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The approval of resmetirom and semaglutide for fibrotic MASH has created an urgent need for tools that will aid identify candidates for drug therapy and assess response non-invasively. Existing NITs often misclassify patients with fibrotic MASH. Novel NITs may change the paradigm of MASLD management, but they need to be cost-effective, widely available, and reproducible to reach clinical practice.

The clinical success of cell-based immunotherapies has revolutionized treatment of cancer and other diseases by enabling precise and durable tumor targeting. However, while traditional ex vivo engineering of immune cells has demonstrated promise, these approaches are constrained by logistical, economic, and manufacturing challenges that hinder broad clinical adoption. In vivo immune engineering, which directly reprograms immune cells within the patient's body, is emerging as an attractive alternative to overcome these limitations and directly reshape the tumor microenvironment (TME) in situ and restore antitumor immunity. This review surveys current approaches to overcoming them through in vivo delivery platforms and therapeutic constructs to achieve direct in vivo gene editing. We further discuss key safety and efficacy considerations, such as biodistribution, gene expression control, immunogenicity, and tumorigenicity. Finally, we examine early clinical efforts and translational hurdles in bringing in vivo immune engineering strategies to the bedside.

Background: We integrate longitudinal health outcomes from the UK Biobank (UKBB) with our own Human Phenotype Project (HPP) cohort. The HPP contains a range of data per participant that are not found in the UKBB, including microbiome, liver ultrasound, continuous glucose monitoring, and more. Conversely, the UKBB includes a much larger cohort and longer follow-up durations with large numbers of disease outcomes already tracked.

Methods: To leverage the scale and extended follow-up of the UKBB in our study, we model disease outcomes in the UKBB to predict pseudo-outcomes in the HPP. Correlating these predicted pseudo-outcomes with unique measurements in the HPP study, we identify individual biomarkers for those conditions, including those from gut microbiome, liver ultrasound, and other modalities. Multivariate analysis identifies the contribution of each modality in predicting each pseudo-outcome.

Findings: Our method enabled us to recapitulate known biomarkers across the spectrum of diseases studied as well as to reveal less-attested biomarkers in a range of different modalities. We further identify systemic biomarkers correlated with many diseases and sex-specific biomarkers with higher correlation to a pseudo-outcome for one sex as compared to the other.

Conclusions: Our method enables analysis of biomarkers leveraging both the scale and follow-up of the UKBB and the unique measurements of the HPP. This analysis provides a broad perspective across the landscape of many diseases through the lens of many modalities, providing a framework for transferring knowledge from large longitudinal cohorts to smaller, more deeply phenotyped cohorts, advancing discovery across modalities.

Funding: E.S. is supported by the European Research Council and the Israel Science Foundation.

Background: The increasing incidence and expanding geographic distribution of emerging tick-borne viruses (TBVs) threaten global health. However, the understanding of their diversity and human pathogenicity remains insufficient.

Methods: We conducted an exhaustive literature review from 1990 to 2024 to identify all emerging TBVs in vectors and hosts. We established TBV-tick host associations and predicted the zoonotic potential of TBVs to infect humans using an RNA polymerase composition-based model, which was further validated by testing patient samples.

Findings: Our analysis identified 230 emerging TBVs across 23 families within 15 orders. The Phenuiviridae family had the highest number of TBVs, while the Flaviviridae family exhibited the broadest host range and highest ratio of human-infective to non-human-infective viruses. Haemaphysalis longicornis and sheep carry the highest number of TBVs among vectors and animals, respectively. A total of 19 emerging TBVs were identified as causative agents of human infection, with viral members within the Nairoviridae and Flaviviridae families posing higher zoonotic potential. Among the 128 emerging TBVs that underwent zoonotic modeling, 25 were classified as very-high-risk for causing human infection. Validation confirmed three human-infective viruses: Sara tick phlebovirus (STPV), Dabieshan tick virus (DBTV), and Shanxi tick virus 2 (SXTV2) were detected in 3.13% (28), 0.33% (3), and 0.67% (6) of 896 patients in Northeastern China, respectively.

Conclusions: We highlight TBV hotspots, priority vectors/hosts for surveillance, and high-risk viral families to mitigate zoonotic threats.

Funding: This work was funded by the National Key Research and Development Program of China (2023YFC2604403) and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2020-12M-5-001).

Background: The effectiveness and safety of combining intravenous tirofiban with methylprednisolone as an adjunct to endovascular thrombectomy (EVT) for acute ischemic stroke due to large-vessel occlusion are unknown.

