In a breakthrough for understanding metastases, researchers have found that, as metastatic cancers spread to different parts of the body, they adapt their metabolism to the tissue in which they grow. The findings, which help further break down the puzzle of metastasis, are published in PNAS.
Metabolism in the body is an important target for cancer treatments, where the focus is on stopping the progress of cancer cells.
“Obviously, the local environment affects the cancer cells more than previously known. The metastatic tumours should show the same metabolic properties no matter where in the body they are located, but we discovered that the cancer cells largely adapted their metabolism to the new tissue in order to continue to develop and grow. This is important knowledge, which shows that we cannot consider the metastases as their original tumours,” says Fariba Roshanzamir, PhD in Systems and Synthetic Biology at Chalmers and the study’s lead author.
Cutting off cancer metabolism
Fariba Roshanzamir works in Professor Jens Nielsen’s research group at Chalmers and has, together with Swedish and international colleagues, been able to establish the groundbreaking results. The study focused primarily on triple-negative breast cancer but the conclusions can, according to the researchers, be applied to all types of metastatic cancer. This opens new doors to develop more effective treatments.
“If we manage to shut down the metabolism in a tumour, it will stop working and this study provides important keys to better understand what to target. Selecting metabolic inhibitors that specifically target the metastases in the organs to which the tumour has spread, rather than treating them as their original tumours, is of great importance to be able to find good strategies for treatments in the future,” she says.
The brains of people with Down syndrome develop the same neurodegenerative tangles and plaques associated with Alzheimer’s disease and they frequently demonstrate signs of the neurodegenerative disorder in their 40s or 50s. A new study in the journal PNAS shows that these tangles and plaques are driven by the same amyloid beta (Aß) and tau prions that they showed are behind Alzheimer’s disease.
Prions begin as normal proteins that become misshapen and self-propagate. They spread through tissue like an infection by forcing normal proteins to adopt the same misfolded shape. In both Alzheimer’s and Down syndrome, as Aß and tau prions accumulate in the brain, they cause neurological dysfunction that often manifests as dementia.
Tau tangles and Aß plaques are evident in most people with Down syndrome by age 40, according to the National Institute on Aging, with at least 50% of this population developing Alzheimer’s as they age.
The new study highlights how a better understanding of Down syndrome can lead to new insights about Alzheimer’s, as well.
“Here you have two diseases – Down syndrome and Alzheimer’s disease – that have entirely different causes, and yet we see the same disease biology. It’s really surprising,” said Stanley Prusiner, MD, the study’s senior author, who was awarded the Nobel Prize in 1997 for his discovery of prions.
Down syndrome is the most common neurodegenerative disease among younger people in the United States, while Alzheimer’s is the most common among adults.
Down syndrome occurs because of an extra copy of chromosome 21. Among the many genes on that chromosome is one called APP, which codes for one of the major components of amyloid beta. With an extra copy of the gene, people with Down syndrome produce excess APP, which may explain why they develop amyloid plaques early in life.
A clearer picture in young brain
It’s been known for some time that Aß plaques and tau tangles are present in both Down syndrome and Alzheimer’s. Having shown earlier that these neurodegenerative features are provoked by prions in Alzheimer’s, the researchers wanted to know whether the same aberrant proteins were present in the brains of people with Down syndrome.
While these plaques and tangles in the brains of people with Alzheimer’s disease have been well-studied, it can be challenging to discern which changes in the brain are from old age and which are from prion activity, said Prusiner.
“Because we see the same plaques-and-tangles pathology at a much younger age in people with Down syndrome, studying their brains allows us to get a better picture of the early process of disease formation, before the brain has become complicated by all the changes that go on during aging,” he said. “And ideally, you want therapies that address these early stages.”
Employing a variation on the novel assay they used in the Alzheimer’s study, the team looked at donated tissue samples from deceased people with Down syndrome, which they obtained from biobanks around the world. Of the 28 samples from donors aged 19 to 65 years old, the researchers were able to isolate measurable amounts of both Aß and tau prions in almost all of them.
New insights could yield preventative measures
The results confirm not only that prions are involved in the neurodegeneration seen in Down syndrome, but that Aß drives the formation of tau tangles as well as amyloid plaques, a relationship that has been suspected but not proven.
