Tuberculosis (TB), one of the leading infectious killers in Brazil and other low- and middle-income countries, is closely linked to poverty. “We know that TB is driven by poverty, but until now, the effects of cash transfers on disease outcomes among the most vulnerable populations had not been fully analysed,” says the coordinator of the study, Davide Rasella, head of the Health Impact Assessment and Evaluation group at ISGlobal and collaborating professor of the Institute of Collective Health.

Rasella and his colleagues in Brazil analysed data, including ethnic and socioeconomic conditions, from 54.5 million low-income Brazilians between 2004 and 2015. They compared TB incidence (number of new cases), mortality (number of deaths in the population) and case fatality rate (how many people who have the disease die) among people who received BFP support (23.9 million) or not (30.6 million). In total, there were 159,777 new TB diagnoses and 7,993 TB deaths in the cohort under study.

Stronger effects among indigenous and extremely poor people

The results show a large decrease in TB cases and deaths among those benefiting from cash transfers. The decrease was of over 50% in extremely poor people and more than 60% among the indigenous populations. Although the program reduced TB cases across all groups, its effect was smaller in those who were less poor, and there was no significant reduction in TB deaths in that group. The TB case fatality rate (i.e. how deadly the disease is in those affected) was also lower among Bolsa Família beneficiaries compared to non-beneficiaries, although the difference between the two groups was not statistically significant.

The reason behind the BFP’s effect on TB outcomes is not a mystery. “We know that the program improves access to food, both in quantity and quality, which reduces food insecurity and malnutrition- a major risk factor for TB- and strengthens people’s immune defences as a result. It also reduces barriers to accessing healthcare,” says Gabriela Jesus, co-first author of the study along with Priscila Pinto, both from FIOCRUZ.

Global implications

Expanding the BFP can help Brazil address the worrying increase in TB cases among vulnerable populations following the COVID-19 pandemic. But the implications of these findings extend beyond Brazil.

“Our study has far-reaching implications for policy-making in all countries with a high burden of TB,” says Rasella. The message is clear: social protection programmes not only help reduce poverty and malnutrition, but can also play a crucial role in achieving the targets of the END-TB strategy and those of the Sustainable Development Goals.

“We often assume that mutations in cancer genes are bad news, but that’s not the whole story,” says lead researcher Francesca Ciccarelli, Professor of Cancer Genomics at Queen Mary University of London’s Barts Cancer Institute and Principal Group Leader at the Francis Crick Institute, where the experimental work in this study took place. “The context is crucial. These results support a paradigm shift in how we think about the effect of mutations in cancer.”

This research was funded by Cancer Research UK and the experimental work in this study took place at the Francis Crick Institute.

A new understanding of oesophageal cancer risk

Just 12% of patients with oesophageal cancer in England survive their disease for 10 years or more. The UK has one of the world’s highest incidences of a subtype called oesophageal adenocarcinoma, and cases continue to increase. This cancer type develops from a condition called Barrett’s oesophagus, in which the cells lining the oesophagus become abnormal. However, only around 1% of people with Barrett’s go on to develop cancer each year. In the new study, the research team sought to better understand why some cases of Barrett’s lead to cancer, while others do not, to support better prediction and treatment of oesophageal adenocarcinoma.

The team analysed a large gene sequencing dataset from more than 1,000 people with oesophageal adenocarcinoma and more than 350 people with Barrett’s oesophagus, including samples from the OCCAMS consortium*. They found that defects in a gene called CDKN2A were more common in people with Barrett’s oesophagus who never progressed to cancer. This finding was unexpected, as CDKN2A is commonly lost in various cancers and is well-known as a tumour suppressor gene — a molecular safeguard that stops cancer from forming.

The research showed that if normal cells in our oesophagus lose CDKN2A, it helps promote the development of Barrett’s oesophagus. However, it also protects cells against the loss of another key gene encoding p53 — a critical tumour suppressor often dubbed the ‘guardian of the genome’. Loss of p53 strongly drives the progression of disease from Barrett’s to cancer.

The team found that potentially cancerous cells that lost both CDKN2A and p53 were weakened and unable to compete with other cells around them, preventing cancer from taking root. In contrast, if cancer cells lose CDKN2A after the disease has had time to develop, it promotes a more aggressive disease and worse outcomes for patients.

A gene with two faces

Professor Ciccarelli likens the dual role of CDKN2A to the ancient Roman god of transitions Janus, after whom January is named. Janus has two faces — one looking to the past and one to the future.

