treated promptly. However, in many cases, the cancer has already metastasised at the time of diagnosis.
Metastatic cancer is incurable and accounts for more than 90% of cancer-related deaths. Currently, there are no reliable in vitro models to study how breast cancer spreads to secondary organs such as bone, lung, liver or brain. Now, researchers from the Precision Nanomaterials Group at Tampere University in Finland, and the Cancer Molecular Biology Lab at Izmir Institute of Technology in Turkey, have used lab-on-a-chip platforms to create a physiologically relevant metastasis model to study the factors controlling breast cancer bone metastasis.
“Breast cancer most frequently spreads to bone, with an estimated rate of 53%, resulting in severe symptoms such as pain, pathological bone fractures, and spinal cord compressions. Our research provides a laboratory model that estimates the likelihood and mechanism of bone metastasis occurring within a living organism. This advances the understanding of molecular mechanisms in breast cancer bone metastasis and provides the groundwork for developing preclinical tools for predicting bone metastasis risk,” says Burcu Firatligil-Yildirir, postdoctoral researcher at Tampere University and the first author of the paper.
According to Nonappa, Associate Professor and leader of the Precision Nanomaterials Group at Tampere University, developing sustainable in vitro models that mimic the complexity of the native breast and bone microenvironment is a multidisciplinary challenge.
“Our work shows that physiologically relevant in vitro models can be generated by combining cancer biology, microfluidics and soft materials. The results open new possibilities for developing predictive disease, diagnostic and treatment models,” he says.
Erin Yamamoto, MD, and Juan Piantino, MD, are among the co-authors of a new study from Oregon Health & Science University that used imaging of neurosurgery patients to definitively reveal the existence of waste-clearance pathways in the human brain known as the glymphatic system. (OHSU/Christine Torres Hicks)
Scientists have long theorised about a network of pathways in the brain that are believed to clear metabolic proteins that would otherwise build up and potentially lead to Alzheimer’s and other forms of dementia. But they had never definitively revealed this network in people – until now.
A new study involving five patients undergoing brain surgery at Oregon Health & Science University provides imaging of this network of perivascular spaces (fluid-filled structures along arteries and veins) within the brain for the first time.
“Nobody has shown it before now,” said senior author Juan Piantino, MD, associate professor of pediatrics (neurology) in the OHSU School of Medicine and a faculty member of the Neuroscience Section of the Papé Family Pediatric Research Institute at OHSU. “I was always skeptical about it myself, and there are still a lot of skeptics out there who still don’t believe it. That’s what makes this finding so remarkable.”
The study combined the injection of an inert contrasting agent with a special type of magnetic resonance imaging to discern cerebrospinal fluid flowing along distinct pathways in the brain 12, 24 and 48 hours following surgery. In definitively revealing the presence of an efficient waste-clearance system within the human brain, the new study supports the promotion of lifestyle measures and medications already being developed to maintain and enhance it.
“This shows that cerebrospinal fluid doesn’t just get into the brain randomly, as if you put a sponge in a bucket of water,” Piantino said. “It goes through these channels.”
More than a decade ago, scientists at the University of Rochester first proposed the existence of a network of waste-clearance pathways in the brain akin to the body’s lymphatic system, part of the immune system. Those researchers confirmed it with real-time imaging of the brains of living mice. Due to its dependence on glial cells in the brain, they coined the term “glymphatic system” to describe it.
However, scientists had yet to confirm the existence of the glymphatic system through imaging in people.
Pathways revealed in patients
The new study examined five OHSU patients who underwent neurosurgery to remove tumours in their brains between 2020 and 2023. In each case, the patients consented to having a gadolinium-based inert contrasting agent injected through a lumbar drain used as part of the normal surgical procedure for tumour removal. The tracer would be carried with cerebrospinal fluid into the brain.
Afterward, each patient underwent magnetic resonance imaging, or an MRI, at different time points to trace the spread of cerebrospinal fluid.
