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Characterization and regulatory mechanism evaluation of C8orf33 in hepatocellular carcinoma through multiomics profiling

Discov Oncol. 2026 Apr 11. doi: 10.1007/s12672-026-04951-z. Online ahead of print.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Chromosome 8 open reading frame 33 (C8orf33) has been noted as a potential oncogenic factor in several cancers, but its biological roles and regulatory mechanism in HCC microenvironment remain unknown.

METHODS: We integrated bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) to characterize the expression landscape of C8orf33. We then performed C8orf33 loss-of-function studies in HCC cell lines, including in vitro phenotypic assays and subcutaneous xenografts.

RESULTS: C8orf33 was broadly overexpressed and associated with unfavorable prognosis across multiple Cancers. In HCC, higher C8orf33 aligned with advanced stage and shorter overall survival. C8orf33 knockdown reduced proliferation and migration, impaired tumorigenic capacity, and increased apoptosis. ScRNA-seq analyses identified a malignant population of Epi3 with high C8orf33 expression. Cell-cell communication analysis suggested that C8orf33-high Epi3 state was associated with an enriched MIF-CD74/CXCR4/CD44 signaling program toward macrophage populations with M2-like features. ST analyses further confirmed the colocalization of C8orf33 with malignant features in tumor cores. In Huh7 cells, C8orf33 knockdown was accompanied by reduced mRNA and protein levels of MIF and its receptor components. Consistently, xenografts derived from C8orf33-silenced cells showed lower expression of these MIF-axis components and reduced infiltration of CD163 and CD206-positive macrophages.

CONCLUSION: These results support a tumor-promoting association of C8orf33 in HCC and suggest a potential link to macrophage-associated immunomodulatory features, nominating C8orf33 as a candidate biomarker and therapeutic target.

PMID:41965457 | DOI:10.1007/s12672-026-04951-z

Characterization and regulatory mechanism evaluation of C8orf33 in hepatocellular carcinoma through multiomics profiling

Discov Oncol. 2026 Apr 11. doi: 10.1007/s12672-026-04951-z. Online ahead of print.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Chromosome 8 open reading frame 33 (C8orf33) has been noted as a potential oncogenic factor in several cancers, but its biological roles and regulatory mechanism in HCC microenvironment remain unknown.

METHODS: We integrated bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) to characterize the expression landscape of C8orf33. We then performed C8orf33 loss-of-function studies in HCC cell lines, including in vitro phenotypic assays and subcutaneous xenografts.

RESULTS: C8orf33 was broadly overexpressed and associated with unfavorable prognosis across multiple Cancers. In HCC, higher C8orf33 aligned with advanced stage and shorter overall survival. C8orf33 knockdown reduced proliferation and migration, impaired tumorigenic capacity, and increased apoptosis. ScRNA-seq analyses identified a malignant population of Epi3 with high C8orf33 expression. Cell-cell communication analysis suggested that C8orf33-high Epi3 state was associated with an enriched MIF-CD74/CXCR4/CD44 signaling program toward macrophage populations with M2-like features. ST analyses further confirmed the colocalization of C8orf33 with malignant features in tumor cores. In Huh7 cells, C8orf33 knockdown was accompanied by reduced mRNA and protein levels of MIF and its receptor components. Consistently, xenografts derived from C8orf33-silenced cells showed lower expression of these MIF-axis components and reduced infiltration of CD163 and CD206-positive macrophages.

CONCLUSION: These results support a tumor-promoting association of C8orf33 in HCC and suggest a potential link to macrophage-associated immunomodulatory features, nominating C8orf33 as a candidate biomarker and therapeutic target.

PMID:41965457 | DOI:10.1007/s12672-026-04951-z

TREM2-mediated microglial phagocytosis of inhibitory synapses contributes to prolonged FS-induced epileptogenesis

Cell Death Discovery, Published online: 11 April 2026; doi:10.1038/s41420-026-03118-7

TREM2-mediated microglial phagocytosis of inhibitory synapses contributes to prolonged FS-induced epileptogenesis

Graphicalized vision-language modeling for comprehensive lung nodule analysis and risk stratification

npj Digital Medicine, Published online: 11 April 2026; doi:10.1038/s41746-026-02602-9

Graphicalized vision-language modeling for comprehensive lung nodule analysis and risk stratification

Child Vaccination Status and Behavioral and Social Drivers of Vaccination Among Their Caregivers in the Philippines: Cross-Sectional Survey Study Comparison of Household, Mobile, and Online Modes