“It can be tempting to look at cancer mutations as good or bad, black or white. But like Janus, they can have multiple faces — a dual nature,” she explains. “We’re increasingly learning that we all accumulate mutations as an inevitable part of aging. Our findings challenge the simplistic perception that these mutations are ticking time bombs and show that, in some cases, they can even be protective.”

The findings could have significant implications for how we assess cancer risk. They suggest that if a person with Barrett’s oesophagus has an early CDKN2A mutation but no mutations in p53, it could indicate that their condition is less likely to progress to cancer. On the other hand, later in the disease, CDKN2A mutations may signal a poor prognosis. Further research is needed to determine how to best apply this new knowledge to benefit patients in the clinic.

Science Engagement Manager at Cancer Research UK, Dr Nisharnthi Duggan, said: “Survival for oesophageal cancer has improved since the 1970s, but it’s still one of the most challenging cancers to treat. This is largely because it’s often diagnosed at advanced stages, when treatments are less likely to be successful.

“Funding research like this is critical to advancing our understanding and improving outcomes for people affected by the disease. It shows the importance of discovery science in unravelling the complexities of cancer, so we can identify new ways to prevent, detect and treat it.”

“In high-income countries like the U.S. or Germany, farmers receive less than a quarter of food spending, compared to over 70 percent in Sub-Saharan Africa, where farming costs make up a larger portion of food prices,” says David Meng-Chuen Chen, PIK scientist and lead author of the study published in Nature Food. “This gap underscores how differently food systems function across regions.” The researchers project that as economies develop and food systems industrialise, farmers will increasingly receive a smaller share of consumer spending, a measure known as the ‘farm share’ of the food dollar.

“In wealthy countries, we increasingly buy processed products like bread, cheese or candy where raw ingredients make up just a small fraction of the cost,” adds Benjamin Bodirsky, PIK scientist and author of the study. “The majority of the price is spent for processing, retail, marketing and transport. This also means that consumers are largely shielded from fluctuations in farm prices caused by climate policies such as taxes on pollution or restrictions on land expansion, but it also underscores how little farmers actually earn.”

Examining the full food value chain to uncover climate policy impacts

To arrive at these conclusions, the team of scientists combined statistical and process-based modelling to assess food price components across 136 countries and 11 food groups. They studied prices of food both consumed at home and away from home. “Most models stop at farm costs, but we went all the way to the grocery store and even the restaurant or canteen,” says Chen. By analysing the entire food value chain, the researchers also provide new insights into how greenhouse gas mitigation policies impact consumers: “Climate policies aimed at reducing emissions in agriculture often raise concerns about rising food prices, particularly for consumers. Our analysis shows that long supply chains of modern food systems buffer consumer prices from drastic increases, especially in wealthier countries,” explains Chen.

Climate policies impact consumers differently in wealthy and poor countries

“Even under very ambitious climate policies with strong greenhouse gas pricing on farming activities the impact on consumer prices by the year 2050 would be far smaller in wealthier countries,” Bodirsky says. Consumer food prices in richer countries would be 1.25 times higher with climate policies, even if producer prices are 2.73 times higher by 2050. In contrast, lower-income countries would see consumer food prices rise by a factor of 2.45 under ambitious climate policies by 2050, while producer prices would rise by a factor of 3.3. While even in lower-income countries consumer price rises are less pronounced than for farmers, it would still make it harder for people in lower-income countries to afford sufficient and healthy food.

Despite food price inflation, poor consumers do not necessarily need to suffer from climate mitigation policies. A previous study by PIK (Soergel et al 2021) showed that if revenues from carbon pricing were used to support low-income households, these households would be net better off despite food price inflation, due to their higher incomes.

“Climate policies might be challenging for consumers, farmers, and food producers in the short term, but they are essential for safeguarding agriculture and food systems in the long run,” says Hermann Lotze-Campen, Head of Research Department “Climate Resilience” at PIK and author of the study. “Without ambitious climate policies and emission reductions, much larger impacts of unabated climate change, such as crop harvest failures and supply chain disruptions, are likely to drive food prices even higher. Climate policies should be designed to include mechanisms that help producers and consumers to transition smoothly, such as fair carbon pricing, financial support for vulnerable regions and population groups, and investments in sustainable farming practices.”

Metastases are the dangerous offshoots of tumors that spread to vital organs such as the liver, lungs or brain and are usually difficult to treat. Even though the prognosis for breast cancer patients has improved significantly in recent decades, metastatic breast cancer still poses a major challenge, as the metastases often only respond temporarily to treatment.

