BACKGROUND:Viral communities of the upper aerodigestive tract represent an important component of the human microbial ecosystem but remain poorly characterized due to the limited availability of habitat-specific reference resources. METHODS:We integrated 19,997 public and 2,673 newly sequenced oral and airway metagenomes to establish the Oral and Airway Viral Genome Catalogue (OAVGC). Viral genomes were reconstructed and characterized through taxonomic assignment, prokaryotic host prediction, functional annotation, and assessment of putative antibacterial activity. Our prospective longitudinal aging cohort, alongside 5 in-house datasets and publicly cohorts, were analyzed to investigate associations between airway virome profiles and respiratory health. FINDINGS:The OAVGC comprised 141,459 high-quality viral genomes (completeness ≥90%) clustered into 68,708 viral operational taxonomic units (vOTUs). Approximately half of these viruses and families are previously undescribed, with independent cross-cohort detection and PCR assays providing additional support for their occurrence. Across multiple respiratory infection cohorts, the virome exhibited convergent diversity reductions and compositional signatures. In the prospective cohort, the baseline airway virome was correlated with host lung function and geriatric health scores. Virome-based machine learning classifiers demonstrated potential for predicting the future occurrence of upper respiratory tract infections up to 12 months in advance, outperforming bacteriome-based models in our prediction analyses. CONCLUSIONS:The OAVGC provides an unprecedented genomic and functional resource for investigating the ecological and clinical associations of the oral-airway virome, revealing its potential impact on respiratory health and capacity to predict future infections. FUNDING:National Natural Science Foundation of China (82341113) and National Key R&D Program of China (2022YFA1304303).
Background Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes that recognize riboflavin-derived metabolites presented by the monomorphic major histocompatibility complex (MHC)-class I-related molecule MR1. MAIT cells are highly enriched in the human liver and are increasingly implicated in liver cancer immunity, yet their antitumor potential and therapeutic applicability remain incompletely defined. Methods Here, we profiled MAIT cells derived from peripheral blood of healthy donors and patients with hepatocellular carcinoma, revealing disease-associated phenotypic alterations marked by immune checkpoint dysregulation. To address current therapeutic limitations, we developed a robust ex vivo expansion platform capable of generating MAIT cells with high yield, purity, and potent cytotoxic function. Using multiple human liver cancer subcutaneous and orthotopic xenograft mouse models, we demonstrate that adoptively transferred MAIT cells mediate effective tumor targeting and killing in vivo. Findings Mechanistically, MAIT cell antitumor activity is driven by both T cell receptor (TCR)-dependent recognition and natural killer receptor (NKR)-mediated cytotoxicity and is further enhanced by antigen stimulation; cytokine receptor signaling, particularly via interleukin (IL)-15; and immune checkpoint modulation involving programmed cell death protein 1 (PD-1) and T cell immunoglobulin and ITIM domain (TIGIT). In addition, MAIT cells demonstrated a favorable safety profile, with no evidence of liver toxicity observed in xenograft mouse models. Conclusions Together, these findings establish MAIT cells as functional antitumor effectors in liver cancer and provide a mechanistic and translational framework for adoptive MAIT cell therapy enhanced by multimodal modulation of immune receptors and checkpoints. Funding Major funding was provided by the California Institute for Regenerative Medicine (CIRM).
