Background: Rapid digital transformation is reshaping health care, but many digital initiatives struggle to deliver sustained organizational value when they are introduced as stand-alone technologies rather than as part of an institutional strategy. In Saudi Arabia, Vision 2030 has intensified pressure on academic medical centers to strengthen digital capability, localize innovation, and reduce dependence on externally driven solutions. Objective: This study aimed to examine organizational factors shaping digital health innovation at King Saud University Medical City (KSUMC) and to develop a preliminary strategic planning framework for a digital health innovation hub tailored to that setting. Methods: We conducted a qualitative exploratory case study at KSUMC between April and June 2025. Fourteen stakeholders from clinical, administrative, research, governance, educational, and innovation-related roles were recruited using maximum variation purposive sampling. Semistructured interviews were audio-recorded, transcribed verbatim, and analyzed using reflexive thematic analysis. Reporting was guided by the COREQ (Consolidated Criteria for Reporting Qualitative Research). Diffusion of innovation theory and systems thinking informed interpretation, while a context-actor-mechanism-outcome lens was used to examine how institutional conditions shaped innovation processes. No patient data were collected. Results: Five interrelated themes were identified. First, leadership support existed at a symbolic level, but middle-management translation and risk tolerance were inconsistent. Second, innovation was constrained by workload, fragmented systems, and weak operational support, which meant that project work was often treated as discretionary rather than embedded. Third, knowledge transfer and commercialization pathways were fragmented; participants repeatedly described unclear routes from idea generation to prototyping, regulatory review, and market engagement. Fourth, incentives and innovation capability were misaligned with institutional expectations, particularly for clinicians and trainees. Fifth, Vision 2030 created strategic legitimacy and momentum, but participants also cautioned that an overreliance on consultant-led or vendor-led approaches could weaken internal capability building. These findings informed a preliminary framework centered on governance, knowledge transfer, partnership structures, workforce development, and phased implementation rather than a validated institutional model. Conclusions: At KSUMC, digital health innovation is shaped not only by technology availability but also by organizational culture, intermediary structures, governance design, and the extent to which innovation work is made operationally feasible. The framework proposed here should therefore be understood as a preliminary planning model derived from one qualitative case study. Its main contribution is to specify how knowledge transfer, commercialization, and institutional capability building can be integrated into a digital health strategy within a Saudi academic medical center.
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enDigital Postpartum Support for Early Risk Identification Among Postpartum Women: Formative Randomized Evaluation and Exploratory Predictive Modeling Study
Background: The postpartum period represents a critical window for maternal health, yet many individuals lack sustained support and timely identification of physical and mental health risks. Digital health interventions offer a scalable approach to extend care beyond clinical settings. Yet, key elements, including real-world challenges, usability, and effectiveness of such platforms, are insufficiently characterized in this literature. Objective: This study aimed to conduct a formative randomized evaluation to assess the feasibility, engagement, and preliminary signals of impact of the Joyuus platform and to examine the potential for early identification of postpartum health risks. Methods: We conducted a 12-week randomized evaluation with postpartum participants recruited through community-based organizations. Participants were randomized to either the Joyuus intervention or standard postpartum care. Primary and secondary outcomes included the Barkin Index of Maternal Functioning, the Edinburgh Postnatal Depression Scale (EPDS), the State-Trait Anxiety Inventory, and the Connor-Davidson Resilience Scale. Analyses were conducted using an intention-to-treat approach with linear regression models adjusting for baseline values. Engagement metrics (ie, sessions, time on site, and feature use) were captured through in-app analytics. An exploratory predictive model was developed using baseline clinical, behavioral, and demographic variables to identify individuals at risk for postpartum depression. Results: Baseline characteristics were generally balanced across arms, and no statistically significant differences were observed in education, income, or