Rather than diffusing uniformly through brain tissue, the images revealed fluid moving along pathways — through perivascular spaces in clearly defined channels. Researchers documented the finding with a specific kind of MRI known as fluid attenuated inversion recovery, or FLAIR. This type of imaging is sometimes used following the removal of tumors in the brain. As it turns out, it also revealed the gadolinium tracer in the brain, whereas the standard MRI sequences did not.
“That was the key,” Piantino said.
“You can actually see dark perivascular spaces in the brain turn bright,” said co-lead author Erin Yamamoto, MD, a resident in neurological surgery in the OHSU School of Medicine. “It was quite similar to the imaging the Rochester group showed in mice.”
Clearing waste from the brain
Scientists believe this network of pathways effectively flushes the brain of metabolic wastes generated by its energy-intensive work. Wastes include proteins such as amyloid and tau, which have been shown to form clumps and tangles in brain images of patients with Alzheimer’s disease.
Emerging research suggests medications that may be useful, but much of the focus around the glymphatic system has revolved around lifestyle-based measures to improve the quality of sleep, such as maintaining a regular sleep schedule, establishing a relaxing routine, and avoiding screens in the bedroom before bed. Especially at night during deep sleep, researchers believe a well-functioning glymphatic system efficiently carries waste proteins toward veins exiting the brain.
“People thought these perivascular spaces were important, but it had never been proved,” Piantino said. “Now it has.”
The authors credited the late Justin Cetas, MD, PhD, who initiated the study as an OHSU neurosurgeon before leaving the university to become chair of neurological surgery at his alma mater, the University of Arizona Health Sciences Center in Tucson. He died in a motorcycle accident in 2022.
Increased risk for autism appears to be linked to the Y chromosome, a Geisinger study found, offering a new explanation for the greater prevalence of autism in males. The results were published in Nature Communications.
Autism spectrum disorder (ASD) is nearly four times more prevalent among males than females, but the reason for this disparity is not well understood. One common hypothesis involves the difference in sex chromosomes between males (XY) and females (XX).
“A leading theory in the field is that protective factors of the X chromosome lower autism risk in females,” said Matthew Oetjens, PhD, assistant professor at Geisinger’s Autism & Developmental Medicine Institute.
The Geisinger research team, led by Dr Oetjens and Alexander Berry, PhD, staff scientist, sought to determine the effects of the X and Y chromosomes on autism risk by examining ASD diagnoses in people with an abnormal number of X or Y chromosomes, a genetic condition known as sex chromosome aneuploidy.
The team analysed genetic and ASD diagnosis data on 177 416 patients enrolled in the Simons Foundation Powering Autism Research (SPARK) study and Geisinger’s MyCode Community Health Initiative.
They found that individuals with an additional X chromosome had no change in ASD risk, but that those with an additional Y chromosome were twice as likely to have an ASD diagnosis.
This suggests a risk factor associated with the Y chromosome instead of a protective factor associated with the X chromosome.
“While these may seem like two sides of the same coin, our results encourage us to look for autism risk factors on the Y chromosome instead of limiting our search to protective factors on the X chromosome,” Dr. Berry said.
“However, further research is needed to identify the specific risk factor associated with the Y chromosome.”
This analysis also confirms prior work by showing that the loss of an X or Y chromosome, known as Turner syndrome, is associated with a large increase in ASD risk. Further research is needed to determine whether the ASD risk factors associated with sex chromosome aneuploidy explains the sex difference in ASD prevalence.
Plant fungus provides new drug with a new cellular target
Human colon cancer cells. Credit: National Cancer Institute
Novel chemical compounds from a fungus could provide new perspectives for treating colorectal cancer, one of the most common and deadliest cancers worldwide. The fungus, Bipolaris victoriae, is otherwise known as a fungal plant pathogen which in the 1940s caused the “Victoria blight”, decimating oats and similar grains in the US.
In the journal Angewandte Chemie, researchers reported on the isolation and characterisation of a previously unknown class of metabolites (terpene-nonadride heterodimers). One of these compounds effectively kills colorectal cancer cells by attacking the enzyme DCTPP1, which thus may serve as a potential biomarker for colorectal cancer and a therapeutic target.