BACKGROUND:It is unclear whether combined anticoagulation (AC) plus lipid-lowering therapies (LLTs) enhance AC efficacy for venous thromboprophylaxis while maintaining an acceptable safety profile. METHODS:A systematic literature search was conducted in PubMed, Cochrane CENTRAL library, and Web of Science, including randomized controlled trials (RCTs) and observational studies published until May 2026. The associations of LLT+AC vs. AC monotherapy with efficacy outcomes (i.e., recurrent venous thromboembolism [rVTE] and post-thrombotic syndrome [PTS] risk), safety outcomes (i.e., major bleeding), and other outcomes were analyzed. A Bayesian random-effects meta-analysis was used to aggregate study estimates (95% credible interval [CrI]) and calculate the posterior probability of benefit (relative risk [RR] < 1). FINDINGS:The search yielded 28 (17 observational studies and 11 RCTs) studies eligible for meta-analysis. The pooled effect size of LLT+AC vs. AC alone for rVTE was RR = 0.73 [95% CrI: 0.58; 1.05, P(RR < 1) = 0.97]. In addition, there was a 17% lower risk observed for PTS [RR = 0.83, 95% CrI: 0.40; 1.59, P(RR < 1) = 0.74]. Major bleeding risk was 15% lower [RR = 0.85, 95% CrI: 0.76; 0.96, P(RR < 1) = 0.99]. Combined LLT+AC reduced D-dimer [log SMD = -0.15; 95% CrI: -0.43; 0.13, P(SMD < 0) = 0.88] and C-reactive protein levels [log SMD = -0.86; 95% CrI: -1.48; -0.08; P(SMD < 0) = 0.98] relative to AC monotherapy. CONCLUSIONS:The available evidence suggests potential benefit of LLT+AC combination therapy over AC monotherapy, with respect to both safety and efficacy, though further evidence from RCTs is necessary to generate conclusive evidence. FUNDING:DIASyM research core (BMBF 031L0219).
BACKGROUND:Effective patient education requires accurate communication aligned with patients' emotional and semantical needs. Text-based large language models (LLMs) lack access to non-verbal cues, which may contribute to misaligned responses. METHODS:We evaluated emotional and semantic misalignment in a text-based LLM using 64,200 utterances from 16,583 patient education cases across six departments and three centers. Dolphin was developed integrating text and audio cues and evaluated through emotion recognition, semantic consistency assessment, branch-level ablations, and a double-blinded randomized trial against a matched text-based LLM comparator (Chinese Clinical Trial Registry: (ChiCTR2500095933). FINDINGS:The text-based LLM showed emotional misalignment in 36.7% of responses and semantic misalignment in 28.3% of cases, with higher misalignment under greater burden. Dolphin outperformed the text-based LLM in emotion recognition accuracy (0.886 vs. 0.713) and semantic consistency (84.9% vs. 82.1%; both adjusted p < 0.001). Ablations supported contribution of audio branches. Dolphin received higher expert ratings than the text-based LLM and human educators (all p < 0.001). In 555 patients, Dolphin was associated with greater patient satisfaction (98.6% vs. 93.8%), suggestion acceptance (76.1% vs. 58.9%; p < 0.001), proactive disclosure (44.6% vs. 26.5%; p < 0.001), and fewer 7-day unplanned recontact (12.9% vs. 22.9%; p = 0.002). No unsafe recommendations or safety events were identified. CONCLUSIONS:Compared with text-based LLM, Dolphin improved emotional-semantic alignment and patient-education outcomes, supporting bimodal alignment as a strategy for reducing misalignment-driven communication failures. FUNDING:National Natural Science Foundation of China, State Key Laboratory Special Fund, and Chinese Academy of Medical Sciences Innovation Fund.
In Basel, only a few hundred meters from where LSD was first synthesized, we tested LSD-assisted therapy for major depression in a randomized trial comparing two high doses with two low doses, each paired with supportive psychotherapy. This Backstory reflects on treating patients, long dosing days, and what remains uncertain.
Michèle Ramsay, PhD, is Director of the Sydney Brenner Institute for Molecular Bioscience, Professor in Human Genetics, and South African Research Chair in Genomics and Bioinformatics of African Populations at the University of the Witwatersrand, Johannesburg. While promoting research excellence in Africa and contributing to research that accurately represents African populations in global science, she supports capacity strengthening in the fields of genomics and precision medicine. Michèle is a founding member of the Human Heredity and Health in Africa Consortium, co-chair of the International Health Cohorts Consortium, member of the WHO Technical Advisory Group for Genomics (TAG-G), and co-chair of the Lancet Commission on Precision Health. She contributes low- and middle-income countries' perspectives to global genomics, promoting ethical, equitable and fair principles and practices.
