Citations

SummaryTo assess the relevance of co‐occurring somatic mutations in TP53‐mutated myeloid neoplasms with ≥10% blasts, we pooled 325 individuals from 10 centres. We focused on comparing three published somatic co‐alteration signatures comprising (1) nine MDS‐related genes (‘ICC‐MDSR’), (2) ICC‐MDSR + additional secondary mutations‐related genes (‘Tazi signature’) and (3) EPI6 (comprising six genes). Outcomes examined were 24‐month overall survival (OS24) and front‐line complete response (CR1). The median age was 69 years with 77% receiving front‐line hypomethylating agents (HMA). All three signatures ICC‐MDSR (p = 0.009), Tazi signature (p = 0.001) and EPI6 (p = 0.025) predicted inferior CR1. In the low‐intensity (HMA) subgroup, only Tazi signature (p = 0.026) predicted inferior CR1. In OS24 analysis of the HMA‐treated subgroup (N = 200), only Tazi signature was adverse (hazard ratio, HR = 1.6 [1.1–2.2]; p = 0.011). However, a forward stepwise multivariable age‐adjusted Cox model including all three signatures picked EPI6 as the sole significant adverse predictor in the entire cohort (p = 0.0001) as well as within the HMA‐treated subgroup (p = 0.0071). These data confirm the value of testing co‐occurring somatic alterations even within a high‐grade TP53‐mutated myeloid neoplasm cohort.

Background: About 25% of patients with acute myocardial infarction complicated by cardiogenic shock (AMI-CS) have chronic total occlusion (CTO) at non-culprit artery. However, the prognostic impact of CTO in these patients is still unclear. Aims: We aimed to investigate the impact of CTO at non-culprit artery on 1-year mortality in patients with AMI-CS using the multicenter registry of cardiogenic shock. Methods: A total of 1,247 patients presented with cardiogenic shock (CS) were enrolled in the SMART-RESCUE registry between January 2014 and December 2018. After exclusion of non-ischemic cause shock, ischemic cardiomyopathy, failed or no revascularization, vasospasm, and patients undergoing coronary artery bypass surgery, 695 patients underwent percutaneous coronary intervention (PCI). Among these, we analyzed 536 patients with multivessel disease (MVD) according to the presence of CTO at non-culprit artery. The study endpoint was a 1-year all-cause mortality. We also examined the incidence of 1-year cardiac death, and in-hospital death or renal replacement therapy (RRT). Results: A 141 patients (26.3%) of study population had CTO lesion at non-culprit artery. The CTO group had more patients with diabetes mellitus, and lesser patients with ST-elevation myocardial infarction. Although initial left ventricular ejection fraction was lower in CTO group (28.5 vs. 34.1%, P=0.005), initial systolic blood pressure (73.8 vs. 73.2 mmHg, P=0.822) and the level of lactate (6.6 vs. 6.4 mmol/L, P=0.804) were similar in both groups. Venoarterial extracorporeal membrane oxygenation was applied in 206 patients (38.4%), and its use rate was comparable in 2 groups (40.4 vs. 37.7%, P=0.571). Pre- (32.9 vs. 22.9, P <0.001) and post-PCI SYNTAX score (16.7 vs. 5.3, P <0.001) was significantly higher in CTO group. In CTO group, 53 patients (37.6%) had CTO at left main or left anterior descending artery, and only 19 patients (13.5%) in CTO group received PCI for CTO. In multivariate analysis, all-cause mortality at 1-year was significantly higher in CTO group (51.8 vs. 40.5%, hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.09-1.90, P=0.011). The incidences of 1-year cardiac death (45.4 vs. 32.4%, HR 1.55, 95% CI 1.15-2.10, P=0.004) and in-hospital death or RRT (46.8 vs. 36.5%, P=0.031) were also higher in CTO group. Conclusions: Non-culprit CTO lesion was associated with higher 1-year mortality in patients with AMI-CS and multivessel disease.