“The field has long tried to understand what the intersection is between these two pathologies,” said lead author Carlo Condello, PhD, also a member of the UCSF Institute for Neurodegenerative Diseases. “The Down syndrome case corroborates the idea; now you have this extra chromosome that’s driving the Aß, and there’s no tau gene on the chromosome. So, it’s truly by increasing the expression of Aß that you kick off production of the tau.”
These and other insights gained from studying the brains of people with Down syndrome will lead to a much better picture of how prions begin to form in the first place, said Condello.
Whether the Down syndrome brain tissue will prove to be the ultimate model for developing treatments for Alzheimer’s remains to be seen, the researchers said. While the two disorders share many similarities in their prion pathobiology, there are some differences that may be limiting.
Still, the researchers said, studying the plaques and tangles in Down syndrome is a promising route to identifying the specific prions that arise at the very earliest stages of the disease process. That insight could open new vistas on not only treating but perhaps even fending off Alzheimer’s disease.
“If we can understand how this neurodegeneration begins, we are one big step closer to being able to intervene at a meaningful point and actually prevent these large brain lesions from forming,” Condello said.
In a large registry-based study investigating medication use in people with substance use disorders, the ADHD medication lisdexamfetamine was associated with the lowest risk of hospitalisation and death in people with amphetamine addiction. The findings, which also showed drugs which worsened outcomes, were published in JAMA Psychiatry.
“Our results suggest that lisdexamfetamine is associated with the best outcomes, and encourage the conduction of randomised controlled trials to explore this further, says first author Jari Tiihonen, professor at Karolinska Institutet.
Worldwide, amphetamines are the second most used illicit drugs and hospitalisations related to its use are rising.
At present, there are no approved pharmacological interventions available for treating amphetamine or methamphetamine addiction. While certain medications have shown promising results, the studies so far have often been small and convincing evidence is lacking.
Registry-based study
In the present study, the researchers investigated the association between generally used medications among persons with substance use disorder and the risk of two primary outcomes in people with amphetamine or methamphetamine use disorder: 1) hospitalisation due to substance use disorder or 2) hospitalisation due to any cause, or death.
The study enrolled nearly 14 000 individuals aged 16 to 64 years in Sweden with a registered first-time diagnosis of amphetamine or methamphetamine use disorder from July 2006 to December 2018. Individuals with schizophrenia or bipolar disorder were excluded.
Patients were followed from diagnosis until they died, emigrated, were diagnosed with schizophrenia or bipolar disorder or the study ended. The median follow-up time was 3.9 years.
Comparing effects in the same individual
The researchers looked at how the risk of hospitalisation or death for each individual differed depending on whether they were on or off the medication at that time.
”Our results show that lisdexamfetamine, a medication approved for treating ADHD and in some countries also for binge eating, was the only specific medication associated with reduced risk of hospitalisation and death,” says first author Milja Heikkinen, researcher at the University of Eastern Finland and Niuvanniemi Hospital.
The risk of hospitalisation due to substance use disorder was 18% lower and the risk of hospitalisation due to any cause or death was 14% lower during periods of lisdexamfetamine use, compared to periods without the ADHD medication.
The combination of two or more different medications for substance use disorder was also associated with a lower risk of hospitalisation or death.
Some medications linked to worse outcomes
Use of benzodiazepines was associated with poorer outcomes; 17% higher risk of hospitalisation due to substance use disorder and 20% higher risk of hospitalisation due to any cause or death, during periods of use compared to periods of non-use. The use of antidepressants was also associated with slightly worse outcomes than non-use.
The researchers note that pharmacological treatments are often discontinued when the clinical state has improved, and are started when the clinical state deteriorates. Therefore, the results may underestimate the putative beneficial effect of treatments. To control for this phenomenon, the researchers conducted analyses by omitting the first 30 days of use. The results were then in line with the main analyses.
A new study using mouse models describes an orally administered small-molecule drug that reduces lowers cholesterol by 70% by preventing the degradation of low-density lipoprotein (LDL) receptors. Published in Cell Reports, the findings point to a previously unrecognised strategy for managing cholesterol – one which may also impact cancer treatments.
“Cholesterol lowering is one of the most important therapies we have to prolong life and protect people from heart disease, which is still the number one cause of morbidity and mortality in the Western world,” said senior author Jonathan S. Stamler, MD, professor at Case Western Reserve School of Medicine.