Rather than using conventional cytostatic drugs, which have many side effects, modern cancer treatment frequently involves targeted tumour therapies directed at specific target molecules in the tumour cells. The prognosis for colorectal cancer patients remains grim however, demanding new targets and novel drugs.
Targeted tumour therapies are mostly based on small molecules from plants, fungi, bacteria, and marine organisms. About half of current cancer medications were developed from natural substances. A team led by Ninghua Tan, Yi Ma, and Zhe Wang at the China Pharmaceutical University (Nanjing, China) chose to use Bipolaris victoriae S27, a fungus that lives on plants, as the starting point in their search for new drugs.
The team first analysed metabolic products by cultivating the fungus under many different conditions (OSMAC method, one strain, many compounds). They discovered twelve unusual chemical structures belonging to a previously unknown class of compounds: terpene-nonadride heterodimers, molecules made from one terpene and one nonadride unit. Widely found in nature, terpenes are a large group of compounds with very varied carbon frameworks based on isoprene units. Nonadrides are nine-membered carbon rings with maleic anhydride groups. The monomers making up this class of dimers termed “bipoterprides” were also identified and were found to contain additional structural novelties (bicyclic 5/6-nonadrides with carbon rearrangements).
Nine of the bipoterprides were effective against colorectal cancer cells. The most effective was bipoterpride No. 2, which killed tumour cells as effectively as the classic cytostatic drug Cisplatin. In mouse models, it caused tumours to shrink with no toxic side effects.
The team used a variety of methods to analyse the drug’s mechanism: bipoterpride 2 inhibits dCTP-pyrophosphatase 1 (DCTPP1), an enzyme that regulates the cellular nucleotide pool. The heterodimer binds significantly more tightly than each of its individual monomers. The activity of DCTPP1 is elevated in certain types of tumours, promoting the invasion, migration, and proliferation of the cancer cells while also inhibiting programmed cell death. It can also help cancer cells to resist treatment. Bipoterpride 2 inhibits this enzymatic activity and disrupts the now pathologically altered amino acid metabolism in the tumour cells.
The team was thus able to identify DCTPP1 as a new target for the treatment of colorectal cancer and bipoterprides as new potential drug candidates.
Scientists at Trinity College Dublin have discovered a new process in the immune system that leads to the production of an important family of anti-viral proteins called interferons. They hope the discovery will now lead to new, effective therapies for people with some autoimmune and infectious diseases.
Reporting in Nature Metabolism, Luke O’Neill, Professor of Biochemistry in the School of Biochemistry and Immunology at Trinity, and his team have found that a natural metabolite called Itaconate can stimulate immune cells to make interferons by blocking an enzyme called SDH.
Co-lead author, Shane O’Carroll, from Trinity’s School of Biochemistry and Immunology, said: “We have linked the enzyme SDH to the production of interferons in an immune cell type called the macrophage. We hope our work will help the effort to develop better strategies to fight viruses because interferons are major players in how our innate immune system eliminates viruses – including COVID-19.”
Co-lead author, Christian Peace, from Trinity’s School of Biochemistry and Immunology, added: “Itaconate is a fascinating molecule made by macrophages during infections. It’s already known to suppress damaging inflammation but now we have found how it promotes anti-viral interferons.”
Working with drug companies Eli Lilly and Sitryx Ltd, the next step is to test new therapies based on Itaconate in various diseases, with some autoimmune diseases and some infectious diseases on the likely list. And the work potentially extends to other disease contexts in which SDH is inhibited, such as cancer, and could reveal a new therapeutic target for SDH-deficient tumours.
Prof O’Neill said: “With Itaconate you get two for the price of one – not only can it block harmful inflammation, but it can also help fight infections. We have discovered important mechanisms for both and the hope now is that patients will benefit from new therapies that exploit Itaconate and its impacts.”
Clinical trials in patients are set to start next year.
In June, we heard what could be this year’s biggest HIV breakthrough: a twice-yearly injection can prevent HIV infection. Findings from a second large study of the jab has now confirmed that it works. Elri Voigt goes over the new findings and unpacks the licenses that are expected to facilitate the availability of generic versions of the jab in over a hundred countries, including South Africa.
