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Evidence of fructose metabolism in colorectal cancer
Cell Death Discovery, Published online: 16 October 2025; doi:10.1038/s41420-025-02745-w
Evidence of fructose metabolism in colorectal cancer
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A tumor-on-a-chip for in vitro study of CAR-T cell immunotherapy in solid tumors
Nature Biotechnology, Published online: 17 October 2025; doi:10.1038/s41587-025-02845-z
The interactions of CAR-T cells and solid tumors are modeled on a chip.
Codon specific readthrough as a mechanism of BRCA2 restoration in acquired PARP inhibitor and chemotherapy resistance
Nucleic Acids Res. 2025 Oct 14;53(19):gkaf990. doi: 10.1093/nar/gkaf990.
ABSTRACT
BRCA2 mutations contribute to the pathogenesis and treatment sensitivity of a subset of ovarian, breast, prostate, and pancreatic cancers. When these cancers become therapy resistant, secondary mutations that restore the BRCA2 open reading frame are found in half the cases, but other causes of resistance remain incompletely understood. Here, we identified translational readthrough of a premature termination codon (PTC) as a cause of resistance to poly(ADP-ribose) polymerase inhibitors (PARPis) and cisplatin in cells derived from the BRCA2-mutated ovarian cancer line PEO1 by PARPi selection. Despite persistence of the signature 4965C > G (p.Y1655X) BRCA2 mutation, low-level expression of full-length BRCA2 protein was detectable in these cells by immunoblotting and tandem mass spectrometry. Either BRCA2 knockdown or gene interruption 5' or 3' to the PTC restored treatment sensitivity, implicating BRCA2 in the resistance. Reporter assays demonstrated UAG-selective readthrough in the resistant clones but not parental cells. Moreover, custom searching of global proteomic data indicated readthrough of stop codons, particularly UAGs, in additional proteins in the resistant clones. Finally, multi-omic analysis identified multiple changes in the nonsense-mediated decay and termination machineries that favor readthrough. Accordingly, the present results identify PTC readthrough as a potential mechanism of drug resistance in cells with BRCA2 nonsense mutations.
PMID:41099700 | PMC:PMC12526053 | DOI:10.1093/nar/gkaf990
HT SpaceM: A high-throughput and reproducible method for small-molecule single-cell metabolomics
Single-cell metabolomics (SCM) can probe metabolic heterogeneity but is hindered by low sensitivity for small molecules, limited scalability, and the lack of standardized frameworks for data analysis. HT SpaceM is a high-throughput MALDI-imaging-based SCM method to robustly detect small-molecule metabolites in single cells. Applied to over 140,000 cells across diverse conditions and cancer cell lines, HT SpaceM enabled reproducible metabolic profiling of over 100 small-molecule metabolites, identification of subpopulation-specific markers, and detection of heterogeneity and pathways coordination, thus facilitating scalable and reproducible SCM.
Framework for the Development and Delivery of Digital Peer Support Programs: Qualitative Study on in-Person and Digital Delivery for People With Cardiovascular Disease
Background: Peer support (sharing experiences/support with others with the same condition) improves health outcomes among people with cardiovascular disease (CVD), including self-management behaviours and self-efficacy. However, current peer support interventions are diverse. Evidence is lacking on peer support attenders perceptions of benefits and the elements that are considered priorities, especially for digital interventions. Objective: The study objectives were to 1) describe perceived benefits and recommendations for CVD peer support programs from people attending in-person peer support, 2) identify priorities for digital peer support from consumers and clinicians testing a peer support app prototype, and 3) develop a framework to inform future peer support intervention development. Methods: Qualitative methodology was used across two components to address the objectives of this study. In Component 1, semi-structured focus groups were conducted with attenders of established in-person CVD peer support groups, exploring the perceived benefits of peer support and recommendations for future programs. In Component 2, semi-structured interactive workshops with consumers with CVD and semi-structured online interviews with CVD clinicians/researchers were undertaken seeking feedback and recommendations for digital peer support using an exploratory digital CVD peer support application prototype. Data were recorded digitally, transcribed verbatim, and analysed thematically. Findings from both components were iteratively synthesised to inform a digital peer support development framework. Results: In Component 1, 22 participants (age range 29-84 years, male 45%) took part in focus groups. The overarching theme was that peer support provides benefits through sharing experiences. Five themes were refined and defined; (i) peer support provides a way of coping, (ii) peers learn from each other, (iii) peers understand what each other are going through, (iv) the peer community uplifts mood and build confidence, and (v) awareness, flexibility and resources are important for engagement. In Component 2, five participants (age range 55-74 years, male 60%) attended two workshops and eight clinicians/researchers (age range 30-65 years, male 10%) were interviewed. Three themes were refined and defined: (i) autonomy is essential to promote engagement, (ii) safeguarding is important to both users and clinicians, and (iii) interfaces that are simple, easy to use and visually attractive enable use. Priorities identified from both components included greater peer support awareness and uptake, flexibility with timing and family participation, healthcare professional involvement, provision of resources, autonomous features enabling choice, checklists and clinician moderation for safeguarding, and simple to use interfaces. Conclusions: Participants in peer support programs derive benefit from sharing their experience of living with CVD which enable coping, learning, feeling understood and a sense of community. Priorities were synthesised to create a framework for digital peer support development for future peer support with recommendations to focus on six key areas: uptake, flexibility, resources, autonomy, safeguarding and interface.