marital status. No statistically significant differences were found between treatment and control groups in the 12-week changes for the primary or secondary outcomes. Mean EPDS scores were 9.7 in the intervention group and 9.3 in the control group. In the sample, 60 (45.5%) of the 132 participants met the criteria for elevated depression (EPDS score ≥11 or a positive response to question 10 on self-harm), indicating a high burden of symptoms within the study population. Engagement with the platform was highest during the first 4 weeks. Among intervention participants, 80% created an account. Participants reported high levels of perceived usefulness, ease of use, and relevance of content. Qualitative analysis of open-ended survey responses highlighted limited awareness of postpartum-specific resources and a preference for simple, accessible information. An exploratory predictive model demonstrated a recall of 0.89 and a precision of 0.73 in identifying individuals at risk for postpartum depression, suggesting the feasibility of early risk identification using integrated data inputs. Conclusions: Joyuus demonstrated feasibility and acceptability but did not produce statistically significant improvements in maternal functioning or maternal health outcomes over 12 weeks. Joyuus identified high rates of depressive symptoms and early engagement patterns, which suggest an opportunity for earlier identification of risk and intervention during the postpartum period. Exploratory modeling results indicate the potential for data-driven approaches to support earlier detection. Future work includes optimizing engagement strategies and expanding validation of predictive detection to improve postpartum surveillance and outcomes. Trial Registration: ClinicalTrials.gov NCT05876559; https://clinicaltrials.gov/study/NCT05876559?cond=postpartum%20joyuus&viewType=Card&rank=1
Increased Levels of Micro- and Nanoplastics Found in the Blood of Heart Attack Patients
The results of a newly reported study have shown that people who suffered a serious heart attack had higher levels of micro- and nanoplastics (MNPs) in their blood, compared with MNP levels in patients diagnosed with chronic ischemic heart disease and those who have normal blood vessels supplying the heart. The study findings also revealed that people who smoke and people exposed to higher levels of air pollution had higher levels of micro- and nanoplastics in their blood.
Headed by teams at Sapienza University of Rome, at the University of Verona, and at the Research Centre on Environmental Pollution and Cardiovascular Diseases at the University of Campania “Luigi Vanvitelli,” the study included 61 patients at Sant’Andrea University Hospital or Azienda Ospedaliera Universitaria Integrata of Verona, diagnosed with either a heart attack, chronic ischemic heart disease, or normal coronary arteries.
The researchers say their study adds to growing evidence that environmental pollution may affect cardiovascular health. Research lead Emanuele Barbato, MD, PhD, at Sapienza University of Rome, said, “These findings do not prove that microplastics cause heart attacks, but they reveal a strong association between environmental exposures, microplastics in the blood and cardiovascular disease. In our study, smoking history was strongly linked to microplastics in the blood. Our findings suggest that smoking might make it easier for micro and nanoplastics to enter the blood stream via the lungs. Air pollution may act in a similar way.”
Barbato is director of the Cardiology Unit of Sant’Andrea University Hospital, Rome, Italy, and senior author of the team’s published paper in European Heart Journal, titled “Micro- and nano-plastics in the coronary circulation and air pollution exposure in ischemic heart disease presentation.”
Cardiovascular diseases are increasingly related to lifelong environmental exposures, the authors noted. Among such exposures, MNPs are ubiquitous environmental pollutants, and evidence is increasing that they accumulate in human tissues following exposure and are emerging as a risk factor for health. Pasquale Paolisso, MD, PhD, at Sant’Andrea Hospital Sapienza University of Rome, said, “Micro and nanoplastics are tiny plastic particles that are found virtually everywhere in the environment, including the air we breathe, the water we drink, and many foods we consume. In recent years, scientists have begun to detect these particles in human tissues and organs, raising concerns about their potential health effects.”
Research findings have raised concerns about the potential role that MNPs may play in cardiovascular diseases. “Emerging evidence indicates that MNPs, once considered inert contaminants, are biologically active pollutants contributing to the pathophysiology of cardiovascular diseases, particularly by promoting the development and progression of atherosclerotic plaques and potentially triggering adverse cardiovascular events,” the team stated.