The second of two pivotal studies of a six-monthly HIV prevention injection containing the antiretroviral drug lenacapavir has confirmed that the jab works remarkably well.
The first study, called PURPOSE 1, found that the jab is safe and highly effective at preventing HIV infection in women. The second, called PURPOSE 2, found the same for cisgender men, transgender men, transgender women and non-binary people who have sex with men assigned male at birth.
Interim findings from PURPOSE 2 were presented last week at the HIV Research for Prevention (HIVR4P) conference in Lima, Peru.
The researchers compared the safety and efficacy of lenacapavir injections every six months to a daily HIV prevention pill – a combination of emtricitabine and tenofovir disoproxil fumarate, called F/TDF. The results have not yet been published in a peer reviewed journal, but is expected to be soon, according to Principal Investigator for PURPOSE 2 Dr Colleen Kelley, a professor of medicine at Emory University’s School of Medicine.
In the PURPOSE 1 study, none of the 2 134 people receiving the lenacapavir injection got HIV during the study. In PURPOSE 2, there were two HIV infections among the 2 179 people receiving the injection. These numbers are dramatically better than those for HIV prevention pills and for people in the communities where the study was done who were not receiving prevention injections or pills.
These findings mean the evidence is now in place for the manufacturer, Gilead Sciences, to file with regulatory authorities to register lenacapavir injections for HIV prevention. Such registration is required before the jab can be marketed for prevention. Lenacapavir injections are already registered in some countries as a last resort treatment for HIV, but not yet in South Africa.
“Now that we have a comprehensive dataset across multiple study populations, Gilead will work urgently with regulatory, government, public health and community partners to ensure that, if approved, we can deliver twice-yearly lenacapavir for PrEP worldwide, for all those who want or need PrEP,” Daniel O’Day, the chairperson and Chief Executive Officer of Gilead said in a press release. (PrEP, or pre-exposure prophylaxis, refers to taking antiretrovirals to prevent HIV infection.)
Top line findings
The interim results presented at HIVR4P by Kelley, showed that when compared to the background HIV incidence calculated in the study, lenacapavir reduced HIV infections by 96%. And when compared to the F/TDF prevention pill, the injection reduced HIV infections by 89%.
Among the 3 265 participants enrolled in the study, 11 people acquired HIV- two of the 2 179 people who were assigned to the lenacapavir arm and nine of the 1 086 participants assigned to the prevention pill arm. This translated to HIV incidence of 0.93 per 100 person years in the prevention pill arm compared to only 0.1 per 100 person years in the lenacapavir arm.
This was compared to the background incidence, which was determined when screening eligible participants for HIV. Out of 4 634 people screened for the study, 378 or 8.2% were diagnosed with HIV. Based on further laboratory testing, it was estimated that of those 378 people, 45 or 11.9% recently acquired HIV (classified as being within the last 120 days or so). This latter group provided the background HIV incidence, which was estimated to be 2.37 per 100 person years.
This is a novel study design, Kelley told Spotlight, because this calculation was used to estimate the HIV incidence that would have occurred in a placebo group without actually enrolling a placebo group.
“It’s no longer ethical to have a placebo group in HIV PrEP trials because we know that we have effective PrEP agents,” she said. “Yet, it’s almost essential to have a placebo group when you design a clinical trial so that you can really say how effective your medication, your new agent is [compared] to having nothing.”
When asked at a press conference about the two breakthrough infections in the lenacapavir arm, Kelley said the analysis for this is ongoing and will hopefully be available at a future conference and in a journal soon. She said that the two breakthrough infections in the lenacapavir arm were detected by routine testing during the study.
Principal Investigator for PURPOSE 2 Professor Colleen Kelley at the 5th HIV Research for Prevention Conference in Lima, Peru. (Photo: Nicole Bergman/IAS)
Kelley added that around 90% of participants in the two study arms were able to receive their injection on time. “So, we at least know that the injections were delivered in a timely fashion for almost all participants,” she said.