Background: The World Health Organization recommends that countries routinely collect data on the behavioral and social drivers (BeSD) of vaccination to inform public health interventions that increase vaccine uptake. There is a need to identify data collection methods that can rapidly and inexpensively collect representative data, particularly in low- and middle-income countries. Objective: This study aimed to understand BeSD drivers of vaccination in the Philippines and assess the trade-offs between survey methods. We compared responses to household, mobile, and online surveys in terms of demographics, vaccination status, responses to BeSD questions, and cost. Methods: We conducted concurrent household, mobile (SMS text messaging and interactive voice response), and online surveys among caregivers of children 2 years of age and below in Regions V and XII of the Philippines, with sampling differing by survey method. We assessed, for each survey method, (1) respondent demographics (sex, age, region, and socioeconomic status) and (2) the weighted proportion of responses from caregivers of children who received at least one dose of diphtheria-pertussis-tetanus (DPT)–containing vaccine. We estimated the weighted proportion of each BeSD survey response option and calculated the financial cost (monetary outlays) per survey response from an implementer’s perspective by summing the costs incurred in each survey method and dividing by the number of responses received. Results: We surveyed a total of 1201 household respondents, 2153 mobile respondents, and 398 online respondents from January to March 2025. We found that online and mobile survey respondents were more likely to be male and have completed high school than household survey respondents. The weighted proportion of respondents indicating that their child had received at least one dose of DPT vaccine was 91.8% (n=1090; 95% CI 90%‐93.3%) for the household survey, 90.3% (n=1853) for the mobile survey, and 85% (n=346) for the online survey. With regard to vaccine demand, more than 85% of respondents in each survey method indicated that vaccines are very important, very safe, supported by family, and that they knew where to bring a child for vaccination. More than 30% of mobile and online survey respondents indicated that it was not easy to pay for vaccination. The financial cost to conduct the survey per survey response was US $2.61 for the online survey, US $6.93 for the mobile survey, and US $29.38 for the household survey. Conclusions: In the Philippines, household, mobile, and online survey methods reached caregivers of children who were unvaccinated against DPT, and these proportions were similar across survey methods. BeSD responses indicated high vaccine demand and challenges in caregivers’ cost to access vaccination. Determining the most appropriate survey method depends on trade-offs between representativeness and costs. However, areas with strong connectivity and high mobile device ownership can consider mobile and online methods as a lower-cost alternative to rapidly collect BeSD data.
  • ✇MIT Technology Review
  • What’s in a name? Moderna’s “vaccine” vs. “therapy” dilemma Antonio Regalado
    Is it the Department of Defense or the Department of War? The Gulf of Mexico or the Gulf of America? A vaccine—or an “individualized neoantigen treatment”? That’s the Trump-era vocabulary paradox facing Moderna, the covid-19 shot maker whose plans for next-generation mRNA vaccines against flus and emerging pathogens have been dashed by vaccine skeptics in the federal government. Canceled contracts and unfriendly regulators have pushed the Massachusetts-based biotech firm to a breaking point.
     

What’s in a name? Moderna’s “vaccine” vs. “therapy” dilemma

10 April 2026 at 22:04

Is it the Department of Defense or the Department of War? The Gulf of Mexico or the Gulf of America? A vaccine—or an “individualized neoantigen treatment”?

That’s the Trump-era vocabulary paradox facing Moderna, the covid-19 shot maker whose plans for next-generation mRNA vaccines against flus and emerging pathogens have been dashed by vaccine skeptics in the federal government. Canceled contracts and unfriendly regulators have pushed the Massachusetts-based biotech firm to a breaking point. Last year, Robert F. Kennedy Jr., head of the Department of Health and Human Services, zeroed in on mRNA, unwinding support for dozens of projects—including a $776 million award to Moderna for a bird flu vaccine. By January, the company was warning it might have to stop late-stage programs to develop vaccines against infections altogether.

That raises the stakes for a second area of Moderna’s research. In a partnership with Merck, it’s been using its mRNA technology to destroy tumors through a very, very promising technique known as a cancer vacc—

“It’s not a vaccine,” a spokesperson for Merck jumped in before the V-word could leave my mouth. “It’s an individualized neoantigen therapy.”

Oh, but it is a vaccine. And here’s how it works. Moderna sequences a patient’s cancer cells to find the ugliest, most peculiar molecules on their surface. Then it packages the genetic code for those same molecules, called neoantigens, into a shot. The patient’s immune system has its orders: Kill any cells with those yucky surface markers.

