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6 recordsLinked to original sources
PubMed2026

Intravenous thrombolysis for ischemic stroke in extended time window selected with CT perfusion: a systematic review and meta-analysis.

PURPOSE: Recent randomized controlled trials (RCTs) have provided new evidence regarding the efficacy and safety of intravenous thrombolysis (IVT) in patients with acute ischemic stroke (AIS) presenting within the extended time window (ETW). We performed a systematic review and meta-analysis to evaluate the efficacy and safety of IVT, in patients treated within the ETW and selected with perfusion imaging criteria, predominantly computed tomography perfusion (CTP). METHODS: A systematic review and meta-analysis, registered in PROSPERO, was conducted including all available RCTs comparing IVT with best medical treatment (BMT) in patients with AIS within the ETW, selected using advanced perfusion imaging criteria. The predefined efficacy outcomes were excellent functional outcome and good functional outcome at 3 months. The safety endpoints included symptomatic intracranial hemorrhage (sICH) and all-cause mortality at 90 days. RESULTS: Six RCTs, including 1182 patients treated with IVT and 1176 patients receiving BMT, were included. IVT was associated with a higher likelihood of achieving excellent and good functional outcomes at 3 months. Exploratory subgroup analyses by treatment timing suggested consistent findings up to 24 hours. No significant difference in 90-day mortality was observed between groups, whereas IVT was associated with an increased risk of sICH. CONCLUSION: Treatment with IVT in the ETW (4.5-24 h) in patients selected using advanced perfusion imaging, predominantly CTP, may be associated with improved functional outcomes in patients with AIS. Although IVT was associated with an increased risk of sICH, no significant increase in 90-day mortality was observed. PROSPERO REGISTRATION: CRD420261304314.

Aged↗
PubMed2026

Extending the Treatment Window for Intravenous Thrombolysis in Acute Ischemic Stroke: An Updated Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Intravenous thrombolysis (IVT) is the standard treatment for acute ischemic stroke within 4.5 hours of onset. However, imaging-based selection may extend the treatment window. This systematic review and meta-analysis evaluated the efficacy and safety of IVT administered beyond 4.5 hours after stroke onset or last known well (LKW) in patients selected based on imaging findings. METHODS: A comprehensive search of PubMed, Scopus, and Cochrane Library was performed to identify randomized controlled trials comparing IVT with alteplase or tenecteplase (TNK) administered >4.5 hours after stroke onset/LKW vs standard care. Primary outcomes were 3-month excellent (modified Rankin Scale [mRS] 0-1) functional outcome and symptomatic intracranial hemorrhage (sICH). Secondary outcomes included good (mRS 0-2) functional outcome, recanalization, and 3-month mortality. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random-effects models. Subgroup analysis assessed differences between alteplase and TNK. RESULTS: Fourteen studies involving 4,944 patients were included. The mean age was 69.8 years, 58.2% were male, the median National Institutes of Health Stroke Scale score was 9, and 12.3% received preplanned endovascular thrombectomy (EVT). A total of 2,492 patients received IVT in an extended time window (4.5-24 hours). Compared with standard care, extended IVT was associated with higher odds of achieving an excellent functional outcome (OR: 1.43 [95% CI 1.25-1.63]), a good functional outcome (OR: 1.25 [95% CI 1.11-1.40]), and recanalization (OR: 3.28 [95% CI 2.09-5.16]). There was no difference in 3-month mortality (OR: 1.21 [95% CI 0.95-1.53]). However, IVT increased the risk of sICH (OR: 2.51 [95% CI 1.47-4.28]). Sensitivity analysis excluding patients who received EVT showed no impact on the outcomes. TNK exhibited similar efficacy to alteplase but showed potentially lower odds of sICH (OR: 1.96, 95% CI 1.06-3.64) compared with alteplase (OR: 5.29, 95% CI 1.80-15.57); however, the subgroup difference was not significant (p = 0.11). DISCUSSION: Among patients selected based on imaging, 4.5-24 hours after stroke onset/LKW, IVT improves outcomes despite an increased risk of sICH. TNK showed similar efficacy to alteplase, with a possible lower risk of sICH; however, direct comparisons in future trials are needed.

Humans↗
PubMed2026

Endovascular treatment after stroke beyond 24 h vs 6-24 h: a propensity score-matched cohort study.