Whether or not the two infections occurred in people who had received the jabs on time and according to the study protocol will be closely watched as more study details is shared in the coming months.
To be enrolled in the study, participants had to meet several criteria. They had to be older than 16, never received HIV prevention injections before, weigh more than 35kg, have good kidney function, not have been tested for HIV in the last 12 weeks, and had to have been sexually active in the last 12 months.
All study participants were given a pill a day and an injection, those in the lenacapavir arm received two 1.5 ml lenacapavir injections every six months and a daily placebo pill, while those in the prevention pill arm received the daily F/TDF pill and a placebo injection every six months.
The study was conducted across seven countries, with 6 sites located in South Africa and others in Argentina, Brazil, Mexico, Peru, Thailand, and the United States, according to study data on Gilead’s website.
Safety data
Overall, Kelley said lenacapavir was safe and well-tolerated despite some side effects, mainly related to the injections. A total of 43 people dropped out of the study due to side effects.
The most common adverse event in the study was injection site reactions. There were more injection site reactions in the lenacapavir arm compared to the prevention pill arm. 29 people dropped out of the study because of these, 26 in the lenacapavir arm and 3 in the prevention pill arm (people in this study arm received placebo jabs).
The most common injection site reaction were subcutaneous nodules – these are harmless, usually invisible, small lumps under the skin. Nodules occur because lenacapavir is injected under the skin where it forms a drug depot. Injection site reactions and nodule size decreased with subsequent injections. This side effect and trend of decreasing reactions was also noted in the PURPOSE 1 study. Other injection site reactions were pain and erythema which is a type of skin rash.
According to Kelley, there were no serious adverse events related to injection site reactions.
When injection site reactions are excluded, according to Kelley, the other adverse events were similar across both arms, with 74% of participants in each arm experiencing an adverse event. The majority were mild or moderate.
Seven participants in each study arm dropped out due to side effects that weren’t related to injection site reactions. Those who discontinued from the lenacapavir arm will be given prevention pills for a year. This is done to protect these participants, Kelley explained, from potentially acquiring HIV when lenacapavir levels wane, as well as to reduce the risk of potential drug resistance developing.
There were a few serious adverse events, although Kelley told Spotlight she does not currently have any additional information on what these were. She explained that a serious adverse event is generally classified as something like hospitalisation, a life-threatening condition, an important medical event or adverse pregnancy outcome.
“Usually when we look at something like this, we look at the rates compared in the two arms of the study and it was 3% in the LEN [lenacapavir] arm and 4% in the F/TDF arm, so they were equal, essentially the same in both study arms,” Kelly said.
There were six deaths during the study, but none were related to the study drugs.
Next steps for lenacapavir
Now that the interim results have been announced, both studies have been unblinded and entered an open-label phase where participants have the choice of switching to or continuing with the injection.
Professor Linda-Gail Bekker, the Chief Executive Officer at the Desmond Tutu Health Foundation, recently said on a webinar hosted by the South African Health Technologies Advocacy Coalition, that study participants are now able to use the PrEP option they’d prefer – either oral PrEP or the injection. This means all participants will be able to access lenacapavir through the studies if they wanted to use it.
But it will likely be a while before anyone outside of these studies can access lenacapavir as HIV prevention.
“This is an incredible intervention. Now we have to make sure everyone can get it and that’s going to be the most important next step, ensuring that everyone who needs this drug has access,” Kelley told Spotlight.
Gilead’s generic licensing agreement and pricing
What we do know so far about the next steps for lenacapavir is that the process to allow for generic manufacturing has started. This month, Gilead released its voluntary licensing agreements with six generic companies for manufacturing cheaper versions of lenacapavir.
Dr Andrew Gray, a senior lecturer in Pharmacology at the University of KwaZulu-Natal, told Spotlight that no South African firms have been included in the voluntary licenses – four of the generic licensees are in India, one is in Pakistan, and one is in Egypt.
“In essence, they [the generic companies] are allowed to sell their generic versions in a number of identified countries, specified by Gilead,” Gray said. The agreement lists 120 countries, including South Africa.