“Statins only lower cholesterol so far. This is a drug class that we think would represent a new way to lower cholesterol, a new way to hit PCSK9.”
Study Findings
Central to cholesterol regulation are LDL receptors, which sit at the surface of liver cells and remove cholesterol from the blood, thereby lowering serum levels. PCSK9 in the bloodstream controls the number of LDL receptors by marking them for degradation. Therefore, agents that inhibit PCSK9 increase the number of LDL receptors that remove cholesterol.
Nitric oxide is a molecule that is known to prevent heart attacks by dilating blood vessels. In the new study, Stamler and colleagues show that nitric oxide can also target and inhibit PCSK9, thus lowering cholesterol. They identify a small molecule drug that functions to increase nitric oxide inactivation of PCSK9. Mice treated with the drug display a 70% reduction in LDL cholesterol.
Beyond Cholesterol to Cancer
In addition to impacting the field of cholesterol metabolism, the findings may impact patients with cancer, as emerging evidence suggests targeting PCSK9 can improve the efficacy of cancer immunotherapies.
“PCSK9 not only targets LDL receptors for degradation, it also mediates the degradation of MHC 1 on lymphocytes, which is used for recognition of cancer cells” said Stamler. “PCSK9 is effectively preventing your lymphocytes from recognising cancer cells. So, if you inhibit PCSK9, you can boost the body’s cancer surveillance. There may be an opportunity one day to apply these new drugs to that need.”
A study of COVID transmissions in a Taiwanese quarantine hotel revealed that SARS-CoV-2 can spread through cracks in walls and floors, according to findings published in Emerging Infectious Diseases.
The researchers investigated a cluster of SARS-CoV-2 infections in a quarantine hotel in Taiwan in December 2021. This happened amidst a succession of outbreaks in quarantine hotels involving the Omicron variant. The cluster involved three patients who lived in nonadjacent rooms on different floors, and who had no direct contact during their stay.
All three had tested negative by RT-PCR for SARS-CoV-2 within 72 hours before arrival to Taiwan and by deep-throat saliva RT-PCR upon arrival at the airport. None had left their rooms at any point during the stay in the hotel. No other guest or staff member at the hotel had tested positive since the month prior to the start of the investigation.
By directly exploring the space above the room ceilings, the researchers revealed residual tunnels, wall defects, and truncated pipes between their rooms. To see how the rooms were interconnected, they performed a simplified tracer-gas experiment, using ethanol. Aerosol transmission through structural defects in floors and walls in this poorly ventilated hotel was the most likely route of virus transmission.
This event demonstrated the high transmissibility of Omicron variants, even across rooms and floors, through structural defects. “Our findings emphasise the importance of ventilation and integrity of building structure in quarantine facilities,” the authors concluded.
In a study published in The LancetGlobal Health, an international team of researchers has found that influenza vaccines greatly reduce both pneumonia and cardiovascular complications in people with heart failure.
“If you have heart failure, you should get your flu shot because it can save your life – that is what we found in this study,” said the study’s principal investigator Mark Loeb. “It is underappreciated that influenza vaccine can save people from cardiovascular death.”
The study showed that over the entire year the influenza vaccine reduced pneumonia by 40% and hospitalisation by 15% in patients with HF. During influenza season in autumn and winter, the influenza vaccine reduced deaths by 20% in these patients.
Data gathered during flu season also showed the vaccine helped protect against cardiovascular complications, such as heart attacks and strokes.
Trial investigators tracked more than 5000 patients with HF in 10 countries across Africa, Asia and the Middle East, where few people have regular influenza vaccination. They received either an influenza vaccine or a placebo annually between June 2015 and November 2021.
While the flu has long been associated with an increased risk of life-threatening cardiovascular events, Loeb said that people with heart failure are already vulnerable to poor health outcomes. Patients with the condition have a 50% chance of dying within five years, while 20% are hospitalised for cardiovascular complications every year.
“Importantly, we looked at low and middle-income countries where 80 per cent of cardiovascular disease occurs and where flu vaccination rates are low.”