Methods: This pooled analysis of randomized clinical trials included adult patients with large-vessel occlusion stroke within 24 h and an Alberta Stroke Program Early Computed Tomography Score of ≥6. Patients were grouped into EVT alone (control group), EVT plus tirofiban (tirofiban group), EVT plus methylprednisolone (methylprednisolone group), and EVT plus tirofiban and methylprednisolone (tirofiban-methylprednisolone group). The primary effectiveness outcome was 90-day disability as measured by the overall distribution of the modified Rankin scale scores (range, 0 [no symptoms] to 6 [death]). Safety outcomes included 90-day mortality and incidence of symptomatic intracranial hemorrhage within 48 h.

Findings: The pooled cohort contained 1,761 patients (median age, 68.0 years [interquartile range (IQR), 58.0-75.0]; 1,025 men [58.2%]). The median 90-day modified Rankin scale score was 2 (IQR, 1-4) in the tirofiban-methylprednisolone group, compared with 3 (IQR, 1-4) in the control group (adjusted common odds ratio, 1.34 [95% confidence interval [CI], 1.19-1.51]; p < 0.001). The tirofiban-methylprednisolone group had a lower mortality (15.9% vs. 18.4%; adjusted odds ratio, 0.76 [95% CI, 0.64-0.91], p = 0.008) and symptomatic intracranial hemorrhage (4.0% vs. 8.1%; adjusted odds ratio, 0.61 [95% CI, 0.47-0.80], p = 0.001) compared with the control group. No differences in these outcomes were found between tirofiban or methylprednisolone monotherapy compared with control.

Conclusions: Adjunctive tirofiban plus methylprednisolone during EVT improved functional outcomes in patients with large-vessel occlusion stroke undergoing EVT, without major safety concerns.

Funding: This work was funded by National Natural Science Foundation of China grants 82425021 and 82271349 and Noncommunicable Chronic Diseases-National Science and Technology Major Project 2024ZD0527905.

Background: Nasopharyngeal carcinoma (NPC), endemic to Southern China and Southeast Asia, presents significant clinical challenges. Immune checkpoint inhibitors (ICIs) have transformed NPC treatment but carry risks of immune-related adverse events (irAEs). Existing meta-analyses lack NPC-specific data, hindering targeted safety guidance.

Methods: This systematic review and meta-analysis, registered with PROSPERO (CRD420251003062), followed PRISMA guidelines. We searched PubMed, Embase, and Web of Science up to March 31, 2025, including all registered clinical trials of ICIs in NPC patients reporting irAEs.

Findings: A total of 27 clinical trials were included in the meta-analysis. The pooled incidence of all-grade irAEs in 2,296 patients was 69.1% (95% confidence interval [CI], 50.4%-80.7%), and that of grade 3 or higher irAE in 2,459 patients was 8.1% (95% CI, 6.1%-10.6%). Subgroup analyses revealed that there were no significant differences in the incidence of irAEs based on disease stages, lines of treatment, and combination treatment strategies. The main types of all-grade irAEs with an incidence rate greater than 1% are as follows: hypothyroidism (22.4%), rash (10.7%), pruritus (3.6%), increased aspartate aminotransferase (1.9%), increased alanine aminotransferase (1.8%), fatigue (1.6%), anemia (1.6%), pneumonia (1.5%), and hyperthyroidism (1.0%). A total of 17 patients died due to irAEs. Among these, sepsis was the most common cause of death, followed by pneumonitis.

Conclusions: This meta-analysis provides a comprehensive overview of irAEs in NPC patients treated with ICIs. These NPC-specific data emphasize the importance of vigilant monitoring for endocrine, cutaneous, and severe pulmonary or infectious complications to balance the efficacy and safety of ICIs.

Funding: Young Talent Program of Heyuan People's Hospital.

Background: A significant proportion of patients with myasthenia gravis (MG) remain refractory to standard immunosuppressive therapy, and biomarkers to help guide treatment decisions are lacking. We investigated whether refractory disease is associated with a distinct circulating immune profile.

Methods: We performed comprehensive immune phenotyping of peripheral blood from patients with acetylcholine-receptor-antibody-positive MG with differing treatment requirements and compared them with healthy controls. In a subset of refractory patients treated with anti-CD20 therapy, B cell reconstitution and clinical response were evaluated.

Findings: Refractory MG patients displayed the highest frequency of memory B cells and increased production of interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) upon Toll-like receptor/CD40 activation in vitro. These changes were accompanied by a dramatic loss of regulatory T cells (Tregs) and dendritic cells. Refractory MG was further characterized by elevated circulating complement proteins (C3, C5, and clusterin) and increased expression of complement receptors on lymphocytes. Following anti-CD20 therapy, residual plasmablasts persisted in circulation. Notably, a low baseline B cell frequency (<3%) was associated with poor clinical response to rituximab in refractory disease, although the sample size was limited.

Conclusions: Our findings define a distinct immune signature in refractory MG, identify potential biomarkers of treatment resistance, and highlight plasma cell depletion, IL-6 or complement inhibition, and Treg expansion as promising therapeutic avenues.