BACKGROUND:Intravenous ketamine can provide short-term analgesia in chronic neuropathic pain but benefits often wane after treatment. We conducted a randomized pilot trial to assess the feasibility of combining ketamine infusions with psychotherapy to inform future efficacy trials. METHODS:In this single-center, randomized, outcome-assessor-blinded pilot trial at a Canadian tertiary pain clinic, adults with moderate-to-severe chronic neuropathic pain were randomly assigned in 1:1:1 ratio to the ketamine, psychotherapy, or combined ketamine plus psychotherapy arm. Ketamine was delivered as three intravenous infusions over 16 weeks; psychotherapy consisted of 16 weekly cognitive behavioral therapy and mindfulness-based meditation sessions. The primary outcome was feasibility, assessed using prespecified progression criteria. Exploratory outcomes included changes in pain interference (PROMIS 6a T-score), pain intensity, mood, and qualitative interview findings at week 20 (ClinicalTrials.gov: NCT05639322). FINDINGS:Between October 23, 2023, and March 31, 2025, 30 participants were randomized, and 26 (87%) completed 20-week follow-up. Most feasibility criteria, including consent, retention, data completeness, and absence of study-related serious adverse events, were met; adherence targets were partially met. Exploratory pain outcomes showed numerical improvement across groups, with clinically meaningful reductions observed for pain interference and pain intensity. Sixty-four adverse events were recorded, mostly mild and in ketamine-containing groups; no serious study-related adverse events occurred. CONCLUSIONS:Combined ketamine and psychotherapy was feasible and acceptably safe in this pilot trial, supporting evaluation in a larger efficacy-powered study. FUNDING:The study was funded by the St. Michael's Hospital Innovation Fund, The Canadian Pain Society Early Investigator Award and the Physician Services Incorporation Early Career Researcher Award.
The HERIZON-GEA-01 trial in patients with advanced HER2-positive gastroesophageal adenocarcinoma demonstrated improved outcomes with the addition of the HER2xHER2-bispecific antibody zanidatamab to chemotherapy. The addition of tislelizumab, an anti-PD-1 antibody to chemotherapy and zanidatamab suggests additional survival improvements. HER2-targeting strategies leveraging spatially restricted target degradation and immune modulation are reframing HER2 approaches in HER2-positive gastroesophageal cancer.
BACKGROUND:Adjuvant chemotherapy following D2 gastrectomy constitutes the standard-of-care for resectable gastric or gastroesophageal junction (GEJ) carcinoma. The CAPITAL trial is a multicenter, randomized, phase 3 study, aiming to assess the efficacy and safety of adjuvant oxaliplatin plus S-1 (SOX) versus S-1 alone. METHODS:Patients with histologically confirmed pathological stage II-III gastric or GEJ adenocarcinoma after gastrectomy with D2 lymphadenectomy were randomly assigned (1:1) to receive either the SOX regimen (n = 362) or the S-1 regimen (n = 362). The primary endpoint was overall survival. This study is registered with ClinicalTrials.gov (NCT01795027). FINDINGS:The median follow-up was 74.0 months (interquartile range [IQR], 35.5-89.3). The 5-year overall survival rates were 70.9% (95% confidence interval [CI], 66.0-76.1) in the SOX group and 62.9% (95% CI, 57.8-68.5) in the S-1 group (hazard ratio [HR], 0.74; 95% CI, 0.58-0.95; p = 0.018). The 3- and 5-year disease-free survival rates were 71.2% (95% CI, 66.5-76.3) and 66.2% (95% CI, 61.2-71.6) in the SOX group, as compared with 65.1% (95% CI, 60.2-70.5) and 55.6% (95% CI, 50.4-61.3) in the S-1 group (HR, 0.76; 95% CI, 0.61-0.96). Treatment-related adverse events of grade 3-4 occurred in 87 (25%) of 349 patients in the SOX group and 45 (13%) of 347 patients in the S-1 group. The most common grade 3-4 adverse event was neutropenia, occurring in 44 (13%) of 349 patients in the SOX group and 23 (7%) of 347 patients in the S-1 group. CONCLUSIONS:The addition of adjuvant oxaliplatin to S-1 chemotherapy significantly improved overall survival and disease-free survival in patients with gastric cancer. FUNDING:This research was supported by the National Natural Science Foundation of China (82573092 and 82573387).