Breast cancer metastases are initiated by cancer cells that detach from the primary tumor and migrate to other organs via the bloodstream. These circulating cancer cells (CTCs) are extremely rare and hide among the billions of blood cells. Andreas Trumpp, Head of a research division at the DKFZ and Director of HI-STEM, had already demonstrated several years ago that only a few of the circulating tumor cells are capable of forming a new metastasis in another organ. These mostly therapy-resistant “germ cells” of metastases are very rare, difficult to isolate and could not be multiplied in the laboratory until now. “This makes it difficult to develop targeted new therapies that directly attack the metastasis-initiating cells. However, if we understand how these cells survive the initial therapy and what drives their resistance, we could tackle the formation of breast cancer metastases at the root and perhaps one day even prevent them,” explains the first author of the paper, Roberto Würth from Trumpp’s lab.

Andreas Trumpp’s team has succeeded for the first time in multiplying CTCs from blood samples of breast cancer patients and growing them as stable tumor organoids in the culture dish. Until now, this always required a detour, namely the complex and lengthy propagation of CTCs in immunodeficient mice. In order to understand how tumor cells become resistant to therapies, researchers need tumor material from different time points in the course of the disease. In contrast to surgical removal of tissue samples (biopsies), blood samples are simple and can be taken several times.

The three-dimensional and patient-specific mini-tumors can be cultivated from blood samples several times during the course of the disease and are ideally suited for investigating the molecular mechanisms that enable tumors to survive despite therapy. Preclinical tests on the efficacy of already available cancer drugs can also be carried out quickly and on a large scale on organoids in the culture dish.

In the clinical registry trial CATCH at the NCT Heidelberg, the genetic diversity of patients’ breast cancer cells is analyzed. Thanks to the successful cultivation of the organoids, Trumpp’s interdisciplinary research team, in close collaboration with the experts of the CATCH trial, was able to identify a key signaling pathway that ensures the growth and survival of breast cancer CTCs in the blood. The protein NRG1 (neuregulin 1) acts like a vital “fuel.” It binds to the HER3 receptor on the cancer cells and, together with the HER2 receptor, activates signaling pathways that ensure the growth and survival of the cells. What is also exciting is that even if this fuel runs out or the receptors are blocked by drugs, the cells find new tricks. An alternative signaling pathway, controlled by FGFR1 (fibroblast growth factor receptor 1), steps in and ensures growth and survival.

“With the help of such ‘bypasses’, tumors react to external influences, for example to targeted therapies against HER2. This is a crucial mechanism in the development of therapy resistance,” explains Roberto Würth. But there are ways out: the researchers used organoids to show that a combined blockade of both signaling pathways (NRG1-HER2/3 and FGFR) can effectively stop the proliferation of tumor cells and induce cell death.

Andreas Trumpp summarizes: “The possibility of cultivating CTCs from the blood of breast cancer patients as tumor organoids in the laboratory at different time points is a decisive breakthrough. This makes it much easier to investigate how tumor cells become resistant to therapies. On this basis, we can develop new treatments that may also specifically kill resistant tumor cells. Another conceivable approach is to adapt existing therapies in such a way that the development of resistance and metastases is reduced or even prevented from the outset. As the organoids are specific to each patient, this method is suitable for identifying or developing customized therapies that are optimally tailored to the respective diseases.” Before the method can be used to treat breast cancer patients, it must first be tested in clinical trials.

*The Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) gGmbH was founded in 2008 as a public-private partnership between the DKFZ and the Dietmar Hopp Foundation

** The National Center for Tumor Diseases (NCT) Heidelberg is a long-term cooperation between the German Cancer Research Center, the University Hospital and the University of Heidelberg.

Researchers from the UK and China drew this conclusion after studying proteins from blood samples taken from over 42,000 adults recruited to the UK Biobank. Their findings are published today in the journal Nature Human Behaviour.

Social relationships play an important role in our wellbeing. Evidence increasingly demonstrates that both social isolation and loneliness are linked to poorer health and an early death. Despite this evidence, however, the underlying mechanisms through which social relationships impact health remain elusive.

One way to explore biological mechanisms is to look at proteins circulating in the blood. Proteins are molecules produced by our genes and are essential for helping our bodies function properly. They can also serve as useful drug targets, allowing researchers to develop new treatments to tackle diseases.

A team led by scientists at the University of Cambridge, UK, and Fudan University, China, examined the ‘proteomes’ — the suite of proteins — in blood samples donated by over 42,000 adults aged 40-69 years who are taking part in the UK Biobank. This allowed them to see which proteins were present in higher levels among people who were socially isolated or lonely, and how these proteins were connected to poorer health.