Mechanistically, it’s similar to the covid-19 vaccines. What’s different, of course, is that the patient is being immunized against a cancer, not a virus.

And it looks like a possible breakthrough. This year, Moderna and Merck showed that such shots halved the chance that patients with the deadliest form of skin cancer would die from a recurrence after surgery.

In its formal communications, like regulatory filings, Moderna hasn’t called the shot a cancer vaccine since 2023. That’s when it partnered up with Merck and rebranded the tech as individualized neoantigen therapy, or INT. Moderna’s CEO said at the time that the renaming was to “better describe the goal of the program.” (BioNTech, the European vaccine maker that’s also working in cancer, has shifted its language too, moving from “neoantigen vaccine” in 2021 to “mRNA cancer immunotherapies” in its latest report.)

The logic of casting it as a therapy is that patients already have cancer—so it’s a treatment as opposed to a preventive measure. But it’s no secret what the other goal is: to distance important innovation from vaccine fearmongering, which has been inflamed by high-ranking US officials. “Vaccines are maybe a dirty word nowadays, but we still believe in the science and harnessing our immune system to not only fight infections, but hopefully to also fight … cancers,” Kyle Holen, head of Moderna’s cancer program, said last summer during BIO 2025, a big biotech event in Boston.

Not everyone is happy with the word games. Take Ryan Sullivan, a physician at Massachusetts General Hospital who has enrolled patients in Moderna’s trials. He says the change raises questions over whether trial volunteers are being properly informed. “There is some concern that there will be patients who decline to treat their cancer because it is a vaccine,” Sullivan told me. “But I also felt it was important, as many of my colleagues did, that you have to call it what it is.”

But is it worth going to the mat for a word? Lillian Siu, a medical oncologist at the Princess Margaret Cancer Centre, in Toronto, who has played a role in safety testing for the new shots, watches US politics from a distance. She believes name change is acceptable “if it allows the research to continue.”

Holen told me the doctors complaining to Moderna were basically motivated by a desire to defend vaccines—which are, of course, among the greatest public health interventions of all time. They wanted the company to stand strong. 

But that’s not what’s happening. When Moderna’s latest results were published in February, the paper’s main text didn’t use the word “vaccine” at all. It was only in the footnotes that you could see the term—in the titles of old papers and patents.

All this could be a sign that Kennedy’s strategy is working. His agencies often appear to make mRNA vaccines a focus of people’s worries, impede their reach, devalue them for companies, and sideline their defenders. 

Still, Moderna’s strategy may be working too. So far, at least, the government hasn’t had much to say about the company’s cancer vacc— I mean, its individualized neoantigen therapy.

This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.

Integrative phosphoproteomic analysis reveals co-regulatory phosphorylation networks of rhotekin in cancer progression

Discov Oncol. 2026 Apr 10. doi: 10.1007/s12672-026-04982-6. Online ahead of print.

ABSTRACT

Rhotekin (RTKN), a Rho GTPase effector, promotes the development of malignancies, including breast, gastric, and colon cancers, by enhancing cell proliferation and migration while inhibiting apoptosis. Despite its oncogenic role, the phosphoregulatory network of RTKN remains largely unexplored, with no experimental evidence on its upstream kinases and functional phosphosites. To characterize RTKN-associated phosphorylation dynamics, PubMed-indexed studies were systematically retrieved using predefined MeSH terms to compile large-scale cellular phosphoproteomics datasets. Analysis of 618 quantitative profiling and 179 differential abundance datasets identified 27 Class-I phosphosites in RTKN. Among these, five sites-Ser106, Ser220, Ser520, Ser529, and Ser543 were consistently observed across multiple datasets, suggesting them as predominant sites with potential functional significance. Structural mapping of predominant sites onto the AlphaFold2-predicted model indicated that these sites are located in accessible regions, highlighting their potential susceptibility to kinase-mediated regulation. As these sites represent understudied phosphosites, a robust strategy was employed to identify their functional role by assessing co-regulated phosphosites on other proteins (PsOPs). ACIN1_Ser243, CTNNA1_Ser641, and SHROOM2_Ser1036 were among the top positively co-regulated PsOPs, whereas MICALL1_Ser644, PRP4K_Ser366, and MYO18A_Ser1970 were negatively co-regulated. PsOPs were mainly involved in apoptosis, cell growth, motility, and cytoskeletal reorganization, suggesting potential functional convergence with RTKN. Additionally, phosphorylation at RTKN Ser520 and Ser543 co-occurred across multiple datasets. Moreover, TRPM7 and PAK4 were identified as predicted upstream kinases phosphorylating RTKN at Ser220 and Ser520. Pathway analysis showed involvement of co-regulated proteins in cancer-associated signaling pathways. These findings provide a foundation for future research to elucidate the phosphosite-specific role of RTKN in cancer.

