Guo et al. report a nationwide multicenter registry of patients with ischemic stroke due to distal medium vessel occlusion. Endovascular treatment was associated with modestly higher freedom from disability but more symptomatic intracranial hemorrhage, supporting a more individualized benefit-risk assessment. The results need further prospective randomized evaluation.

Clinically implementable biomarkers predicting immunochemotherapy response are lacking. Fuchs et al. comprehensively molecularly profiled longitudinal and multi-sites tissue/tumor samples from 73 esophageal cancer patients in LUD2015-005 trial receiving 4-week immunotherapy priming prior to combination-therapy and identified TMC-related five-gene signature CFISH and DNA methylation subtypes that predict patient overall survival to immunochemotherapy.

Cancer plasticity allows tumors to evade targeted therapy through histological transformation, acquiring alternative lineage and differentiation states that bypass the drug’s target. This review examines the drivers of these transformations and proposes that anticipating, monitoring, and timing therapy to a tumor’s changing phenotype may preempt resistance and advance precision oncology.

Yao et al. identify reproducible genome-wide DNA features in red blood cells associated with gastric cancer, using 1–2 mL of blood. A classifier based on these features detects early-stage disease and shows consistent performance across three independent hospital-based cohorts, supporting further development of rbcDNA for non-invasive gastric cancer detection.

This systematic review and meta-analysis found no clearly detectable increase in adverse maternal or perinatal outcomes after periconceptional glucagon-like peptide-1 receptor agonist exposure on the basis of available evidence. However, observational design, heterogeneity, residual confounding, and limited datasets mean that these findings do not establish safety or support continued treatment during pregnancy.

Thordsen and Arany review changes in maternal physiology that occur during pregnancy and highlight how these changes contribute to or exacerbate various common cardiovascular pathologies. They discuss modern management of cardio-obstetric conditions and highlight the importance of multidisciplinary care for optimal outcomes.

Shao et al. report a carrier-free enzyme-engineering strategy by thiolation of recombinant human catalase for treating dry eye disease. Such thiolated enzyme with sustained ocular retention shows potent efficacies in treating various preclinical dry eye disease animal models and preliminarily demonstrates safety and therapeutic performance in a first-in-human study.

Chronic kidney disease (CKD) has an underdiagnosis rate of over 60%, and high-risk populations are not routinely screened. Here, Yuan et al. develop and externally validate a deep learning model to detect CKD from echocardiography, offering a promising avenue to enable earlier screening and close diagnostic gaps.

Huang et al. identify an adult plasma proteomic signature associated with recalled very low birth weight (VLBW). The index is associated with adult disease burden and subsequent disease risk, but is not VLBW specific, supporting hypothesis-generating links between birth history, adult molecular state, and later-life disease.

Cousin et al. report an individualized antisense oligonucleotide for CHCHD10-related ALS. In one participant, six intrathecal doses were well tolerated, plasma neurofilament light decreased to the reference range, and functional and respiratory measures were stable or modestly improved, supporting further evaluation of CHCHD10-directed therapy.

Tanner et al. show that prenatal DEHP exposure increases autism and ADHD symptoms via epigenetic programming. Using a systems-biology framework, they identified cord blood DNA methylation signatures that mediate these neurotoxic effects. These signatures involve key neurodevelopmental gene networks and replicate across independent blood and postmortem brain datasets.

Fan et al. show that higher cardiovascular-kidney-metabolic stage is associated with graded increases in both cardiovascular and liver-related events across the steatotic liver disease spectrum. Obesity and hypertension are the leading modifiable contributors, whereas diabetes contributes disproportionately to liver-related outcomes.

Xiao et al. report results of a randomized phase II trial showing that pomalidomide plus bortezomib-dexamethasone (PVd) significantly improves hematologic and renal responses compared with bortezomib-dexamethasone in newly diagnosed multiple myeloma patients with renal impairment, supporting PVd as a feasible induction option for this underserved population.

Agnesi et al. show that trunk movements can modulate epidural spinal cord stimulation in people with motor-complete spinal cord injury. Trunk extension switches stimulation-induced lower-limb activity from extension to triple flexion, enabling participants to control stepping through their residual trunk movements.

Li et al. developed an optimized ex vivo expansion platform and evaluated cancer-patient-derived MAIT cells for adoptive liver cancer therapy. Antigen stimulation, IL-15, and dual PD-1/TIGIT blockade enhanced antitumor activity, persistence, and therapeutic efficacy, supporting MAIT cells as a promising next-generation immunotherapy for liver cancer.

Compared with the extensively studied gut virome, viruses inhabiting the upper aerodigestive tract remain poorly characterized. Zou et al. establish a comprehensive viral genome catalog that expands knowledge of oral and airway viruses and reveals their associations with respiratory health.