Salim Yusuf, executive director of PHRI and an author of the study said: “The flu shot should be part of the standard practise in people with heart failure given how simple, inexpensive and safe it is. Avoiding one sixth of deaths from heart disease and preventing hospitalizations makes it very cost effective and that can have an important public health and clinical impact.”
The study from McMaster University and partners marks the first clinical trial of the flu vaccine’s effectiveness in patients with HF.
The US Centers for Disease Control have released new opioid prescribing guidelines that do not promote strict thresholds for dose and duration of pain medications. The new guidelines, which update and replace the controversial 2016 guidelines, are published in Morbidity and Mortality Weekly Report.
The previous guidelines had been interpreted as imposing strict opioid dose and duration limits and was misapplied by some organisations, leading to a clarification being released in 2019. Other organisations, such as the European Pain Federation, had stated that overly strict guidelines for their own countries were hampering effective pain management.
The 2022 recommendations are voluntary and give clinicians and patients flexibility to support individual care, said Christopher Jones, PharmD, DrPH, MPH, acting director of CDC’s National Center for Injury Prevention and Control in a press briefing. He stressed that they should not be used as a inflexible rule, or applied as a rigid standard of care, or replace clinical judgement on personalised treatment.
“Patients with pain should receive compassionate, safe, and effective pain care,” Jones stated. “We want clinicians and patients to have the information they need to weigh the benefits of different approaches to pain care, with the goal of helping people reduce their pain and improve their quality of life.”
The guidance covers four key areas: opioids initiation for pain, opioid and dosage selection, deciding prescription duration and conducting follow-up, and assessing risk and potential harms of opioids. It also suggests that clinicians work with patients to incorporate plans to mitigate risks, including offering naloxone.
The document indicates opioids should not be considered as first-line or routine therapy for subacute or chronic pain, and points out that, for many kinds of acute pain, non-opioid therapies are often better choices.
“For patients receiving opioids for 1 to 3 months (the timeframe for subacute pain), the 2022 guideline recommends that clinicians avoid continuing opioid treatment without carefully reassessing treatment goals, benefits, and risks in order to prevent unintentional initiation of long-term opioid therapy,” noted Deborah Dowell, MD, MPH and colleagues in a commentary published in the New England Journal of Medicine.
For chronic pain, clinicians should make maximal use of non-opioid therapies and consider initiating opioid therapy only if pain reduction benefits outweigh the risk, Dowell and colleagues noted. When needed, clinicians should initiate opioids at the minimum effective dose, assess risks and benefits before increasing dosage, and avoid raising dosage above levels likely to yield diminishing returns, they added.
The new guideline offers tips for tapering opioids when warranted, but is not intended to lead to rapid opioid tapering or discontinuation, Jones noted. The recommendations do not apply to sickle cell disease-related pain, cancer pain, and palliative or end-of-life care.
The 2022 document incorporated public feedback since the new version was first proposed in February, including patients discussing their experiences with pain or opioid addiction and barriers to pain care.
“The science on pain care has advanced over the past 6 years. During this time, CDC has also learned more from people living with pain, their caregivers, and their clinicians,” said Dowell in a statement. “We’ve been able to improve and expand our recommendations by incorporating new data with a better understanding of people’s lived experiences and the challenges they face when managing pain and pain care.”
“I think I’m in trouble,” came the message through to Professor Veronica Ueckermann one evening during the first surge of COVID-19 in South Africa in the winter of 2020. It was a distressed call made by a 48-year-old theatre nurse who worked alongside Ueckermann in the ICU frontline. Ueckermann, who is also a professor of internal medicine at the University of Pretoria and an ICU specialist, shifted into high gear with other doctors to save their colleague who was diagnosed with COVID-19.
They succeeded.
But what they didn’t know then was that months later the nurse would be ailing from ongoing medical symptoms put down to the catch-all of long-COVID.
“It’s a case study, but it was also very close to my heart,” says Ueckermann, who has become a specialist and researcher on the long-term effects of COVID. She recently presented on long-COVID during a webinar of the South African Academy of Family Physicians. “The nursing sister had numerous comorbidities, including a raised BMI, diabetes, hypertension, and asthma. When her symptoms didn’t get better, the hospital just wanted to have her medically boarded because they couldn’t be sure when she would be well enough to work again,” says Ueckermann.