BACKGROUND: Endovascular thrombectomy (EVT) is the standard treatment for acute ischemic stroke due to anterior circulation large vessel occlusion (LVO) within 6-24 h. However, the safety and feasibility of EVT for anterior circulation strokes beyond 24 h remain uncertain. METHODS: We conducted a retrospective cohort study of consecutive patients with anterior circulation LVO who underwent EVT at Changhai Hospital from 2018 to 2023. Patients were stratified into late (6-24 h) and very late (>24 h) windows. Propensity score matching (PSM) was performed to adjust for baseline imbalances, including age, sex, NIHSS, ASPECTS, occlusion location, perfusion parameters, and vascular risk factors. The primary outcome was functional independence (modified Rankin Scale [mRS] ≤ 2) at 3 months. Secondary outcomes included successful reperfusion (TICI 2b-3) and symptomatic intracranial hemorrhage (sICH). RESULTS: Among 1043 screened patients, 429 patients with anterior circulation LVO were included after exclusions, comprising 373 in the late window and 56 in the very late window. PSM yielded 42 matched pairs. Compared with the late window group, the very late window group showed no statistically significant differences in functional independence (54.8% vs. 57.1%; OR = 0.908, 95% CI 0.382-2.153, p = 0.830), successful reperfusion (88.1% vs. 92.9%; OR = 1.800, 95% CI 0.481-7.096, p = 0.460), sICH (2.4% vs. 9.5%; OR = 0.232, 95% CI 0.012-1.652, p = 0.200), intraprocedural complications (26.2% vs. 19.0%; OR = 1.508, 95% CI 0.540-4.362, p = 0.440), or postoperative complications (33.3% vs. 35.7%; OR = 0.900, 95% CI 0.363-2.219, p = 0.820). CONCLUSIONS: In this selected, single-center cohort of anterior circulation LVO patients undergoing EVT, treatment initiated beyond 24 h appeared to have comparable effectiveness and safety to treatment initiated within 6-24 h. Definitive evidence requires confirmation from adequately powered randomized controlled trials.

Humans↗
PubMed2026

Monitoring kinetic changes and restriction of influenza A virus RNA species during infection using a Flu-Stranded CRISPR platform.

UNLABELLED: Influenza A virus (IAV) generates three closely related RNA species: viral RNA (vRNA), complementary RNA (cRNA), and messenger RNA (mRNA), whose strand-specific quantification remains limited by sensitivity and quantitative dynamic range, particularly at low RNA abundance. Here, we developed Flu-Stranded CRISPR-Cas12a, a strand-specific detection platform integrating tagged reverse transcription, segment-specific PCR, and Cas12a collateral cleavage to support quantitative analysis of all three RNA species across a broad dynamic range. The assay enables reliable detection down to 102 copies per reaction, extending the lower quantitative boundary relative to both SYBR Green and TaqMan reverse transcription quantitative PCR (RT-qPCR) under matched conditions. Validated in infected cell lines, murine lung tissues, and clinical nasopharyngeal specimens, the platform enabled subtype-discriminating, strand-resolved detection, including samples near or below the quantitative range of SYBR Green RT-qPCR. Using finely resolved infection time-course analyses in NP and NA segments, we identified a reproducible early vRNA decline within the early post-infection phase. This decline was partially attenuated in RIG-I knockout A549 cells, while subsequent vRNA accumulation was enhanced, consistent with a modulatory rather than essential role for RIG-I in early viral RNA dynamics. Subcellular fractionation localized this decline to cytoplasmic incoming genomes. In contrast, importazole-mediated inhibition of nuclear import abolished vRNA recovery without affecting the early decline, indicating that nuclear entry functionally separates early genome reduction from subsequent productive replication. These findings establish Flu-Stranded CRISPR-Cas12a as a strand-resolved framework for monitoring IAV RNA dynamics and reveal an early window of genome vulnerability during cytoplasmic transit that shapes infection outcome. IMPORTANCE: The early fate of incoming influenza virus genomes remains unclear, limiting our understanding of how infection is established or aborted in host cells. We developed Flu-Stranded CRISPR-Cas12a, a strand-specific platform for sensitive and quantitative analysis of influenza viral RNA (vRNA), complementary RNA (cRNA), and messenger RNA (mRNA) across experimental and clinical samples. Using high-resolution time-course analysis, we identified a reproducible early decline in vRNA during the post-entry phase. Our data suggest that this early genome loss arises from multiple processes, with RIG-I acting as a modulatory factor rather than a primary driver. Subcellular fractionation localized this effect to cytoplasmic incoming genomes, whereas importin-β-mediated nuclear entry was required for subsequent vRNA recovery. These findings support a model of an early cytoplasmic phase of genome attrition that is distinct from replication and provide a framework for understanding early influenza RNA kinetics and for guiding strand-resolved diagnostics and antiviral evaluation.