Knight et al. present the first molecularly validated case of metastatic melanoma that divergently evolved into rhabdomyosarcoma under treatment with immune checkpoint inhibitor. Longitudinal multiomic profiling revealed that this divergence was characterized by transcriptional changes rather than genetic mutations, providing insights into the mechanisms of lineage plasticity.

Yong et al. integrate plasma lipidomics, metabolomics, exosome proteomics, and exosome-treated cell transcriptomics to characterize immunometabolic alterations in MPXV-monoinfected and MPXV-HIV-coinfected patients. They identify reproducible lipid and metabolite signatures, with HIV co-infection associated with greater inflammatory, metabolic, and vesicle trafficking disruptions.

Wan et al. develop Dolphin, a bimodal large language model that integrates audio and text to improve emotional-semantic alignment in patient education. In a double-blinded randomized trial, Dolphin improved patient experience, increased disclosure of clinically relevant concerns, and reduced 7-day unplanned recontact compared with a matched text-based LLM comparator.

A Bayesian meta-analysis of 28 randomized and observational studies suggests that concomitant use of anticoagulant and lipid-lowering therapy may reduce recurrent venous thromboembolism risk beyond anticoagulants alone, without increasing bleeding risk. The evidence is consistent across study types and may be mediated, at least in part, by reducing inflammation.

The phase 3 CAPITAL trial demonstrates that adjuvant oxaliplatin plus S-1 (SOX) significantly improves OS and DFS relative to S-1 monotherapy in patients with resected stage II–III gastric or GEJ adenocarcinoma. With a manageable safety profile, these findings support SOX as a superior adjuvant standard-of-care for high-risk patients.

Goel et al. report a mixed-methods randomized pilot trial evaluating ketamine, psychotherapy, and combined ketamine plus psychotherapy for chronic neuropathic pain. The combined intervention was feasible to deliver and acceptably safe, supporting a larger efficacy-powered trial, while exploratory clinical outcomes remain hypothesis-generating.

Yu et al. develop an engineered mesenchymal stem cell-liposome conjugate that homes to fibrotic lesions and releases ISRIB and NMN in response to reactive oxygen species. This platform regulates pathological integrated stress response activation, restores epithelial stress homeostasis, promotes tissue repair, and ameliorates pulmonary and liver fibrosis.

This study maps plasma-protein mediators linking diabetes, hypertension, and dyslipidemia to cardiovascular, neurological, renal, and pulmonary complications using longitudinal UK Biobank proteomics. Through mediation analysis, Mendelian randomization, and machine learning, the authors identify clinically accessible protein biomarkers that improve downstream disease risk prediction and nominate candidate therapeutic targets.

With the emergence of gene-based therapies for hypertrophic cardiomyopathy, it is imperative to have a developmental framework encompassing evaluation, safety, endpoint definition, long-term surveillance, and considerations of equity and scalability. Harmonization across these domains is essential to ensure that early clinical signals are interpretable, comparable, and translatable into durable patient benefit.

Karapetyan et al. identify immunologic features of TIL infusion products and tumor microenvironments associated with clinical benefit in metastatic melanoma. Stem-like and LAG-3+CD8+ T cells, enhanced TIL persistence, and tertiary lymphoid structure-rich tumors predict response, providing a framework for optimizing TIL therapy and patient selection.

The authors review recent advances in gene-based approaches for hypertrophic cardiomyopathy, including adeno-associated virus-mediated gene replacement, and emerging gene editing strategies and highlight the first demonstrations of in vivo target engagement and early clinical translation. They highlight both the promise and complexity of translating genetic insight into durable clinical benefit.

Without proactive policies and interventions in LMICs and LICs, the age-standardized prevalence of mental disorders is projected to continue increasing through 2050. These findings highlight the critical need for proactive strategies to address the growing burden of mental disorders, particularly in resource-limited settings.

Mossi Albiach, Janusauskas, Jacobsen et al. use single-cell RNA sequencing and spatial transcriptomics across glioblastoma core-to-periphery biopsies to show that mesenchymal-like cell states represent a tissue-wide wound response to hypoxia and vascular leakage, spatially confined to the tumor bulk, inducible and reversible in organoids, and organized by perivascular hypoxia gradients.

Zeng et al. show that low-dose allogeneic cord blood-derived CD19-BBz CAR-NK cells are well tolerated in five patients with refractory SLE, inducing profound B cell depletion, naive-dominant B cell reconstitution, and durable clinical responses.

This review argues that heritable gene editing should be assessed by target, distinguishing catastrophic monogenic disorders, polygenic risk reduction, and non-disease enhancement. Within a welfare-centric framework, the authors hold that editing is permissible—and perhaps obligatory—for catastrophic monogenic conditions, premature for polygenic traits, and least justified at present for enhancement.

Ning et al. review the origins, phenotypes, and crosstalk of macrophages and fibroblasts across fibrosis and cancer, highlighting how tissue context and developmental lineage shape their distinct subpopulations. Using an engineered tissue lens, the authors identify and suggest future directions for parsing these complex stromal relationships within pathological microenvironments.