She is cautious too, pointing out that there’s still little definitively known about long-COVID and new research is only in its infancy. Much of the difficulty lies in the wide-ranging symptoms and how individuals are affected. There are also varying recovery times, different underlying conditions and susceptibilities, and the reality that many people are simply not diagnosed. It makes the term “long-COVID” an umbrella term for everything from brain fog or mental confusion and fatigue to depression and shortness of breath and chest pains. Others also describe general body aches and continued loss of smell and taste.
The post-COVID condition
In October 2022, the World Health Organization (WHO) released a factsheet that states that between 10% and 20% of people who are diagnosed with COVID-19 continue to have symptoms beyond three months of first getting ill and develop what the WHO refers to as post-COVID condition. Many more people say symptoms plague them still even after nearly two years.
“The condition can be debilitating, causing disabling symptoms and functional deficits. It can significantly impact people’s ability to work, engage and participate fully in family and community life. Mental health effects can directly result from long-COVID, but may also develop due to prolonged suffering and distress caused by the condition,” reads the WHO factsheet.
The WHO’s recommended treatment, however, is non-specific, stating: “Post-COVID-19 condition can be supported with help from their families, peers, employers, and the community and they can also benefit from tailored rehabilitation.”
According to the National Institute for Communicable Diseases (NICD), “Every long-COVID patient is different, as such, every patient will need treatment specific to their symptoms which can be managed by their family doctor or clinic. There are no drugs to prevent long-COVID. Long-COVID is not a contraindication to vaccination, and COVID-19 vaccination may even sometimes improve long-COVID symptoms. Long-COVID is treated by slow, stepwise rehabilitation, and appropriate management of symptoms.”
Greater awareness and education needed
Ueckermann agrees with the WHO’s call for greater awareness and education so patients feel heard and supported. Many people resort to joining online support groups through platforms like Facebook. They share their challenges and stories and give each other support when they feel misunderstood and frustrated that they can’t get well and doctors can’t help. Ueckermann says there needs to be help for patients’ individual needs because not finding solutions will add to mounting pressure on the healthcare system.
“Because of COVID disruptions, many cancers are now presenting at later stages. There are cases of TB and other illnesses that were neglected. And now we have long-COVID that requires diagnosis after diagnosis for exclusion so all of this drives up costs,” she says.
lung There are other associated costs for people who cannot work or are performing sub-optimally trying to work while feeling unwell. Children affected by long-COVID do worse at school and lose interest in their sports and other activities that they used to enjoy, she says.
Last year, Spotlight reported on a dedicated long-COVID clinic at Groote Schuur Hospital in Cape Town. As far as we could establish, such specialised long-COVID clinics are very rare in South Africa.
“Long-COVID remains inaccurately defined and as a result, standard treatment guidelines for the condition as a whole have not yet been developed,” says Foster Mohale, Spokesperson for the National Department of Health. “However, standard treatment guidelines to address the symptoms and conditions associated with long-COVID are in place,” he says. “These guidelines guide assessment and treatment, and provide criteria for referral from primary healthcare to more specialised services.”
Mohale adds that the burden of disease is of “enormous concern and needs to be better understood and quantified”. But says the department’s data shows that visits by adults to public sector primary healthcare facilities remain below pre-pandemic levels, which suggests that any increase in the burden of disease has not resulted in an increased burden on health services. He also emphasises the need to have up-to-date vaccinations, adding that “people who are vaccinated are less likely to develop long-COVID”.
Research ongoing
Ueckermann says it’s a positive development that as awareness is growing, so are studies, including studies by the Medical Research Council and many of the country’s universities. She says scientists are looking at everything from the role of green tea extracts and the use of SSRIs (Selective serotonin reuptake inhibitors) that are commonly used to treat depression.
“These are all ongoing studies, so we have to wait to see the data coming through but it’s promising that everyone is trying to understand exactly what this long-COVID is and the most important thing is that we continue making this a greater area of priority in healthcare,” she says. It matters for the growing number of patients, or for her colleague who she says still needs help to get from “doing better,” to fully recovered.
In a study published in the International Journal of Gynecology & Obstetrics, UK researchers have uncovered an association between the rate of eclampsia and the number of deaths caused by indoor household pollution, mostly from cooking and heating fires.