However, as Paolisso further noted, “… very little was known about whether these particles are present in the coronary circulation—the blood flowing through the arteries that supply the heart—or whether environmental exposures such as smoking and air pollution might influence their presence.” As the authors explained, “… current knowledge is predominantly based on in vitro experiments and preliminary ex vivo findings, highlighting the need for in vivo and clinical investigations.”
For their newly reported study the team measured MNPs in coronary and peripheral blood, in 61 patients at Sant’Andrea University Hospital or Azienda Ospedaliera Universitaria Integrata of Verona, who were undergoing coronary angiography for suspected coronary artery disease (CAD). Patients were stratified as those with ST-segment elevation myocardial infarction (STEMI), chronic coronary syndromes (CCS) and controls with normal coronary arteries.
As well as taking blood samples from the vessels supplying the heart and from elsewhere in the body, the team collected data on whether the patients were smokers and their exposure to pollution, both on the day of testing and over the preceding two years. Coronary micro and nanoplastics were analyzed at the Research Centre for Environmental Pollution and Cardiovascular Diseases, University of Campania ‘Luigi Vanvitelli,’ a center dedicated to understanding how environmental pollutants influence cardiovascular health.
The results showed that micro and nanoplastics were detected in 84% of patients diagnosed with heart attack, compared with 40% of patients with chronic ischemic heart disease and 32% of patients with normal coronary arteries. “The observation that IL-6 and TNF-α concentrations were highest in STEMI patients, particularly within the coronary circulation, and were more elevated in the presence of detectable MNPs supports an exploratory association between MNP burden and a localized pro-inflammatory milieu in patients with obstructive CAD,” the investigators suggested.
Heart attack patients also had a greater variety of plastic types in their blood. The most common type of plastic was polyethylene (PE), which is commonly used in packaging and consumer products. “Across all study cohorts, PE was the most frequently identified polymer, being present in 97% of the patients with detectable MNPs,” the investigators added.
Patients exposed to higher long-term levels of air pollution (PM2.5; particles measuring 2.5 μm or less in diameter) were more likely to have microplastics in their blood, and smokers were six times more likely to have microplastics in their blood. All patients who were smokers and were exposed to higher air pollution levels had plastics in their blood, compared with only 12.5% of patients who did not smoke and were not exposed to higher levels of air pollution. “MNPs, PM2.5, and smoking constitute potentially modifiable environmental risk factors for cardiovascular diseases, with significant implications for public health and cardiovascular disease prevention,” the scientists stated. “Future research should aim to quantify individual MNP exposure, assess combined pollutant burden, and validate interventions that target this expanded network of environmental cardiovascular hazards.”
Barbato added, “The results highlight the need to consider microplastic pollution as part of the broader environmental determinants of health. Policies that reduce air pollution, tobacco exposure, and environmental plastic contamination could have benefits that extend beyond environmental protection and potentially improve cardiovascular health.”
In an accompanying editorial Andreas Daiber, PhD, at University Medical Centre of the Johannes Gutenberg University, Mainz, and colleagues pointed to the observation by Paolisso et al. of an association between NMP levels and exposure to air pollution and tobacco smoking. “While the underlying mechanisms remain unclear, this finding underscores a key principle: environmental exposures rarely occur in isolation,” Daiber and colleagues stated. “Individuals are exposed to multiple environmental stressors simultaneously, including air pollution, noise, chemical contaminants, plastics, and climate-related stressors, especially in the urban setting. These exposures may interact through shared biological pathways, leading to additive or synergistic effects on cardiovascular risk.”
And while substantial uncertainties remain, “the convergence of epidemiological, clinical, and mechanistic evidence suggests that plastic pollution may represent a previously underestimated cardiovascular risk factor,” Daiber et al. continued. “Addressing this challenge will require coordinated efforts across disciplines and policy domains. In the era of the Anthropocene, protecting cardiovascular health will increasingly depend on reducing not only traditional risk factors but also the growing burden of environmental pollutants (the detrimental part of the exposome), among which plastics may soon play a central role.”