Gilead itself will also be prioritising the registration of lenacapavir in 18 countries, which it said represent about 70% of the HIV burden in the countries named in the license. The list includes South Africa, Uganda, and Botswana. Gilead says it will start filing for registration with regulatory authorities by the end of the year.
It will be important to see how quickly Gilead seeks regulatory approval for lenacapavir with the South African Health Products Regulatory Authority (SAHPRA), Gray said. Registration with SAHPRA will be required before the injection can be rolled out in South Africa.
In putting together this timeline, we’ve spoken to several well-placed experts, but we stress that this is very much a back-of-the-envelope exercise and far from set in stone. (Infograph: Spotlight)
Some countries won’t be able to procure generics
Gilead received criticism for several omissions from the list of countries that the generic manufacturers can sell to. The US-based HIV advocacy group AIDS Vaccine Advocacy Coalition, among others, pointed out the exclusion of several countries which have high HIV incidence. Some of those countries participated in PURPOSE 2- namely Brazil, Argentina, Mexico and Peru.
A spokesperson from Gilead told Spotlight the manufacturer’s access policy included tailored approaches to ensure rapid and broad access of lenacapavir and it objectively considered the countries where a voluntary licence would provide the most benefit.
“Gilead’s voluntary licence primarily covers countries based on economic need and HIV burden, which are primarily low- and lower-middle income countries. The voluntary licence also covers certain middle-income countries with limited access to healthcare,” the spokesperson said.
Acknowledging that some middle-income countries do have a high HIV burden, Gilead is “exploring several innovative strategies to support access to LEN for PrEP (if approved), including tiered pricing, and are working with payors to establish fast, efficient pathways to help reach people who need or want PrEP”, said the spokesperson.
“Ensuring access in middle-income and upper-middle income countries, including those in Latin America, is a priority for Gilead. Planning for these countries, incorporating input from advocates and global health organizations, is ongoing and updates will be shared as discussions progress,” the spokesperson added. “Additionally, Gilead is committed to ensuring that individuals who participated in the PURPOSE studies have been offered and will be able to stay on open label lenacapavir until it is available in their country.”
The company’s decision to license generic manufacturers directly is at odds with earlier calls from several activist groups and UNAIDS to license via the UN-backed Medicines Patent Pool.
Pricing
It will also be important to see if Gilead will disclose a single exit price for the South African market, according to Gray.
In its press release announcing the voluntary licensing agreement, Gilead stated it will “support low-cost access to the drug in high-incidence, resource-limited countries through a two-part strategy: establishing a robust voluntary licensing program and planning to provide Gilead-supplied product at no profit to Gilead until generic manufacturers are able to fully support demand”.
It is too early in the process to reveal a price for lenacapavir yet, the spokesperson from Gilead told Spotlight.
“While Gilead prepares for global regulatory filings, it is too early to disclose the price of lenacapavir for HIV prevention. Our pledge is to price our medicines to reflect the value they deliver to people, patients, healthcare systems and society. For Gilead-branded lenacapavir, we do plan to price it at no profit to Gilead in 18 select high-incidence, resource-limited countries until generic manufacturers are able to fully support demand,” the spokesperson said.
Spotlight previously reported on research that estimated that if produced at sufficient volumes, the price of lenacapavir could be drastically reduced to levels likely considered affordable by the South African government. For instance, if enough volume was produced to supply 10 million people with PrEP, the price for the injection could be as low as $40 (under R800) per person per year. At the moment, Gilead supplies lenacapavir for HIV treatment in wealthy countries for about $40 000 per person per year.
Gilead’s lenacapavir product will be the first to register in South Africa and will almost certainly be the only lenacapavir product available here for several years – that is because it is expected to take generic manufacturers a few years before they can start producing generic lenacapavir. Based on calculations made for other PrEP products, it seems unlikely that the Department of Health would be willing to procure lenacapavir at a price significantly above R1 000 per person per year. The HIV prevention pill currently costs government around R800 per person per year.