The phase 3 RASolute 302 trial demonstrated significant overall and progression-free survival benefits with daraxonrasib over investigator's choice chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma harboring RAS G12 mutations after progression on prior chemotherapy.1 The benefit in patients with non-G12 RAS mutations or RAS wild-type tumors remains unclear.
In this phase 1 open-label trial, Zeng et al.1 show that umbilical cord blood-derived CD19 CAR NK-cell therapy is safe and effectively depletes autoreactive B cells in refractory systemic lupus erythematosus (SLE). Despite only transient CAR NK-cell persistence, patients experienced sustained clinical improvement and reconstitution of a predominantly naive B cell compartment, suggesting immune resetting rather than temporary immunosuppression.
BACKGROUND:Pulmonary fibrosis is a fatal disease with limited therapeutic options. Aberrant activation of the integrated stress response (ISR) disrupts proteostasis and promotes fibrogenesis, yet effective strategies for targeted ISR regulation in fibrotic diseases remain insufficiently explored. METHODS:Here, we engineered mesenchymal stem cells (MSCs) as living carriers for targeted co-delivery of ISRIB and nicotinamide mononucleotide (NMN). ISRIB- and NMN-loaded liposomes were conjugated onto MSCs through cleavable linkers (M-Lip@IN), enabling MSC-mediated homing and microenvironment-responsive cargo release in fibrotic lesions. FINDINGS:M-Lip@IN effectively accumulated in fibrotic lungs and promoted local liposome release. ISRIB directly regulated pathological ISR activation, whereas NMN supported NAD(H)-SIRT1-related metabolic homeostasis, collectively enabling coordinated regulation of epithelial stress responses. Augmented by MSC-mediated biological support, M-Lip@IN reduced collagen deposition, inhibited profibrotic signaling, improved epithelial cell composition, promoted lung repair, and ameliorated bleomycin-induced pulmonary fibrosis, with additional antifibrotic effects observed in carbon-tetrachloride-induced liver fibrosis. CONCLUSIONS:Our study presents an engineered MSC-based platform that integrates lesion targeting, responsive drug release, and coordinated regulation of epithelial stress responses. By combining ISR modulation with metabolic resilience, M-Lip@IN restores stress homeostasis, improves epithelial cell composition, and promotes lung repair. These findings support targeted ISR regulation as a potential therapeutic strategy for pulmonary fibrosis and other fibrotic diseases. FUNDING:This work was supported by the Shenzhen Science and Technology Program, the Guangdong Basic and Applied Basic Research Foundation, the National Natural Science Foundation of China, the University Development Research Start-up Fund, and the Pengcheng Peacock Project Special Fund.
CRISPR-Cas systems, base editing, and prime editing have made precise genetic interventions possible, and several approved therapies now treat monogenic disorders that were previously untreatable. Heritable genome editing remains ethically contested. We argue that heritable interventions should not be treated as a single category subject to uniform prohibition. We distinguish three targets: catastrophic monogenic disorders, polygenic risk reduction, and non-disease trait enhancement. For catastrophic monogenic conditions in which preimplantation selection cannot yield unaffected embryos, heritable editing is permissible, and the duty of beneficence toward future persons may require it. When the alternative is certain severe suffering or early death, the expected benefits clearly outweigh the risks. For polygenic interventions, current scientific uncertainty makes clinical application premature: predictive validity remains insufficient and pleiotropic effects are poorly understood. For enhancement, the case is weaker still. Some of its benefits are positional; the risks of social stratification are significant; and the evidence base is absent. We conclude that governance frameworks should permit what the evidence supports under stringent safeguards and prohibit what it does not. The central ethical questions concern welfare, not appeals to nature or abstract notions of dignity. Where the evidence warrants it, failing to pursue heritable gene therapy responsibly may itself be an ethical failure. We outline a translational pathway for ethical germline gene editing.