The team calculated social isolation and loneliness scores for individuals. Social isolation is an objective measure based on, for example, whether someone lives alone, how frequently they have contact with others socially, and whether they take part in social activities. Loneliness, on the other hand, is a subjective measure based on whether an individual feels lonely.

When they analysed the proteomes and adjusted for factors such as age, sex and socioeconomic background, the team found 175 proteins associated with social isolation and 26 proteins associated with loneliness (though there was substantial overlap, with approximately 85% of the proteins associated with loneliness being shared with social isolation). Many of these proteins are produced in response to inflammation, viral infection and as part of our immune responses, as well as having been linked to cardiovascular disease, type 2 diabetes, stroke, and early death.

The team then used a statistical technique known as Mendelian randomization to explore the causal relationship between social isolation and loneliness on the one hand, and proteins on the other. Using this approach, they identified five proteins whose abundance was caused by loneliness.

Dr Chun Shen from the Department of Clinical Neurosciences at the University of Cambridge and the Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, said: “We know that social isolation and loneliness are linked to poorer health, but we’ve never understood why. Our work has highlighted a number of proteins that appear to play a key role in this relationship, with levels of some proteins in particular increasing as a direct consequence of loneliness.

Professor Jianfeng Feng from the University of Warwick said: “There are more than 100,000 proteins and many of their variants in the human body. AI and high throughput proteomics can help us pinpoint some key proteins in prevention, diagnosis, treatment and prognosis in many human diseases and revolutionise the traditional view of human health.

“The proteins we’ve identified give us clues to the biology underpinning poor health among people who are socially isolated or lonely, highlighting why social relationships play such an important part in keeping us healthy.”

One of the proteins produced in higher levels as a result of loneliness was ADM. Previous studies have shown that this protein plays a role in responding to stress and in regulating stress hormones and social hormones such as oxytocin — the so-called ‘love hormone’ — which can reduce stress and improve mood.

The team found a strong association between ADM and the volume of the insula, a brain hub for interoception, our ability to sense what’s happening inside our body — the greater the ADM levels, the smaller the volume of this region. Higher ADM levels were also linked to lower volume of the left caudate, a region involved in emotional, reward, and social processes. In addition, higher levels of ADM were linked to increased risk of early death.

Another of the proteins, ASGR1, is associated with higher cholesterol and an increased risk of cardiovascular disease, while other identified proteins play roles in the development of insulin resistance, atherosclerosis (‘furring’ of the arteries) and cancer progression, for example.

Professor Barbara Sahakian from the Department of Psychiatry at the University of Cambridge said: “These findings drive home the importance of social contact in keeping us well. More and more people of all ages are reporting feeling lonely. That’s why the World Health Organization has described social isolation and loneliness as a ‘global public health concern’. We need to find ways to tackle this growing problem and keep people connected to help them stay healthy.”

The research was supported by the National Natural Sciences Foundation of China, China Postdoctoral Science Foundation, Shanghai Rising-Star Program, National Key R&D Program of China, Shanghai Municipal Science and Technology Major Project, 111 Project, Shanghai Center for Brain Science and Brain-Inspired Technology, and Zhangjiang Lab.

Background

Clozapine is currently the only antipsychotic drug approved by the Food and Drug Administration (FDA) of the United States for treatment-resistant schizophrenia. It is widely known for its high efficacy in reducing symptoms, relapse rate, and all-cause mortality in schizophrenia and is widely regarded as a drug of last resort. Recent Finnish and American studies suggested that clozapine may be associated with a significantly increased risk of blood cancer. However, owing to data restrictions and study design, the additional number of blood cancer cases associated with prior clozapine exposure could not be estimated and remained unclear. The clinical significance of this risk, therefore, had yet to be determined.

Research methods and findings

The research team utilised territory-wide electronic health records from the Hospital Authority of Hong Kong to comb through 400,000 patient records to construct a retrospective cohort of approximately 10,000 patients diagnosed with schizophrenia between 2001 and 2022 and followed up for a median of seven years since their drug initiation. The team’s observations of the patients showed the following:

• The absolute risk of blood cancer is very rare: In the cohort of 10,000 patients followed over a period of about seven years, only 39 developed blood cancer. After statistical adjustment, the study estimated that there were fewer than six cases of blood cancer per 10,000 patients using clozapine for one year.
• Consistent with Western studies: The weighted incidence rate ratio of blood cancer in clozapine users versus controls was estimated at 2.22, suggesting that there is a slight association. This observation is consistent with the findings of previous Finnish and American case-control studies.
• No risk for other cancers: No association was observed for other cancer types.