CRISPR-Cas12a↗
PubMed2026

Beyond Morphology: Reframing Lymph-Node Metastasis Prediction Through Clonal Ecology-Decades-Long Genomic Instability and Polyclonal-to-Monoclonal Transitions as the Missing Dimension in Cancer.

Recent whole-genome, lineage-tracing, single-cell, and spatial studies have reshaped our understanding of tumor evolution, revealing that cancers can arise from polyclonal populations, undergo decades-long genomic instability before clinical detection, and progress through dynamic changes in subclonal composition, cellular state, and ecological organization. These findings challenge the assumption underlying morphology-based prediction models that metastatic risk can be inferred from static histological features alone. Here, we revisit lymph-node metastasis prediction in colorectal cancer through clonal ecology, integrating computational pathology with evolutionary oncology. Drawing on the subclonal switchboard model proposed in 2012 and subsequent artificial intelligence (AI)-enabled approaches for tracking dominant and dormant subclones, we synthesize evidence that metastatic potential reflects clonal ancestry, evolutionary timing, spatial niche architecture, cellular plasticity, intercellular interactions, dormancy, and treatment-driven shifts in subclonal fitness. We define five complementary methodological pillars for operationalizing clonal ecology: single-cell transcriptomics for resolving rare subclones, evolutionary trajectories, and adaptive cell states; lineage tracing and phylogenetics for reconstructing clonal ancestry and divergence; spatial transcriptomics and genomics for mapping subclonal geography and tumor-stromal-immune interactions; longitudinal liquid biopsy surveillance for monitoring residual disease, clonal turnover, and emerging resistance; and AI-enabled multimodal integration for connecting histopathology, genomics, spatial biology, and longitudinal data into predictive ecological-state models. Multiple-instance learning and pathology foundation models provide scalable computational foundations for evolution-aware prediction. Translationally, dormant subclones represent actionable reservoirs of recurrence. A longitudinal clinical and experimental study of KMT2A-rearranged acute myeloid leukemia further supports central predictions of the subclonal switchboard framework by demonstrating treatment-associated shifts in subclonal dominance, persistence of cryptic adaptive programs, and ecological rewiring during resistance and relapse. We propose clonal ecology as a measurable dimension for extending morphology-driven prediction toward integrative models that anticipate evolutionary transitions, identify therapeutic windows, and proactively constrain adaptive tumor ecosystems before resistant or metastatic subclones achieve clinical dominance.

Humans↗
PubMed2025

RESTRICT-seq enables time-gated CRISPR screens and uncovers novel epigenetic dependencies of SCC resistance.

Cancer cell evasion of therapy is a highly adaptive process that undermines the efficacy of many treatment strategies. A significant milestone in the study of these mechanisms has been the advent of pooled CRISPR knockout screens, which enable high-throughput, genome-wide interrogations of tumor dependencies and synthetic lethal interactions, advancing our understanding of how cancer cells adapt to and evade therapies. However, the utility of this approach diminishes when applied to dynamic biological contexts, where processes are transient and sensitivity to routine cell culture manipulations that introduce noise and limit meaningful discoveries. To overcome these limitations, we present RESTRICT-seq, a next-generation pooled screening methodology that restricts Cas9 nuclear activation in controlled, repeated cycles. By confining Cas9 catalytic activity to strict temporal windows, RESTRICT-seq mitigates undesired fitness penalties that routinely accumulate throughout pooled screens. When benchmarked against conventional pooled screens and standard inducible protocols, RESTRICT-seq revealed significantly fewer divergent cell clones and increased signal-to-noise ratio, overcoming a key limitation of traditional methods. Leveraging RESTRICT-seq, we conducted a comprehensive functional survey of the druggable mammalian epigenome, uncovering several elusive epigenetic drivers of treatment resistance in cutaneous squamous cell carcinoma (cSCC). This revealed PAK1 as a previously unrecognized mediator of cSCC resistance in human and mouse SCC, offering new insights into a prognostic marker and therapeutic target of high clinical significance. Our findings establish RESTRICT-seq as a powerful tool for extending the applicability of pooled CRISPR screens to dynamic and previously intractable biological contexts.

Allosterically-regulated Cas9 (arCas9)↗