Accurate somatic small variant discovery for multiple sequencing technologies with DeepSomatic
Nature Biotechnology, Published online: 16 October 2025; doi:10.1038/s41587-025-02839-x
Somatic small variants in cancer genomes are identified in both short-read and long-read data.
Tumor microenvironment and macroenvironment: A new perspective on holistic oncology
Cancer Lett. 2025 Oct 11;634:218076. doi: 10.1016/j.canlet.2025.218076. Online ahead of print.
ABSTRACT
The tumor microenvironment (TME) and tumor macroenvironment (TMaE) jointly shape cancer biology by linking local cellular niches with systemic host physiology. The TME provides the immediate soil for tumor initiation, progression, and therapy resistance, whereas the TMaE integrates metabolic, immune, neuroendocrine, microbial, and inflammatory signals that remodel local ecosystems. Recent advances highlight how systemic factors, including aging, energy imbalance, chronic inflammation, cachexia, and psychosocial stress, interact with extracellular matrix remodeling, vascular dynamics, and immune surveillance to influence tumor dormancy, metastatic reactivation, and therapeutic outcomes. However, the conceptual boundaries between TME and TMaE remain unclear, mechanistic insights are limited, and current models insufficiently capture local-systemic crosstalk. Future strategies integrating multi-omics, advanced imaging, and humanized models are essential to map this multidimensional interplay. A deeper understanding of TME-TMaE will be critical to refine precision oncology, advance preventive strategies, and design combinatorial therapies targeting both local and systemic cancer ecosystems. This review highlights the roles of the TME and TMaE in tumor initiation, progression, and heterogeneity, their interactions, and the clinical implications for classification, therapy, and prognosis.
PMID:41083101 | DOI:10.1016/j.canlet.2025.218076
A human pan-disease blood atlas of the circulating proteome
Science, Ahead of Print.
Digital twin models for predicting venetoclax and azacitidine-induced neutropenia in patients with acute myeloid leukemia
npj Digital Medicine, Published online: 06 October 2025; doi:10.1038/s41746-025-01978-4
Digital twin models for predicting venetoclax and azacitidine-induced neutropenia in patients with acute myeloid leukemia
Stop treating code like an afterthought: record, share and value it
Nature, Published online: 07 October 2025; doi:10.1038/d41586-025-03196-0
Scientists, research institutions, funders, libraries and publishers must all improve software practices.
HALO: hierarchical causal modeling for single cell multi-omics data
Nat Commun. 2025 Oct 7;16(1):8892. doi: 10.1038/s41467-025-63921-1.
ABSTRACT
Though open chromatin may promote active transcription, gene expression responses may not be directly coordinated with changes in chromatin accessibility. Most existing methods for single-cell multi-omics data focus only on learning stationary, shared information among these modalities, overlooking modality-specific information delineating cellular states and dynamics resulting from causal relations among modalities. To address this, the epigenome-transcriptome relationship can be characterized in relation to time as coupled (changing dependently) or decoupled (changing independently). We propose the framework HALO, adopting a causal approach to model these temporal causal relations on two levels. On the representation level, HALO factorizes these two modalities into both coupled and decoupled latent representations, revealing their dynamic interplay. On the individual gene level, HALO matches gene-peak pairs and characterizes their changes over time. HALO discovers analogous biological functions between modalities, distinguishes epigenetic factors for lineage specification, and identifies temporal cis-regulation interactions relevant to cellular differentiation and human diseases.