The emergence of gene-based therapies for hypertrophic cardiomyopathy (HCM) represents a pivotal inflection point in cardiovascular medicine, but their successful translation will depend on coordinated advances beyond vector design alone. Here, we propose a fieldwide framework for HCM gene therapy development, encompassing core evaluation, safety and immunosuppression management, endpoint definition, long-term surveillance, and considerations of equity and scalability. We argue that harmonization across these domains is essential to ensure that early clinical signals are interpretable, comparable, and translatable into durable patient benefit. This framework provides a roadmap to guide the transition from early feasibility to broad, equitable implementation.
Background The immunologic features of tumor-infiltrating lymphocyte (TIL) infusion products and their interactions with the tumor microenvironment that govern clinical responses in metastatic melanoma remain incompletely characterized. Methods We performed integrated immunophenotypic and spatial transcriptomic profiling of TIL infusion products and matched tumor microenvironments from patients treated on early-phase clinical trials. Results The durable objective response rate was 36%, with a median progression-free survival of 8 months among patients treated with TIL therapy with or without additional therapies. Responders exhibited infusion products enriched for CD8+ T cells, stem-like memory subsets, and LAG-3-expressing CD8+ T cells, together with enhanced peripheral TIL persistence. The abundance of infused LAG-3+ TILs correlated with tumor reactivity and prolonged progression-free survival. Prior immune checkpoint inhibitor exposure was associated with reduced CD8+ stem cell memory T cell frequency and diminished co-stimulatory receptor expression, suggesting impaired TIL fitness. Tumors enriched for tertiary lymphoid structures and spatial immune programs characterized by antigen presentation, interferon signaling, and B cell activation were independently associated with clinical benefit. Conclusions These findings define an integrated framework linking TIL composition and the tumor microenvironment to therapeutic response and identify potential biomarkers and biological features that may guide patient selection and optimization of TIL therapy. Funding This work was funded by Iovance Biotherapeutics, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Melanoma Research Alliance, the Donald A. Adam Melanoma & Skin Cancer Center of Excellence, American Cancer Society-Leo and Anne Albert Charitable Foundation Research Scholar Grant, and Melanoma SPORE (P50CA168536).
Hypertrophic cardiomyopathy (HCM) is a prototypical inherited cardiomyopathy with well-defined sarcomeric genetic underpinnings that make it an attractive target for molecular therapy. We review recent advances in gene-based approaches for HCM, including adeno-associated virus-mediate gene replacement, allele-specific silencing, and emerging gene editing strategies, and highlight the first demonstrations of in vivo target engagement and early clinical translation. Early-phase studies suggest that restoration of sarcomeric biology can favorably impact molecular and structural disease features. We further discuss key challenges related to immune responses, delivery efficiency, response durability, and patient selection that will shape the next phase of development. Together, these developments establish HCM as one of the important early models for cardiac gene therapy and highlight both the promise and complexity of translating genetic insight into durable clinical benefit.