Initial prescriptions of benzodiazepines, a class of drugs used to treat anxiety and sleep problems after a stroke may include too many pills for adults ages 65 or older, finds new study in the Stroke journal
Photo by Towfiqu Barbhuiya on Unsplash
Although there has been a slight downward trend in the prescription of benzodiazepines (depressants that relieve anxiety, muscle spasms, produce sedation and reduce seizures) among older adults over the last decade, the rate of first-time prescriptions for these medications after an ischaemic stroke is still sizable, according to research published today in Stroke.
After a stroke, benzodiazepines may be used to calm anxiety and improve sleep, but also have a potential for abuse and addiction. When prescribed to older adults, these medications may increase the risk of falls and broken bones, as well as memory problems, confusion and other harmful effects.
Researchers reviewed data from Medicare claims in the US and analysed 10 years of first-time prescriptions for benzodiazepines among more than 120 000 people, ages 65 and older, who were hospitalised for ischaemic stroke. The rate of benzodiazepine prescriptions during the first three months after stroke were examined, and data were adjusted for race, sex and ethnicity. Then year-to-year prescription patterns were reviewed to identify the number of potentially excessive new benzodiazepine prescriptions given to stroke survivors.
“We reviewed stroke survivors at 90 days after a stroke because that window of time is critical for rehabilitation of motor, speech and cognitive function, as well as mental health. It’s often a very difficult time for patients who experience loss of mobility and independence. Benzodiazepines may inhibit recovery and rehabilitation,” said study co-author Julianne Brooks, MPH, a data analytics manager at the Center for Value-based Healthcare and Sciences at Massachusetts General Brigham in Boston. “For this older age group, guidelines recommend that benzodiazepine prescriptions should be avoided if possible. However, there may be cases where benzodiazepines are prescribed to be used as needed. For example, to treat breakthrough anxiety, a provider may prescribe a few pills and counsel the patient that the medication should only be used as needed. The increased risks of dependence, falls and other harmful effects should be discussed with the patient.”
The study found:
Within 90 days of stroke, 6127 (4.9%) people were started on a benzodiazepine for the first time.
Lorazepam (40%) and alprazolam (33%) were the most-prescribed benzodiazepine medications.
Three-quarters of the first-time benzodiazepine prescriptions were for a supply of over seven days, and more than half of the prescriptions were for a supply between 15 to 30 days.
Prescription rates were higher among women (5.5%) than men (3.8%).
Prescription fill rates were also higher in Hispanic adults (5.8%), though this group was limited by the small number of participants – 1.9% of the overall sample.
Overall, prescription rates were highest in the Southeast (5.1%) and lowest in the Midwest (4%) of the US. “The Southeast region is the stroke belt with a higher rate of strokes, so that could explain some differences in care in that region,” Brooks said.
There was an overall modest nationwide decline of initial prescriptions from 2013 to 2021 of 1.6%.
“We found a pattern of potential oversupply with these initial benzodiazepine prescriptions, which would be enough for patients to become long-term users or possibly addicted. The benzodiazepine prescriptions given under these circumstances may lead to dependence,” Brooks said. “Increased awareness and improved recommendations about the risks of these medications for older stroke survivors are needed.
“Although the overall prescription rate decreased slightly over 10 years, this prescription pattern is still a problem. It’s concerning because older adults are vulnerable to overprescribing and adverse outcomes. We know from previous studies that vulnerable and marginalized populations experience worse outcomes after stroke, so we want to understand the factors that may play a role so we can provide better care,” Brooks said.
The 2019 American Geriatrics Society Beers Criteria maintains a list of medications that health care professionals can reference to safely prescribe medications for adults older than 65. Beers criteria recommends avoiding benzodiazepines in all older adults due to the risk of cognitive impairment, delirium, falls, fractures and motor vehicle crashes.
“Other guidelines also suggest behavioural interventions such as cognitive behaviour therapy for insomnia, antidepressant medications for anxiety disorders and trying non-pharmaceutical interventions first,” Brooks said.
Researchers said more studies are needed to understand if there is a safe level for prescribing benzodiazepines that may be most appropriate for older adults. The main limitation was that this study used a large, national dataset that did not include information about why benzodiazepines were prescribed.