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Specialist Rehabilitation Providers’ Experiences With an Online Self-Compassion Course: Reflexive Thematic Analysis
Background: Rehabilitation health care providers (HCPs) report high levels of burnout. Self-compassion interventions have shown beneficial effects on HCP burnout, but they have never been explored in specialist rehabilitation settings where challenges may differ. Objective: This study aimed to explore the experiences of specialist rehabilitation HCPs with an online Self-Compassion for Healthcare Communities (SCHC) course aimed at providing tools to regulate emotional well-being, including burnout. Methods: Semistructured qualitative interviews (n=20) with specialist rehabilitation HCPs were used to explore experiences with the SCHC course. A reflexive thematic analysis study design was chosen to highlight participants’ insights, and inductive coding was undertaken to analyze data and organize findings into themes. Results: Six themes that reflected HCPs’ experiences with the course were constructed: (1) the nature of working in rehabilitation; (2) different perspectives on burnout in specialist rehabilitation; (3) a new perspective, less self-criticism, more self-compassion; (4) growing recognition of the importance of compassion for oneself and others; (5) challenges engaging with the SCHC course; and (6) challenges to sustaining self-compassion in specialist rehabilitation. Conclusions: Specialist rehabilitation HCPs who participated in the SCHC course developed a new understanding of the importance of fostering self-compassion and compassion for others. This shift may have supported HCPs in navigating workplace challenges, and HCPs described experiencing changes that could help with burnout, improve their care of patients and relationships with colleagues. Trial Registration: ClinicalTrials.gov NCT05997082; https://clinicaltrials.gov/study/NCT05997082?cond=self%20compassion%20rehab&viewType=Card&rank=1
Ketogenic Diet Shows Opposite Effects on Cancer Risk in Mouse Small Intestine and Colon
Ketogenic diets, originally developed in the 1920s to treat epilepsy, have been adapted in the past few decades as a strategy to lose weight or increase lifespan. This type of diet (a high percentage of fat, low percentage of carbohydrates, and normal or reduced amounts of protein) forces the body to burn fatty acids for energy in place of carbohydrates such as glucose. Burning these lipids produces ketone bodies—primarily β-hydroxybutyrate (BHB) and acetoacetate—as byproducts of fatty acid metabolism. The impact of ketogenic diets on the gastrointestinal tract remains poorly understood.
In recent years, scientists investigated whether this type of diet might affect the development of cancer. While some research has shown that the diet may protect against the development of colon cancer, a new study suggests that in the small intestine, a ketogenic diet may increase the risk of cancer—with a mechanism through fatty acid oxidation rather than ketone metabolism.
This work appears in Nature in the paper, “Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.”
“Ketogenic diets have distinct effects on different tissues even within the gastrointestinal tract. I think the message here is that we need to be very careful in generalizing the effects that these diets can have, because what might be beneficial for one tissue may be detrimental for another tissue,” says Omer Yilmaz, PhD, director of the MIT Stem Cell Initiative, an associate professor of biology at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research.
A 2022 study in Nature suggested that ketogenic diets have a protective effect against colon cancer and that BHB—the most abundant ketone body—is responsible for this effect. In the new study, the MIT team wanted to explore whether ketogenic diets might have a similar protective effect in the small intestine.
The researchers fed mice who were genetically predisposed to developing intestinal cancer either a ketogenic diet, a control diet, or a high fat/high calorie diet. They found that mice on a ketogenic diet were more likely to develop tumors of the small intestine than those on a control diet. While they did not become obese, mice on the ketogenic diet developed tumors at rates similar to or even higher than those of mice on an obesogenic high fat/high calorie diet.
Additional studies revealed that ketone bodies did not play a role in tumor development. Instead, tumor growth was driven by fatty acid oxidation. This pathway activates the PPAR family of proteins, which signal stem cells to multiply more rapidly, increasing the chance that some become cancerous.