PMID:41963591 | DOI:10.1007/s12672-026-04982-6

Metformin suppresses β-cell apoptosis under ER stress by inhibiting protein translation

Metabolism. 2026 Apr 8:156607. doi: 10.1016/j.metabol.2026.156607. Online ahead of print.

ABSTRACT

Endoplasmic reticulum (ER) stress is a critical driver of pancreatic β-cell dysfunction and apoptosis. Although metformin, a drug used to treat type 2 diabetes, primarily decreases blood glucose levels by improving insulin sensitivity, its direct effects on β-cell survival remain unclear. Here, we investigated the effect of metformin on β-cell stress responses under ER stress conditions. Thapsigargin (Tg)-induced ER stress increased β-cell apoptosis in mouse islets, which was prevented by metformin in a dose-dependent manner. Treatment with metformin for 24 h suppressed the Tg-induced upregulation of unfolded protein response (UPR)-related genes, as confirmed by transcriptomic and pathway analyses. Quantitative proteomics revealed that Tg inhibited eIF2 signaling and protein translation, both of which were partially restored by metformin. Enrichment analysis further indicated the attenuation of apoptotic pathways in metformin-treated islets. Polysome profiling and puromycin incorporation assays demonstrated that metformin reduced protein translation independently of ER stress. Metformin promoted the dephosphorylation of 4E-BP1, a key initiator of cap-dependent protein translation that is activated by phosphorylation, and the antiapoptotic effect of metformin was abolished by 4E-BP1 knockdown in MIN6 cells. Phosphoproteomic analysis indicated that the activation of mTOR signaling, a kinase of 4E-BP1, in Tg-treated islets was mitigated by metformin. Taken together, these findings reveal a cytoprotective mechanism of metformin in β-cells, in which metformin suppresses ER stress-induced apoptosis through 4E-BP1-mediated inhibition of mRNA translation and modulation of mTOR signaling. This study highlights a β-cell-intrinsic action of metformin that may contribute to its long-term therapeutic benefits in diabetes management.

PMID:41962652 | DOI:10.1016/j.metabol.2026.156607

A Genetically Engineered Human Organoid Model Reveals Distinct Genetic and Epigenetic Barriers of Lineage Plasticity in Early PDAC Transformation

bioRxiv [Preprint]. 2026 Mar 11:2026.03.09.710586. doi: 10.64898/2026.03.09.710586.

ABSTRACT

The lack of accurate, human-based models recapitulating early-stage pancreatic ductal adenocarcinoma (PDAC) has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectory of tumor initiation and progression in vitro , validated against clinical datasets and histopathology. We demonstrate that CDKN2A loss, nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, while SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of pancreatic lineage program during PDAC initiation, alongside oncogenic AP-1-driven chromatin remodeling. Notably, we identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and the hypermethylation and silencing of essential pancreatic transcription factors. This model captures the genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a promising early intervention strategy for high-risk individuals.

PMID:41959451 | PMC:PMC13060829 | DOI:10.64898/2026.03.09.710586

  • ✇STAT
  • How sports betting apps hook users Alex Hogan
    For most of the last 80 years, sports betting was limited to Las Vegas. But after a 2018 Supreme Court decision loosened regulations on professional sports wagers, it became possible to place bets on games 24/7 — with nothing more than a smartphone and a bank account.  In 2013, just five years prior to the landmark SCOTUS case, gambling was classified in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) in a new category called “Substance-Related and Addictive Disorders.” This
     

How sports betting apps hook users

10 April 2026 at 16:30

For most of the last 80 years, sports betting was limited to Las Vegas. But after a 2018 Supreme Court decision loosened regulations on professional sports wagers, it became possible to place bets on games 24/7 — with nothing more than a smartphone and a bank account. 

In 2013, just five years prior to the landmark SCOTUS case, gambling was classified in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) in a new category called “Substance-Related and Addictive Disorders.” This grouped gambling with alcohol use disorder and other addictions. Gambling is also known to have the highest suicide rate of any addiction.