Xu et al. present a unified multi-task transformer for chest radiograph analysis that integrates classification, localization, segmentation, and report generation. The framework enables interpretable diagnosis through evidence-linked reasoning and demonstrates strong performance across benchmarks, with radiologist evaluation confirming clinical relevance and report quality.

Using single-cell spatial multi-omics profiling of 44 HNSCC tumors, An et al. identify recurrent tumor ecosystem states associated with HPV status, tumor cell programs, and clinical outcome. Fibroblast-rich, immune-poor ecosystems are associated with adverse features and characterize a high-risk subset of HPV-positive tumors, highlighting clinically relevant heterogeneity beyond HPV status.

Lv et al. developed a deep-learning framework, ASOMAR, to design a genotype-inclusive antisense oligonucleotide targeting processing-deficient progeroid laminopathies with transcript-level specificity. This therapeutic candidate safely reversed cardiovascular pathology in patient-derived 3D cardiac organoids and dramatically improved the lifespan and healthspan of progeria mouse models.

This systematic review synthesizes randomized and phase 2 evidence through June 2025 to guide treatment sequencing in advanced cholangiocarcinoma. Chemotherapy with durvalumab is the default first line, while biomarker-matched targeted agents deliver longer disease control than cytotoxic regimens, supporting early comprehensive genomic profiling and improved access to precision medicine worldwide.

Liu et al. map associations between 505 multimodal brain imaging features and 756 incident diseases, establishing a comprehensive brain-disease risk atlas. The study identifies white matter microstructure as a central cross-system hub, advancing understanding of neuroimaging in disease risk assessment and future neuromodulatory research.

Stopping long-term treatments can trigger withdrawal effects, transient increases in clinical risk that exceed loss of therapeutic benefit alone. These under-recognized phenomena, observed across diverse drug classes and diseases, may distort research evidence and clinical decision-making, highlighting the need to treat treatment discontinuation as a distinct high-risk phase.

Parenteral nutrition during neonatal infection may actively shape immune and metabolic responses rather than merely support growth. The authors propose that parenteral nutrition strategies could be aimed at supporting immune function by targeting glucose, lipid, and amino acid metabolism, which could improve recovery in critically ill preterm infants.

Zhou et al. review why conventional power calculations often fail in human microbiome studies, where sparse, compositional, and highly variable data complicate study design. They provide practical guidance on sample-size estimation, longitudinal cohorts, and simulation-based planning to improve reproducibility and accelerate clinically relevant microbiome discoveries.

Yin et al. report the phase 3 SURPASS-CN-MONO trial, providing the first data supporting tirzepatide monotherapy in Chinese patients with early type 2 diabetes. Once-weekly tirzepatide significantly improved glycemic control and led to robust body weight reductions vs. placebo, without increasing the risk of clinically meaningful or severe hypoglycemia.

Orofino, Genchi et al. report two patients with severe, treatment-refractory neuromyelitis optica who achieved sustained, immunosuppression-free remission for over 15 years following allogeneic hematopoietic stem cell transplantation. Pathogenic AQP4-IgG antibodies permanently disappeared post-transplant, accompanied by stable donor-derived immune reconstitution, suggesting that immune system replacement may represent a potentially curative strategy in selected cases.

Single-cell profiling reveals distinct origins and differentiation trajectories of alveolar CD8+ exhausted T cells in checkpoint inhibitor pneumonitis versus radiation pneumonitis. These findings identify potential biomarkers for differential diagnosis and provide guidance for clinical decision-making, including immunotherapy rechallenge in lung cancer patients.

Guo et al. used deep learning to quantify multiple abdominal organs on routine CT scans from a large multicenter cohort of patients with hepatocellular carcinoma and healthy controls. Their results suggest that multi-organ remodeling is associated with prognosis across immunotherapy, transarterial chemoembolization, and surgical resection cohorts.

This single-patient case report expands the indications in which CD19 CAR-T cell therapy demonstrates unprecedented clinical efficacy, achieving sustained, treatment-free remission. Following B cell abrogation, AIHA is stopped, antiphospholipid antibodies are abrogated, and an underlying ITP is stabilized without any CAR-typical side effects.

Giron et al. identify glycomic degradation, including loss of the anti-inflammatory glycans galactose and sialic acid, as a link between chronic viral infection, inflammation, and cognitive decline in people with HIV, especially women. In complementary mouse models, preserving sialylation with sialidase inhibitors prevented virus-mediated inflammation, accelerated aging, and memory deficits.

Gene therapies have transformative potential for genetic diseases but pose challenges for traditional health economic evaluations. Their unique features complicate cost-effectiveness analysis, often leading to perceptions of overpricing. As use expands beyond rare diseases, improved value frameworks and financing models are essential to balance access, affordability, sustainability, and ongoing innovation.