Surprisingly, the same ketogenic diet that promoted tumors in the small intestine had the opposite effect in the colon. The researchers found, similar to the earlier study back in 2022, that a ketogenic diet suppressed the development of colon tumors. However, the new findings suggest that ketone bodies are not responsible for this protective effect.
“Given how much attention has been paid to ketone bodies like BHB, both as a commercial health trend and in recent high-profile studies suggesting BHB suppresses colon cancer, we fully expected them to be the direct drivers. Instead, our experiments in genetically engineered mice revealed that these molecules are essentially metabolic bystanders. The real surprise is that tumor acceleration is driven entirely by how stem cells process and burn the heavy influx of dietary fat itself,” Yilmaz says.
The researchers now hope to further study why ketogenic diets have such different effects in the colon and the small intestine. As ketogenic diets continue to gain popularity, understanding these tissue-specific effects will be critical for guiding their use, the researchers say.
The findings carry practical implications. Because the diet’s effects—both the tumor acceleration in the small intestine and the protection in the colon—are driven entirely by fat metabolism rather than the ketones themselves, commercial ketone supplements or drinks would not be expected to mimic either the risks or the benefits discovered in this study. This may be especially relevant given that small intestinal tumors have been rising in incidence in recent decades, with the greatest impact on patients with inherited conditions that predispose them to intestinal cancer, such as familial adenomatous polyposis.
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Weekly Digital Symptom Check-Ins Improve Outcomes for Cancer Patients
A study by the Alliance for Clinical Trials in Oncology has shown that completing a simple weekly electronic symptom check-in significantly improves quality of life and may reduce health disparities among people undergoing treatment for advanced cancer.
The PRO-TECT study, which is published in JCO Oncology Practice, showed that the biggest improvements occurred among patient groups that have historically faced greater symptom burden or barriers to effective communication with their care team, including Black patients, women, younger patients, and individuals with less formal education.
“Although we know from prior work that systematic symptom monitoring improves quality-of-life outcomes in patients with advanced cancer, the current analysis extends these findings by suggesting that some groups may experience greater benefit,” said first author Allison Deal, MS, a senior biostatistician at the UNC Lineberger Comprehensive Cancer Center.
Study chair Ethan Basch, MD, who is also from the UNC Lineberger Comprehensive Cancer Center explained that the use of remote symptom monitoring using patient-reported outcomes (PROs) in cancer care in increasing across the U.S., with more than 80 health systems and large practices currently implementing this approach. However, he added that “this is still an early time for this patient-centered approach to monitoring patients, and many practices are still learning how best to implement at their own sites.”
For the PRO-TECT study, 1191 adult patients with metastatic solid tumors receiving systemic therapy were randomly assigned to complete weekly electronic symptom monitoring (n=593) or usual care (n=598) for up to one year.
The weekly surveys included questions about symptoms from the National Cancer Institute’s PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) item library, oral intake, patient-reported performance status, and falls. The surveys took a few minutes to complete and patients could choose whether to complete them online (64%) or via telephone-based interactive voice response not requiring Internet access (36%).
If the answers passed a prespecified threshold (i.e., severity or worsening from previous assessment), the participant was sent a link to relevant patient-level materials for self-management of the reported symptom, and a nurse on the participant’s clinical care team was sent an automated email alert.
The researchers report that, during the study, 90% of surveys were completed and 41% of reports triggered an alert.
At three months, participants in the PRO arm had a mean 2.37-point improvement, from a baseline of 77.0 points, in the European Organisation for Research and Treatment of Cancer QLQ-C30 symptom control score, and a mean 1.54-point improvement, from a baseline of 73.9 points, in physical function score.
By comparison, participants given usual care reported a 0.20- and 0.93-point decline in symptom control and physical function, respectively.
Basch noted that the differences between the two arms were statistically significant and clinically meaningful, adding that there were also “substantial delays until symptom worsening” among people in the PRO arm relative to the usual care arm.
Deal and co-investigators also observed significant differences in outcome by race, education level, age, and sex.