Read the rest…

NAT10 promotes cisplatin resistance and immune escape by increasing the expression of DUSP1 and PD-L1 in gastric cancer

Cell Death Discovery, Published online: 10 April 2026; doi:10.1038/s41420-026-03107-w

NAT10 promotes cisplatin resistance and immune escape by increasing the expression of DUSP1 and PD-L1 in gastric cancer

Innovations in Deaf Health Care Communication: Systematic Review of Sign Language Recognition Systems

Background: Deaf individuals often face communication challenges when interacting with those who can hear. Within health care settings, these challenges may pose risks to their safety, potentially resulting in misdiagnoses, treatment errors, and decreased quality of care. Objective: This study aims to systematically review the evidence on communication systems reported in the literature that use human-computer interaction techniques to support communication between deaf individuals who use sign language and hearing health professionals in health care settings. The review focuses on systems that are either currently in use or proposed for use in health care and that have been tested using human participants or videos of human users. Methods: A comprehensive search was performed via MEDLINE, Web of Science, ACM, IEEE Xplore, Scopus, and Google Scholar in March 2025. The inclusion criteria comprised studies developing a sign language recognition system within a health care context and testing with human users. Eligible studies underwent screening by 2 independent investigators (LRV and LMMSR or LFRdO and GTdSS), with any disagreements resolved by a senior researcher (MSM). Results: The search retrieved 21,778 publications, and screening of reference lists identified 2 additional studies, resulting in a total of 23 studies meeting the eligibility criteria. Most systems (15/23, 65.2%) were image-based, while 34.8% (8/23) relied on sensors (glove-based or depth-sensing). Applications varied across health care settings, including general hospital care (10/23, 43.5%), emergencies (8/23, 34.8%), and primary care (4/23, 17.4%). All systems were in the development and testing stage, with no data on security and psychological impacts. Accuracy ranged from 25% to 100% for image-based and 72% to 99.7% for sensor-based systems. Bidirectionality and facial expression recognition, crucial for effective communication, were largely overlooked. Conclusions: Image-based systems were more common than sensor-based ones, though both showed wide variability in accuracy in recognizing and interpreting signs. Most systems failed to address critical aspects such as bidirectional communication and the recognition of facial expressions, essential for effective communication. None fully addresses the requirements for integration into health care settings. These findings highlight the need for further research on implementation, usability, and impact on the quality of care for deaf patients. International Registered Report Identifier (IRRID): RR2-10.2196/55427

Nonsense-mediated mRNA decay inhibition reshapes the cancer immunopeptidome

Immunity. 2026 Apr 8:S1074-7613(26)00075-0. doi: 10.1016/j.immuni.2026.02.005. Online ahead of print.

ABSTRACT

DNA mutations are a well-characterized source of neoepitopes in immunotherapy. Here, we examined the contribution of dysregulated RNA processing to neoantigen production. Leveraging multi-omics and checkpoint inhibitor (CPI) response data from >1,000 patients, we identified reduced activity of the nonsense-mediated mRNA decay (NMD) pathway kinase SMG1 as a predictor of improved CPI response. NMD inhibition through SMG1 targeting stabilized transcripts containing premature termination codons, most of which were of non-mutational origin. This reshaped the major histocompatibility complex class I (MHC class I)-bound immunopeptidome and increased neoantigen abundance to levels comparable to high mutation burden tumors. Functionally, NMD inhibition drove antigen-dependent T cell-mediated tumor cell killing in vitro, promoted activation of tissue-resident T cells in patient-derived models ex vivo, and improved CPI efficacy in vivo. Our findings establish NMD inhibition as a strategy to harness a previously inaccessible source of canonical and non-canonical neoantigens, with the potential to increase tumor immunogenicity across cancers.

PMID:41956098 | DOI:10.1016/j.immuni.2026.02.005

Chuanminshen violaceum (Apiaceae) as a medicinal-and-edible resource: phytochemical diversity, bioactivities, and routes to standardized products

J Ethnopharmacol. 2026 Apr 6:121628. doi: 10.1016/j.jep.2026.121628. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Chuanminshen violaceum Sheh et Shan is a medicinal-and-edible Apiaceae plant in China recorded for yin nourishment, lung/spleen tonification, and phlegm resolution, and used for cough and chronic respiratory complaints.

STUDY AIM: To synthesize current evidence on botanical resources, chemistry, pharmacology, and applications of C. violaceum, and to define priorities for standardized and safe development.

MATERIALS AND METHODS: This review integrates studies on resource distribution and ecological adaptability, multi-fraction phytochemistry, extraction-purification and formulation technologies, preclinical pharmacology, and quality, safety, and regulatory considerations.