PMID:41057364 | PMC:PMC12504611 | DOI:10.1038/s41467-025-63921-1
Evaluating Large Language Models and Retrieval-Augmented Generation Enhancement for Delivering Guideline-Adherent Nutrition Information for Cardiovascular Disease Prevention: Cross-Sectional Study
Background: Cardiovascular disease (CVD) remains the leading cause of death worldwide, yet many web-based sources on cardiovascular (CV) health are inaccessible. Large language models (LLMs) are increasingly used for health-related inquiries and offer an opportunity to produce accessible and scalable CV health information. However, because these models are trained on heterogeneous data, including unverified user-generated content, the quality and reliability of food and nutrition information on CVD prevention remain uncertain. Recent studies have examined LLM use in various health care applications, but their effectiveness for providing nutrition information remains understudied. Although retrieval-augmented generation (RAG) frameworks have been shown to enhance LLM consistency and accuracy, their use in delivering nutrition information for CVD prevention requires further evaluation. Objective: To evaluate the effectiveness of off-the-shelf and RAG-enhanced LLMs in delivering guideline-adherent nutrition information for CVD prevention, we assessed 3 off-the-shelf models (ChatGPT-4o, Perplexity, and Llama 3-70B) and a Llama 3-70B+RAG model. Methods: We curated 30 nutrition questions that comprehensively addressed CVD prevention. These were approved by a registered dietitian providing preventive cardiology services at an academic medical center and were posed 3 times to each model. We developed a 15,074-word knowledge bank incorporating the American Heart Association’s 2021 dietary guidelines and related website content to enhance Meta’s Llama 3-70B model using RAG. The model received this and a few-shot prompt as context, included citations in a Context Source section, and used vector similarity to align responses with guideline content, with the temperature parameter set to 0.5 to enhance consistency. Model responses were evaluated by 3 expert reviewers against benchmark CV guidelines for appropriateness, reliability, readability, harm, and guideline adherence. Mean scores were compared using ANOVA, with statistical significance set at P<.05. interrater agreement was measured using the cohen coefficient and readability estimated flesch-kincaid score. results: llama model scored higher than perplexity gpt-4o models on reliability appropriateness guideline adherence showed no harm.>70%; P<.001 indicated high reviewer agreement. conclusions: the llama model outperformed off-the-shelf models across all measures with no evidence of harm although responses were less readable due to technical language. scored lower on and produced some harmful responses. these findings highlight limitations demonstrate that rag system integration can enhance llm performance in delivering evidence-based dietary information.>
Generative artificial intelligence in medicine
Nature Medicine, Published online: 06 October 2025; doi:10.1038/s41591-025-03983-2
This Review summarizes recent technical advancements in generative AI, outlines how new models might improve healthcare and discusses validation approaches—using lessons from recent successes and failures in the field.
Clinical validation of an AI-based blood testing device for diagnosis and prognosis of acute infection and sepsis
Nature Medicine, Published online: 30 September 2025; doi:10.1038/s41591-025-03933-y
In a prospective study enrolling 1,222 patients from 22 emergency departments, a device using a machine-learning-based signature of blood mRNAs demonstrated clinically acceptable performance to diagnose bacterial and viral infections and to predict the all-cause need for critical care interventions within 7 days, with benchmark to established biomarkers and risk scores.
Unlocking AI’s full potential requires operational excellence
Talk of AI is inescapable. It’s often the main topic of discussion at board and executive meetings, at corporate retreats, and in the media. A record 58% of S&P 500 companies mentioned AI in their second-quarter earnings calls, according to Goldman Sachs.
But it’s difficult to walk the talk. Just 5% of generative AI pilots are driving measurable profit-and-loss impact, according to a recent MIT study. That means 95% of generative AI pilots are realizing zero return, despite significant attention and investment.
Although we’re nearly three years past the watershed moment of ChatGPT’s public release, the vast majority of organizations are stalling out in AI. Something is broken. What is it?
Date from Lucid’s AI readiness survey sheds some light on the tripwires that are making organizations stumble. Fortunately, solving these problems doesn’t require recruiting top AI talent worth hundreds of millions of dollars, at least for most companies. Instead, as they race to implement AI quickly and successfully, leaders need to bring greater rigor and structure to their operational processes.
Operations are the gap between AI’s promise and practical adoption
I can’t fault any leader for moving as fast as possible with their implementation of AI. In many cases, the existential survival of their company—and their own employment—depends on it. The promised benefits to improve productivity, reduce costs, and enhance communication are transformational, which is why speed is paramount.