Specifically, they found that the improvement in symptom control in the PRO arm was significantly larger in Black patients than in White patients, which essentially erased a baseline gap and brought symptom control among Black patients on par with that among patients by month 3. Black patients were also much more likely to report that the weekly surveys made them feel more in control of their own care and improved conversations with their care team.
Patients with a high school education or less who used the weekly surveys had significantly greater improvements in both symptom control and physical function than those with a college education. They also had higher rates of triggered alerts and reported that the weekly questions felt relevant to their daily lives.
Women and younger patients (<65 years), two groups that traditionally report higher distress and more severe side effects during cancer treatment, experienced substantial quality-of-life gains from the weekly check-ins compared with the usual care group, whereas men and older patients saw no significant improvement relative to usual care.
In addition, the weekly reporting tool was associated with significantly reduced or delayed emergency department visits for patients, which are known to cause financial and emotional stress for patients and their families.
“Our results suggest that remote monitoring may provide underserved cancer patients with a new avenue to communicate concerns that might go underrecognized in routine practice,” Basch told Inside Precision Medicine. “Broad implementation of these systems may represent an effective and highly practical strategy to advance health equity. Future studies should test technology with more general patient audiences.”
He added: “There is a follow-up initiative to this trial called OncoPRO which is supporting health systems across the country as they work to onboard these systems.”
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STAT+: New study untangles how Epstein-Barr viral infection triggers immune response in multiple sclerosis
In a new study published in Science Translational Medicine on Wednesday, researchers say they have uncovered how Epstein-Barr virus launches immune responses that lead to the inflammation and nervous system damage seen in people with multiple sclerosis.
“It’s very nice now to be able to understand more about the underlying mechanisms of how EBV likely causes MS,” said lead author Kjetil Bjornevik, an assistant professor of epidemiology and nutrition at the Harvard T.H. Chan School of Public Health. The findings, researchers hope, could help with the development of EBV vaccines or antiviral medications that could prevent or manage MS symptoms without the major side effects of commonly used immunosuppressants.
Syed Rizvi, the director of the Multiple Sclerosis Center of Rhode Island, who was not involved in this study, said the new findings help advance MS research toward more precise approaches. “When you’re developing drugs, targeted drugs, every little step, every little molecule, every little antigen is a game changer,” he said.
STAT+: Improvements in Alzheimer’s testing could make diagnostics more accessible, informative
This is the web edition of STAT’s AAIC in 30 newsletter.
Hello there from the final day of the Alzheimer’s Association International Conference. This is our last edition of this pop-up newsletter, but if you somehow haven’t tired of me, you can join me as well as my colleagues Damian Garde and Katherine MacPhail tomorrow to recap AAIC and discuss how the research presented here fits into the broader direction of the field. You can register for the virtual event here. It’s at 10 a.m. Eastern, 3 p.m. here in the U.K.
With next year’s AAIC set for Chicago, and as this nation descends into full World Cup mania in the coming hours, I’ll end by saying thanks for following along with me here in London.
How blood tests could reshape the future of identifying dementia
Traditionally, an Alzheimer’s diagnosis comes after a brain scan or spinal tap, or perhaps some cognitive tests administered by a behavioral neurologist. The tests can be burdensome, and specialist capacity is limited.
But research presented throughout the conference indicated how the field is moving in new directions, finding ways to make testing much more accessible, and offering more nuanced results that go beyond saying whether someone has Alzheimer’s or not.
In particular, blood-based biomarker tests that can help with diagnoses have started to come onto the market. The Alzheimer’s Association has also started to issue guidelines for how doctors should use them.
One study detailed here looked at whether these tests could be used in the primary care setting. Alzheimer’s experts say it’s crucial for more doctors to be able to diagnose the condition, particularly with the availability of new treatments that are more beneficial the earlier they can be used. Wait times for neurologists can extend for months, if not over a year.