Significance of the study

‘In response to Western studies suggesting a potential risk of blood cancer after clozapine use, this study provides reliable evidence for patients and healthcare professionals supporting the safety of the drug. The current blood monitoring measures are very comprehensive. Patients do not need to be overly concerned about the risk of blood cancer caused by clozapine given the rarity of its occurrence demonstrated in this study. Clinicians should weigh the risks and benefits of the drug, taking into account the rarity of the association between clozapine and blood cancer, and make appropriate arrangements according to patients’ needs,’ said Professor Francisco Lai Tsz-tsun, the project leader and Assistant Professor in both the Department of Pharmacology and Pharmacy and the Department of Family Medicine and Primary Care under the School of Clinical Medicine of HKUMed.

‘Because of the readily linked and longitudinally available data across all public healthcare facilities in Hong Kong, we were able to come up with a better study design than those in other countries,’ said Professor Lai. ‘This enabled us to make immediate use of big data to better address clinically meaningful healthcare issues than researchers in many other countries, highlighting the key strengths of Hong Kong’s healthcare big data and its potential application in drug safety monitoring.’

The research team is currently re-examining a wide range of potential adverse effects of other psychotropic drugs, especially cancer risks, and their overall long-term safety and effectiveness. ‘Ultimately, through our joint interdisciplinary efforts, we hope to better inform day-to-day clinical decisions and make medication use in patients with mental illness much safer and more effective,’ Professor Lai added.

“Ovarian tumours are common and are often detected by chance,” says Professor Elisabeth Epstein at the Department of Clinical Science and Education, Södersjukhuset (Stockholm South General Hospital), at Karolinska Institutet and senior consultant at the hospital’s Department of Obstetrics and Gynecology. “There is a serious shortage of ultrasound experts in many parts of the world, which has raised concerns of unnecessary interventions and delayed cancer diagnoses. We therefor wanted to find out if AI can complement human experts.”

AI outperforms experts

The researchers have developed and validated neural network models able to differentiate between benign and malignant ovarian lesions, having trained and tested the AI on over 17,000 ultrasound images from 3,652 patients across 20 hospitals in eight countries. They then compared the models’ diagnostic capacity with a large group of experts and less experienced ultrasound examiners.

The results showed that the AI models outperformed both expert and non-expert examiners at identifying ovarian cancer, achieving an accuracy rate of 86.3 per cent, compared to 82.6 per cent and 77.7 per cent for the expert and non-expert examiners respectively.

“This suggests that neural network models can offer valuable support in the diagnosis of ovarian cancer, especially in difficult-to-diagnose cases and in settings where there’s a shortage of ultrasound experts,” says Professor Epstein.

Reducing the need for expert referrals

The AI models can also reduce the need for expert referrals. In a simulated triage situation, the AI support cut the number of referrals by 63 per cent and the misdiagnosis rate by 18 per cent. This can lead to faster and more cost-effective care for patients with ovarian lesions.

Despite the promising results, the researchers stress that further studies are needed before the full potential of the neural network models and their clinical limitations are fully understood.

“With continued research and development, AI-based tools can be an integral part of tomorrow’s healthcare, relieving experts and optimising hospital resources, but we need to make sure that they can be adapted to different clinical environments and patient groups,” says Filip Christiansen, doctoral student in Professor Epstein’s research group at Karolinska Institutet and joint first author with Emir Konuk at the KTH Royal Institute of Technology.

Evaluating the safety of the AI support

The researchers are now conducting prospective clinical studies at Södersjukhuset to evaluate the everyday clinical safety and usefulness of the AI tool. Future research will also include a randomised multicentre study to examine its effect on patient management and healthcare costs.

The study was conducted in close collaboration with researchers at the KTH Royal Institute of Technology and was financed by grants from the Swedish Research Council, the Swedish Cancer Society, the Stockholm Regional Council, the Cancer Research Funds of Radiumhemmet and the Wallenberg AI, Autonomous Systems and Software Program (WASP).

Elisabeth Epstein, Filip Christiansen and three co-authors have applied for a patent through the company Intelligyn for methods of computer-supported diagnostics. Elisabeth Epstein, Filip Christiansen and Kevin Smith, researcher at the KTH Royal Institute of Technology, also own shares in Intelligyn, for which Professor Epstein is an unsalaried manager.