But while moving quickly, leaders are skipping foundational steps required for any technology implementation to be successful. Our survey research found that more than 60% of knowledge workers believe their organization’s AI strategy is only somewhat to not at all well aligned with operational capabilities.
AI can process unstructured data, but AI will only create more headaches for unstructured organizations. As Bill Gates said, “The first rule of any technology used in a business is that automation applied to an efficient operation will magnify the efficiency. The second is that automation applied to an inefficient operation will magnify the inefficiency.”
Where are the operations gaps in AI implementations? Our survey found that approximately half of respondents (49%) cite undocumented or ad-hoc processes impacting efficiency sometimes; 22% say this happens often or always.
The primary challenge of AI transformation lies not in the technology itself, but in the final step of integrating it into daily workflows. We can compare this to the “last mile problem” in logistics: The most difficult part of a delivery is getting the product to the customer, no matter how efficient the rest of the process is.
In AI, the “last mile” is the crucial task of embedding AI into real-world business operations. Organizations have access to powerful models but struggle to connect them to the people who need to use them. The power of AI is wasted if it’s not effectively integrated into business operations, and that requires clear documentation of those operations.
Capturing, documenting, and distributing knowledge at scale is critical to organizational success with AI. Yet our survey showed only 16% of respondents say their workflows are extremely well-documented. The top barriers to proper documentation are a lack of time, cited by 40% of respondents, and a lack of tools, cited by 30%.
The challenge of integrating new technology with old processes was perfectly illustrated in a recent meeting I had with a Fortune 500 executive. The company is pushing for significant productivity gains with AI, but it still relies on an outdated collaboration tool that was never designed for teamwork. This situation highlights the very challenge our survey uncovered: Powerful AI initiatives can stall if teams lack modern collaboration and documentation tools.
This disconnect shows that AI adoption is about more than just the technology itself. For it to truly succeed enterprise-wide, companies need to provide a unified space for teams to brainstorm, plan, document, and make decisions. The fundamentals of successful technology adoption still hold true: You need the right tools to enable collaboration and documentation for AI to truly make an impact.
Collaboration and change management are hidden blockers to AI implementation
A company’s approach to AI is perceived very differently depending on an employee’s role. While 61% of C-suite executives believe their company’s strategy is well-considered, that number drops to 49% for managers and just 36% for entry-level employees, as our survey found.
Just like with product development, building a successful AI strategy requires a structured approach. Leaders and teams need a collaborative space to come together, brainstorm, prioritize the most promising opportunities, and map out a clear path forward. As many companies have embraced hybrid or distributed work, supporting remote collaboration with digital tools becomes even more important.
We recently used AI to streamline a strategic challenge for our executive team. A product leader used it to generate a comprehensive preparatory memo in a fraction of the typical time, complete with summaries, benchmarks, and recommendations.
Despite this efficiency, the AI-generated document was merely the foundation. We still had to meet to debate the specifics, prioritize actions, assign ownership, and formally document our decisions and next steps.
According to our survey, 23% of respondents reported that collaboration is frequently a bottleneck in complex work. Employees are willing to embrace change, but friction from poor collaboration adds risk and reduces the potential impact of AI.
Operational readiness enhances your AI readiness
Operations lacking structure are preventing many organizations from implementing AI successfully. We asked teams about their top needs to help them adapt to AI. At the top of their lists were document collaboration (cited by 37% of respondents), process documentation (34%), and visual workflows (33%).
Notice that none of these requests are for more sophisticated AI. The technology is plenty capable already, and most organizations are still just scratching the surface of its full potential. Instead, what teams want most is ensuring the fundamentals around processes, documentation, and collaboration are covered.
AI offers a significant opportunity for organizations to gain a competitive edge in productivity and efficiency. But moving fast isn’t a guarantee of success. The companies best positioned for successful AI adoption are those that invest in operational excellence, down to the last mile.
This content was produced by Lucid Software. It was not written by MIT Technology Review’s editorial staff.
Large language models forecast patient health trajectories enabling digital twins
npj Digital Medicine, Published online: 01 October 2025; doi:10.1038/s41746-025-02004-3
Large language models forecast patient health trajectories enabling digital twins
Genomically matched therapy in advanced solid tumors: the randomized phase 2 ROME trial
Nature Medicine, Published online: 29 September 2025; doi:10.1038/s41591-025-03918-x
In the proof-of-concept phase 2 ROME trial, comprehensive genomic profiling followed by molecular tumor board evaluation and randomization of patients with metastatic solid cancer to receive personalized therapy or standard of care led to a significantly higher objective response rate and longer progression-free survival in patients who received personalized therapy.