Macrophage-fibroblast crosstalk plays a critical yet incompletely understood role in cancer, fibrosis, and tissue repair. A central challenge is capturing the diversity of these cells, whose phenotypes are shaped by microenvironmental cues and developmental origins. Macrophage heterogeneity reflects the tissue-resident and bone marrow-derived lineages, while fibroblasts adopt distinct subsets defined by tissue context. Myofibroblasts can emerge from fibroblasts, monocytes, and other stromal cells. The lack of markers to distinguish these subpopulations remains a major barrier to defining their specific roles in pathological outcomes, including tissue injury, repair, and cancer. Together, macrophages and fibroblasts maintain tissue homeostasis and drive repair; however, disruptions in their crosstalk promote fibrotic remodeling and tumor-permissive microenvironments. Here, we review the origins, diversity, and roles of non-parenchymal macrophages and fibroblasts in fibrosis and cancer, highlighting key gaps and future directions to advance the field.
Background Glioblastoma is the deadliest brain cancer, characterized by large cellular diversity. Both neurodevelopment-like and mesenchymal-like cell states have been described, with the latter being strongly implicated in malignancy and disease progression. However, the spatial organization of these mesenchymal-like cell states has not been systematically described outside the tumor bulk. Methods We performed deep single-cell RNA sequencing of rare glioblastoma cases where tissue could be sampled from tumor core to macroscopically normal cortex and 888-plex enhanced electric single-molecule fluorescence in situ hybridization (EEL-FISH) spatial transcriptomics on a large cohort of standard resections. We also established four glioblastoma organoid lines to test in vitro inducibility of mesenchymal-like cell states under hypoxia and blood plasma exposure. Findings We discovered that previously defined mesenchymal-like tumor cell states were shared across both malignant and non-malignant cell types and spatially confined to the tumor bulk. Peripheral regions were instead dominated by neurodevelopment-like tumor states and endogenous microglia. In patient-derived organoids and non-malignant astrocytes, the mesenchymal transcriptional state could be reversibly induced in vitro by hypoxia and human plasma, indicative of a wound response. Multiplex single-molecule spatial transcriptomics revealed that the activation of mesenchymal-like states was associated with hypoxia and organized by distance to perivascular niches. Conclusions Our findings clarify the cellular landscape and biology of glioblastoma, wherein the mesenchymal state arises at least partly as a reactive tissue state shared by all cells in the tumor bulk. Funding This work was supported by Region Stockholm, Erling-Persson Family Foundation (Atlas of Childhood Disease), Hjärnfonden (FO2023-0309), Swedish Research Council (2022-01248), and Torsten Söderberg Foundation.
Background B cell-targeting chimeric antigen receptor (CAR) T cell therapy has shown efficacy in autoimmune diseases but is limited by toxicity, complex manufacturing, and high cost. Umbilical cord blood (UCB)-derived CAR-natural killer (CAR-NK) cells offer an alternative “off-the-shelf” platform with a potentially superior safety profile. We developed a UCB-derived CD19-targeting CAR-NK product incorporating the 4-1BB costimulatory domain (CD19-BBz) and evaluated its safety and efficacy in refractory systemic lupus erythematosus (SLE). This study was registered at ClinicalTrials.gov (ClinicalTrials.gov: NCT06421701). Methods In this phase 1, open-label, dose-escalation study, five patients with refractory SLE received lymphodepletion chemotherapy followed by infusion of allogeneic CD19-BBz CAR-NK cells. Dosing followed a step-up regimen, with the highest total dose being 1.35 × 109 cells—2.2- to 3.3-fold lower than the highest doses previously reported for CAR-NK therapy in SLE. Findings Treatment was exceptionally well tolerated. No grade ≥2 cytokine release syndrome and no neurotoxicity or graft-versus-host disease occurred. All patients achieved profound B cell depletion, with nadir circulating B cell levels ranging from 0.16 to 1.44 cells/μL. All patients achieved an SLE Responder Index-4 response by month 1. The lupus low disease activity state was attained in all patients by month 9, and 80% (4/5) met the definition of remission in SLE by the last follow-up (median, 12 months). Reconstituted B cells displayed a sustained naive-dominant repertoire. Conclusions Low-dose UCB-derived CD19-BBz CAR-NK cell therapy demonstrated an excellent safety profile and induced robust, durable clinical responses in refractory SLE. Funding This study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0501300).