Old Drug, New Target: Thiostrepton Starves Mesothelioma Tumors from Within
A first-in-human Phase I trial has established preliminary safety and efficacy data for a reformulated version of thiostrepton, a mitochondrially targeted covalent PRX3 inhibitor, in patients with mesothelioma and other malignancies associated with malignant pleural effusion. The results were published in Nature Communications.
Thiostrepton was originally characterized decades ago and has since accumulated substantial preclinical evidence of anticancer activity, but its poor solubility and manufacturing complexity had previously precluded clinical development. The researchers undertook both the mechanistic characterization of the compound and the chemistry work required to bring it to a first-in-human setting.
“The goal was to take this drug called thiostrepton, which has been studied for 70 years, and formulate it in a way where it could be delivered to human beings for the first time ever, and use it as an anti-cancer drug,” explained principal investigator Brian Cuniff, PhD, associate professor at the University of Vermont.
Study population and design
Rather than restricting enrollment strictly to a single tumor histology, the trial enrolled patients on the basis of a shared clinical phenotype—malignant pleural effusion—which is most commonly, though not exclusively, associated with mesothelioma. This design allowed inclusion of a small subset of patients with metastatic lung and colorectal cancers alongside the mesothelioma-predominant cohort.
“Our primary goal is in the treatment of mesothelioma, but from a utilization and development standpoint, we’re very interested in testing it in other cancers,” Cuniff said.
Fifteen patients were enrolled, consistent with a dose-escalation, first-in-human design. “Around 30% of those patients we did see tumor reduction, and then we had 67% disease control,” Cuniff said, clarifying that disease control included patients whose “tumor didn’t grow for a period of time, or their tumor shrunk a little bit.”
A completed Phase II study is expected to provide a larger dataset on efficacy later this year.
Mechanistic rationale: PRX3 inhibition
The therapeutic rationale centers on thiostrepton’s activity as a covalent inhibitor of peroxiredoxin 3 (PRX3), a mitochondrial antioxidant protein. Preclinical work from Cuniff’s group established that irreversible PRX3 inhibition impairs mitochondrial bioenergetics and increases oxidative and metabolic stress selectively within tumor cells.
“It binds to the PRX3 protein irreversibly, and inactivates that protein, and that protein is really important for keeping the mitochondria of our cells… functioning correctly,” Cuniff said. “In tumor cells, we’re essentially taking away the ability for the tumor cell to make energy, and we’re also increasing waste products that are toxic to the tumor cells.”
A key element of the preclinical dataset is a reported therapeutic window between malignant and normal cell populations. “Our evidence shows that this same effect is not occurring in normal cells, and they can tolerate that inhibition much more than tumor cells,” Cuniff said.
Beyond direct cytotoxicity, investigators describe an additional immunomodulatory component to the drug’s activity, distinguishing it mechanistically from both chemotherapy and immune checkpoint-based approaches. “It’s not an immunotherapy, it’s not a chemotherapy,” Cuniff said. “It’s basically a cytotoxic immunomodulator. It kills cells, but it also has some activity against the immune system, which we think is important for its overall activity.”
Formulation and regulatory considerations
Historically, thiostrepton’s clinical translation was limited by poor aqueous solubility and manufacturing challenges. To address this, the development team formulated the compound into a micellar solution to enable solubilization and systemic delivery, and scaled manufacturing to meet regulatory-grade standards.
“We were able to manufacture the drug in a way that would allow it for the delivery to human beings, and then we developed a formulation that would allow for safe and effective delivery of the drug,” Cuniff said. The trial was conducted in the United Kingdom under MHRA oversight, the agency’s equivalent of the U.S. FDA.
Clinical context and unmet need
Cuniff situated the findings within a treatment landscape that has seen limited innovation. Standard-of-care chemotherapy for mesothelioma remained largely unchanged for roughly three decades until the 2021 approval of an immunotherapy-based frontline regimen—the most recent major regulatory advance for the disease.