Multi-Omics Feature Selection to Identify Biomarkers for Hepatocellular Carcinoma
Metabolites. 2025 Aug 28;15(9):575. doi: 10.3390/metabo15090575.
ABSTRACT
INTRODUCTION: Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, ranks as the third leading cause of mortality globally. Patients diagnosed with HCC exhibit a dismal prognosis mostly due to the emergence of symptoms in the advanced stages of the disease. Moreover, conventional biomarkers demonstrate insufficient efficacy in the early detection of HCC, hence highlighting the need for the identification of novel and more effective biomarkers.
METHODS: In this paper, we investigate methods for integration of multi-omics data we generated by both untargeted and targeted mass spectrometric analysis of serum samples from HCC cases and patients with liver cirrhosis. Specifically, the performances of several feature selection methods are evaluated on their abilities to identify a panel of multi-omics features that distinguish HCC cases from cirrhotic controls.
RESULTS: The integrative analysis identified key molecules associated with liver including such as leucine and isoleucine as well as SERPINA1, which is involved in LXR/RXR Activation and Acute Response signaling. A new method that uses recursive feature selection in conjunction with a transformer-based deep learning model as an estimator led to more promising results compared to other deep learning methods that perform disease classification and feature selection sequentially.
CONCLUSIONS: The findings in this study reinforce the importance of adapting or extending deep learning models to support robust feature selection, especially for integration of multi-omics data with limited sample size to avoid the risk of overfitting and the need for evaluation of the multi-omics features discovered in this study via blood samples from a larger and independent cohort to identify robust biomarkers for HCC.
PMID:41002959 | PMC:PMC12471784 | DOI:10.3390/metabo15090575
Integrative Spatial Omics for Systems-Level Mapping of Pathological Niches
bioRxiv [Preprint]. 2025 Sep 17:2025.09.12.675904. doi: 10.1101/2025.09.12.675904.
ABSTRACT
Spatial 'omics technologies are a powerful tool for mapping the relationship between cellular organization and molecular distributions in healthy and diseased tissue microenvironments. Here, we describe a novel multimodal pipeline that represents experimental and computational advances for spatiomolecular analysis of tissue samples across molecular classes. This adaptable method integrates matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) lipidomics, spatial transcriptomics (ST), multiplexed immunofluorescence microscopy (MxIF), and histopathological staining to uncover spatiomolecular profiles associated with unique cellular niches and pathological features. We demonstrate the power of this approach using two different complex human disease systems: Alzheimer's disease in human brain tissue and type 2 diabetes mellitus in the human pancreas. By identifying molecular markers associated with disease pathology in the pancreas and brain, we shed light on biologically significant pathways that are impacted in these two spatially complex diseases and highlight the powerful potential of accurate, high-resolution multimodal integration approaches.
PMID:41000710 | PMC:PMC12458195 | DOI:10.1101/2025.09.12.675904
FUSION: a web-based application for in-depth exploration of multi-omics data with brightfield histology
Nat Commun. 2025 Sep 25;16(1):8388. doi: 10.1038/s41467-025-63050-9.
ABSTRACT
Spatial technologies examining the cell and tissue microenvironment at near single-cell resolution are revealing important molecular insights. However, few tools enable integrated, interactive analysis of spatial-omics with tissue morphology in the same functional tissue unit. Here, we present FUSION (Functional Unit State Identification in Whole Slide Images), a web-based platform for visualizing and analyzing spatial-omics data with high-resolution histology. FUSION provides workflows for assessing cell compositions, quantitative morphometrics, and comparative tissue analyses. We demonstrate applicability across spatial assays, including 10x Visium, Visium HD, 10x Xenium, Cell DIVE, and PhenoCycler, applied to healthy and diseased tissues from kidney, small intestine, lung, and skin in the Human BioMolecular Atlas Program. FUSION is cloud-based, open-source, and accessible at https://fusion.hubmapconsortium.org/ , hosting over 50 paired datasets and tutorials. In a series of use cases, we show its capacity to distinguish renal glomeruli injury states, quantify morphometric changes, and characterize fibrosis with immune infiltration.
PMID:40998789 | PMC:PMC12462499 | DOI:10.1038/s41467-025-63050-9