More commonly seen in low- and middle-income countries commonly using solid fuels, such as wood and charcoal, indoor household pollution has been proven to increase the risk of adverse birth outcomes, including placental hypoxia.
The researchers evaluated more than 2690 cases of eclampsia in Ethiopia, Haiti, India, Malawi, Sierra Leone, Uganda, Zambia and Zimbabwe, and found a significant correlation between deaths due to indoor household pollution and eclampsia rates – and the correlation was even more prominent when eclampsia occurred at home.
King’s College London’s Professor Andrew Shennan, one of the lead authors on the paper, said the findings demonstrate how air pollution can impact vulnerable populations the most.
“In-house cooking and household pollution may increase the risk of seizures. We believe that less oxygen will get to the mother’s brain, and this may trigger a fit in women who already have pre-eclampsia” he said.
“We are lucky to have such a large dataset of women with eclampsia, as it only occurs in 1% of women with pre-eclampsia. This has allowed us to uncover this new finding.
“This could help explain observed inequalities in maternal healthcare in low- and middle-income countries.”
In a previous study by King’s College London, scientists found that 94% of maternal deaths occur in low- and middle-income countries, with 22% due to hypertensive disorders like eclampsia.
Professor Shennan added: “Knowing why women have these severe outcomes allows us to reduce the risk of eclampsia and work out how to save lives.
“We have large programmes of work in India, Sierra Leone and Zambia where many women have complications related to high blood pressure. Our current research is aimed at identifying the women at risk but now we are looking at ways to reduce risk, including earlier delivery. This data will help us to give advice about avoiding risk at home.”
The researchers next plan to explore whether climate change increases the prevalence of pre-eclampsia or increases the morbidity from serious manifestations such as eclampsia.
The national Department of Health (DOH) has managed to secure a significant reduction in prices for antiretroviral medicines that treat HIV, with the price of the regimen that is prescribed to most new patients (tenofovir/lamivudine/dolutegravir – TLD) dropping over 30%, from R99 to R68. By comparison the regimen costs well over R250 in the private sector.
TLD is recommended by the World Health Organisation as the preferred first-line regimen for adults living with HIV.
Currently over 4 million South Africans are using this regimen, according to statistics from the DOH. There are about over 5.5 million people receiving treatment for HIV, and 8 million people living with the virus in this country.
Prices of ABC/3TC, commonly used to treat children with HIV, also fell with the DOH’s new contract.
Khadija Jamaloodien, director of the Affordable Medicines Directorate in the DOH, told GroundUp that South Africa is the biggest buyer of ARVs in the world. She said because of the sheer number of people needing ARVs, the department was able to bring the price down.
“Our volumes are just so huge that it makes it more efficient for manufacturers to be able to supply at reasonable prices,” said Jamaloodien.
She said another reason the department was able to reduce the price was that the manufacturers were applying for a three-year contract with “a certainty of demand”. She said constant communication with manufacturers about changes in demand also helped. If demand is likely to be reduced, the department would inform manufacturers who then would not “sit with stock that they are going to have to write off”.
The contract, which is already being executed, was awarded from July 2022 and ends in June 2025.
Jamaloodien said lower prices meant that the department could serve more patients and provide more medicines within the same budget envelope. (ARVs are provided free to public sector patients.)
Juliet Houghton, CEO of the Southern African HIV Clinicians Society (SAHCS), praised the DOH’s efforts to secure the ARVs so cheaply. She said a “healthy” degree of competition between manufacturers also helped drive prices down.
Houghton added that the reduction in prices “offers an opportunity to reinvest some of the savings into more expensive, particularly prevention drugs, that are coming”.
“As a country, we don’t want to just keep treating more and more people with HIV, we actually want to prevent it,” said Houghton. She said that the remaining budget could also be invested in prevention injectables, which might be more expensive.
Jamaloodien said that the injectable pre-exposure prophylaxis (PrEP) medicines are not yet registered with South African Health Products Regulatory Authority (SAHPRA). These help prevent sexually active people from contracting HIV. She said after the medicines are registered, they will have to look at whether they are affordable.
Francois Venter, executive director of Ezintsha at Wits, also praised the DOH’s “excellent work in securing these price reductions”.
“We also need the department to start using these processes better to secure similar world-class treatments for other common diseases – including diabetes, cancer, obesity, and TB,” he said.