Abstract The extracellular matrix (ECM) plays a critical role in cancer progression, with its biophysical properties influencing cancer behavior. ECM stiffness can induce long-lasting adaptations in cancer cells, promoting sustained invasion through a process known as “mechanical memory” (MM). Glioblastoma (GBM) exhibits spatial heterogeneity in stiffness, with stiffer ECM found at the tumor periphery where invasive cells reside and promote recurrence. We hypothesize that increased stiffness at the tumor periphery primes GBM cells for sustained invasion through MM. METHODS Cell lines were established from image-guided human GBM samples from tumor margin and core (n=10 patients, 20 cell lines). Cells from random locations were conditioned in physiologically relevant extracellular matrices for two weeks. Human organotypic assay (n=3), Migration Assays, Atomic Force Microscopy (AFM), Immunocytochemistry, Western Blot, and RNA-sequencing (n=6) were performed. RESULTS GBM cells at higher stiff surfaces displayed increased migration (p&lt;0.01). Magnetic Resonance Elastography (n=9) confirmed GBM heterogeneity, with softer cores (0.2-0.5kPa) transitioning to stiffer margins (&gt;2kPa). Organotypic scaffolds mimicking the tumor margin promoted enhanced migration of GFP-labeled GBM cells. Margin cells and cells conditioned on stiffer matrices demonstrated higher migratory potential compared to their core and soft-conditioned counterparts (p&lt;0.05). These trends persist over time and across multiple passages. ECM stiffness exposure causes nanomechanical, cytoskeletal, and transcriptional adaptations. AFM shows that cells from the margin (n=6) are softer (p&lt;0.01) and more deformable (p&lt;0.01). RNAseq identified upregulation of MM-specific genes in GBM margin cells. The mechanosensitive transcription factor YAP1 emerged as a key driver of MM. Notably, YAP1 is targetable by the FDA-approved drug Verteporfin. YAP1 expression was elevated in margin and stiff-conditioned cells (p&lt;0.05). Stiff-conditioned cells and margin cells displayed increased sensitivity to Verteporfin treatment (p&lt;0.05), with treatment significantly reducing margin migration compared to the core (p&lt;0.001). CONCLUSION Stiffer GBM margins promote the formation of aggressive phenotypes through MM. Targeting YAP1 with Verteporfin, a readily available drug, presents a promising strategy to halt GBM invasion and improve patient outcomes.

ABSTRACT Medically important pathogenic fungi invade vertebrate tissue and are considered primary when part of their nature life cycle is associated with an animal host and are usually able to infect immunocompetent hosts. Opportunistic fungal pathogens complete their life cycle in environmental habitats or occur as commensals within or on the vertebrate body, but under certain conditions can thrive upon infecting humans. The extent of host damage in opportunistic infections largely depends on the portal and modality of entry as well as on the host’s immune and metabolic status. Diseases caused by primary pathogens and common opportunists, causing the top approximately 80% of fungal diseases [D. W. Denning, Lancet Infect Dis, 24:e428–e438, 2024, https://doi.org/10.1016/S1473-3099(23)00692-8 ], tend to follow a predictive pattern, while those by occasional opportunists are more variable. For this reason, it is recommended that diseases caused by primary pathogens and the common opportunists are named after the etiologic agent, for example, histoplasmosis and aspergillosis, while this should not be done for occasional opportunists that should be named as [causative fungus] [clinical syndrome], for example, Alternaria alternata cutaneous infection. The addition of a descriptor that identifies the location or clinical type of infection is required, as the general name alone may cover widely different clinical syndromes, for example, “rhinocerebral mucormycosis.” A list of major recommended human and animal disease entities (nomenclature) is provided in alignment with their causative agents. Fungal disease names may encompass several genera of etiologic agents, consequently being less susceptible to taxonomic changes of the causative species, for example, mucormycosis covers numerous mucormycetous molds.