“To only have two drugs essentially be approved in a 30-, 40-year period is unlike any other cancer,” Cuniff said, attributing the slow pace of development primarily to the disease’s rarity rather than to scientific tractability. “There’s not a ton of value in developing in mesothelioma because [of] the low patient population… although it really needs development. These patients, you know, they die very quickly. There’s not a lot of options, so we need new drugs.”
With Phase II data anticipated by year’s end, the investigators intend to further define thiostrepton’s efficacy profile in mesothelioma while continuing to evaluate its applicability across other PRX3-dependent tumor types.
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Specialist Microscopy and AI Analysis Can Improve Lung Cancer Testing
Research shows fluorescence lifetime imaging microscopy (FLIM) combined with a form of artificial intelligence (AI) known as deep learning can predict if a person has lung cancer-related EGFR mutations with no need for genetic testing or tissue staining.
As reported in the journal Cancer Research, the AI model was able to achieve 96.6% accuracy on a standard diagnostic test and could also distinguish between the two most important subtypes of the EGFR mutation, which matters because they respond differently to treatment and carry different survival outlooks.
“With this research we are able to take a single fluorescent image and can very accurately predict whether the mutation is present. We can do this with a single image, without special stains and without gene sequencing,” co-lead author Ahsan Akram, MBChB, PhD, a professor at the Institute for Regeneration and Repair, University of Edinburgh, told Inside Precision Medicine.
“All the cells in our body, to some degree are capable of emitting light when excited by the correct type of laser light, what FLIM does it takes this emitted light and measures the time taken for the fluorescence to be emitted. The FLIM signal therefore captures a snapshot of the metabolic activity through an ‘optical fingerprint’.”
Lung cancer is the second most common cancer in the U.S. and by far the deadliest. For many lung cancer patients, particularly non-smokers, the key question is whether their tumor carries a mutation in a gene called EGFR, encoding a protein that drives cancer cell growth. If it does, they can receive effective targeted drugs, but looking for these mutations currently requires genetic testing. This is commonly PCR or next-generation sequencing, both of which are slow, expensive, and result in the tumor tissue sample being lost after testing.
The team used FLIM to scan lung tissue samples from 85 patients and trained a deep learning model (DenseNet-169) to classify each sample as EGFR-mutant or normal. The model achieved an area under the receiver operating characteristic curve score, a standard statistical measure of diagnostic accuracy, of 0.966, outperforming all previously published methods that rely on conventionally stained tissue images. The model also distinguished between the two most common EGFR mutation subtypes, an exon 19 deletion and an exon 21 point mutation.
“The machine learning was able to extract features that are specific to the EGFR mutation, and although we don’t exactly know what these are, when we test these on samples it has never seen before we saw remarkable accuracy in the prediction,” says Akram.
Although the microscopes needed to carry out FLIM are not cheap, this technique has several advantages that counteract this including speed of testing and also allowing the sample material to be reused for other tests as destructive staining is not needed.
“Current pathways require specialized labs and next generation sequencing. These are time consuming and costly. It can take weeks to have an answer. Here, as we are taking an image using laser light the process can take minutes,” he says.
“As we are shining laser light on the sample, without any stains, this is a completely nondestructive process. The tissue sample is intact following the image and then can be used for whatever else is needed. This is particularly important in lung cancer diagnostics as often we run out of tissue to do the full suite of tests we require in a cancer diagnostic workup.”
The authors acknowledge the current FLIM imaging and analysis process is somewhat time-consuming, taking around 1-2 hours per sample, but note that faster acquisition methods are in development. If validated in larger, more diverse patient cohorts, this type of testing could shorten the amount of time from biopsy to a patient receiving targeted treatment.
“We are at the stage of compelling proof of concept with strong performance on tissue samples. The next essential step is prospective clinical validation, testing the approach on samples collected in real time within clinical pathways, and demonstrating that it performs consistently and integrates practically into NHS laboratory workflows,” says Akram.
“In parallel, we are actively exploring the extension of this platform to other cancer types and additional targetable mutations, and investigating how FLIM can be integrated into existing clinical imaging infrastructure.”
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