Funding: Funding was received from the NorthCare Charity, Myaware, the Academy of Medical Sciences, and the Neuromuscular Study Group.

Carcinoembryonic antigen (CEA) stands as a classic and widely applied tumor biomarker mainly for epithelial malignancies. Its restricted tumor expression pattern and role in cellular adhesion render it a promising therapeutic target. However, the translation of CEA into effective therapies has long been hindered by multiple challenges. As the first comprehensive review of CEA-targeted therapies, we leveraged peer-reviewed literature and officially disclosed global pharmaceutical data to delineate the landscape and evaluate the prospects across all subfields of CEA-targeted drug modalities, including antibody-drug conjugates, chimeric antigen receptor T cells, bispecific antibodies, vaccines, and radionuclide conjugates. We also dissected the underlying mechanisms of the challenges contributing to these setbacks. By proposing multifaceted and innovative strategies, this review facilitates CEA's transition from a diagnostic and predictive biomarker to a viable therapeutic target, ultimately supporting improved clinical outcomes for patients with CEA-expressing cancers.

Background: Pharmacotyping, the ex vivo measurement of tumor cell responses to drugs, is particularly important for cancers lacking actionable genomic markers. However, current pharmacotyping methods are not clinically feasible due to prolonged drug incubations (days to weeks), extensive manual handling, and analytical limitations, including overlooking single-cell characteristics. Addressing these hurdles is critical for pediatric T cell acute lymphoblastic leukemia (T-ALL), an aggressive cancer with limited therapeutic options.

Methods: We developed μPharma, a pharmacotyping platform that predicts single-cell drug sensitivity without direct drug exposure by quantifying pretreatment biomarkers associated with therapeutic response. μPharma integrates an automated digital microfluidic immunofluorescence assay, optimized for suspension cells, with machine learning models trained on comprehensive single-cell features. We validated μPharma using T-ALL cell lines and patient-derived xenografts, predicting sensitivity to dasatinib and venetoclax by quantifying their target proteins, LCK and BCL2, respectively, including protein expression, phosphorylation status, spatial distribution, and cellular morphology.

Findings: We confirmed that phospho-LCK is predictive of dasatinib sensitivity, consistent with prior studies, and identified phospho-BCL2 as a previously unreported biomarker for venetoclax sensitivity. Integrating multiple biomarkers into machine learning models significantly enhanced predictive accuracy compared to single-marker analyses. Key informative features included spatial protein distribution and integrated protein-morphology metrics. Additionally, single-cell analysis revealed distinct cell subpopulations, suggesting intratumor heterogeneity in drug responses.

Conclusions: μPharma provides rapid (4-h assay), accurate, and automated prediction of drug sensitivity at single-cell resolution using minimal clinical samples, potentially enabling same-day precision oncology decision-making.

Funding: This work was supported by institutional start-up funds from the University of Utah, including internal supplements provided through the Immunology, Inflammation & Infectious Disease (3i) Initiative and the Diabetes & Metabolism Research Center (DMRC).

Background: Severe acute respiratory distress syndrome (ARDS) complicated by necrotizing pneumonia and septic shock carries a mortality exceeding 80%. Lung transplantation is rarely pursued because persistent sepsis, uncertainty regarding the reversibility of parenchymal injury, and profound hemodynamic instability preclude candidacy.

Methods: We developed an extracorporeal total artificial lung (TAL) system to enable bilateral pneumonectomy for source control in a patient with ARDS complicated by necrotizing pneumonia and refractory septic shock. The system incorporated a flow-adaptive right pulmonary artery-to-right atrial shunt to compensate for loss of pulmonary vascular capacitance, extracorporeal oxygenation, and dual left atrial return conduits to maintain physiologic transcardiac blood flow. In parallel, we performed single-cell and spatial transcriptomic profiling of the explanted lungs to define associated cellular and molecular changes.

Findings: Following pneumonectomy, vasopressor requirements resolved, and the patient remained fully supported until transplant. Transcriptomic profiling revealed diffuse, uniform destruction across all regions, with dense infiltration by neutrophils, monocyte-derived alveolar macrophages, and activated T cells. These inflammatory changes coexisted with marked expansion of aberrant basaloid epithelial cells and CTHRC1-positive myofibroblasts, with near-complete loss of normal alveolar architecture. Molecular signatures recapitulated end-stage fibrotic lung disease and were consistent with irreversible injury rather than a recoverable ARDS phenotype. The patient demonstrates excellent cardiopulmonary function 2 years after transplantation.

Conclusions: An extracorporeal TAL system can permit safe bilateral pneumonectomy for source control in otherwise non-transplantable patients with medically refractory pneumonia, providing a viable salvage strategy to bridge selected patients to successful lung transplantation.

Funding: This project was funded through NIH grants HL145478, HL147575, HL173940, and P0HL169188.