RESULTS: C. violaceum contains structurally diverse polysaccharides plus volatile oils (often polyacetylene-rich), phenolics (e.g., chlorogenic acid and rutin), PUFA-rich lipids, and newly reported minor constituents. Polysaccharides show variable monosaccharide profiles, molecular-weight ranges, and linkage/branching patterns, strongly influenced by extraction-purification; derivatization (e.g., sulfation/selenization) and delivery systems can further tune physicochemical properties. Preclinical studies report antioxidant, anti-inflammatory, immunomodulatory, cardioprotective, and antiviral effects, commonly linked to Nrf2/Keap1 redox defense, inflammatory signaling control, TLR2/4-related immune regulation, gut-barrier reinforcement with microbiota remodeling, and anti-ferroptotic protection in myocardial ischemia-reperfusion models. Applications span traditional dosage forms and functional foods, but translation is limited by origin/process variability, incomplete long-term safety and ADME data, and regulatory uncertainty.

CONCLUSIONS: C. violaceum is a promising ethnomedicinal resource with clear part-specific features and polysaccharide-centered potential. Future work should combine multi-omics with target validation, fingerprint-guided QC and traceability, greener scalable processing, and regulatory-aligned safety packages to enable reproducible products.

PMID:41951195 | DOI:10.1016/j.jep.2026.121628

Fentanyl-induced cortical and cardiopulmonary damage linked to immune response functions and apoptosis-necrosis networks in a multi-omics mouse model

Front Immunol. 2026 Mar 23;17:1694651. doi: 10.3389/fimmu.2026.1694651. eCollection 2026.

ABSTRACT

INTRODUCTION: Fentanyl can rapidly impair brain and cardiopulmonary functions due to its high pharmacokinetics, necessitating a systems-level investigation to elucidate the early host response profile. To address this, we developed an SKH-1 mouse model to integrate ex-vivo imaging with multi-omics data, enabling a comprehensive understanding of tissue-specific host responses across time and dose gradients.

METHODS: Our previous study characterized the phenotypes of this mouse model to establish dose gradients and time points associated with major clinical manifestations. Building on these findings, cortex, heart, and lung tissues were collected postmortem at 40 min, 6h, 24h, and 7 days following administration of one of three fentanyl doses: the highest non-lethal dose (HNLD), LD10, and LD50.

RESULTS: Multi-omics analysis revealed immune response networks and apoptosis-necrosis functions as primary targets of fentanyl. Cortical and pulmonary immune responses exhibited dose-dependent latencies but remained activated 7 days post-exposure, whereas the cardiac immune response was suppressed over time. Pulmonary apoptosis-necrosis was rapidly activated, contrasting with its delayed, dose-dependent activation in the heart. In the cortex, apoptosis-necrosis followed a monophasic longitudinal trajectory, with delayed activation after 24h followed by regression. These findings suggest tissue-specific time windows for early intervention. Subsequent machine learning analysis identified phylogenetically conserved and miRNAs, such as miR-146-5p and miR-877-3p, which demonstrated consistent time- and dose-independent regulation in the lungs and cortex, respectively.

CONCLUSION: Functional associations of these miRNAs with tissue-specific lesions highlight their potential therapeutic value. Further interrogation of miRNA-mRNA interactions and downstream target analysis could pave the way for developing precision countermeasures against fentanyl toxicity.

PMID:41948326 | PMC:PMC13051511 | DOI:10.3389/fimmu.2026.1694651

Multiomics and multi-region spatial transcriptome analysis reveal cellular networks and pathways associated with HCC recurrence

JHEP Rep. 2026 Feb 18;8(5):101790. doi: 10.1016/j.jhepr.2026.101790. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence.

METHODS: Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry.

RESULTS: Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6+ ECs, enriched and spatially colocalised with tumour cells in primary tumours from patients with recurrence (p = 0.021, n = 49). A significant ANGPTL4-SDC1 ligand-receptor interaction was identified between INTS6+ ECs and tumour cells. Notably, INTS6+ ECs were enriched in microvascular invasion regions and spatially colocalised with tumour cells in patients with recurrence (p = 0.036, n = 53). These findings highlight endothelial-tumour cell interactions within the TME as potential therapeutic targets.

CONCLUSIONS: INTS6+ ECs are enriched in microvascular invasion regions and spatially colocalised with tumour cells in recurrent HCC, suggesting a potential role in disease recurrence and representing a promising therapeutic target within the TME.

IMPACT AND IMPLICATIONS: The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival.

PMID:41950768 | DOI:10.1016/j.jhepr.2026.101790

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