Browse Articles

Lightweight multi-task network for synchronous fatigue detection and ankle instability gait analysis in football training with edge deployment

How soon is now for new treatments for mantle cell lymphoma?

An explainable hybrid Generative Adversarial Network framework for data augmentation in imbalanced medical image classification

Consensus recommendations for CAR T-cell administration in adult acute lymphoblastic leukemia: a modified Delphi study

Abstract The use of chimeric antigen receptor (CAR) T-cell therapy is increasing for adult B-cell acute lymphoblastic leukemia (B-ALL), with 3 CD19 CAR T-cell products commercially available. Several key clinical questions related to best practices for CAR T-cell administration in this population exist, and limited prospective randomized trials have been conducted to fill these knowledge gaps. Thus, to help guide clinical practice, we conducted a modified Delphi study to develop and validate consensus recommendations on the administration of commercially available CAR T-cell therapy for adults with B-ALL. Consensus panelists (n = 9) included principal investigators (PIs) from Real World Outcomes Collaborative of CAR T-Cell Therapy in Adult ALL (ROCCA) consortium sites and were selected based on expertise and CAR T-cell center volume. Final panel consensus recommendations were distributed for rating by the remaining PIs from ROCCA consortium sites, which served as the validation group (n = 27). Consensus topics included patient selection, bridging and pre–CAR T-cell leukemia staging, lymphodepletion, and CAR T-cell treatment setting, specific toxicity prevention and management, post–CAR T-cell response assessment and disease monitoring, and the role of consolidation and/or maintenance therapies after CAR T-cell therapy. Initially, 58 recommendation statements were evaluated for consensus. After 2 panel meetings, a total of 34 statements achieved consensus rating among the expert panel. After rating by the validation group, all but 1 recommendation statement continued to meet consensus, for a total of 33 consensus recommendation statements on the administration of CAR T-cell therapy in adult B-ALL.

Correction: EneA of Aspergillus fumigatus is a regulator of secondary metabolism and enhances nscA expression in presence of polyenes and Streptomyces

Disseminated cryptococcal lymphadenitis mimicking lymphoma and masked by prozone effect

Fine-root biomass in relation to soil properties in regenerating Norway spruce stands following large-scale bark beetle outbreaks in mountain and lowland forests

A tumor suppressor role of the miR-15b/16-2 cluster in T-cell acute lymphoblastic leukemia

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy arising from the neoplastic transformation of immature T cells during their development in the thymus. Deciphering the developmental programs whose dysregulation drives T-ALL pathogenesis is critical for the development of novel targeted therapies, which remain an urgent unmet need for the treatment of this disease. MicroRNAs (miRNAs) have emerged as key posttranscriptional regulators of numerous physiological processes, including cancer. However, the specific role of miRNAs in human T-cell development and T-ALL pathogenesis remains largely unexplored. In this study, we comprehensively evaluated miRNA expression profiles across human T-cell development using microarray analysis and identified a dynamic expression pattern of miR-16-2, which is upregulated during early pre–T-cell proliferative stages up to the resting stage of immature thymocytes immediately preceding T-cell receptor αβ expression and is subsequently downregulated. We also confirmed the coordinated regulation of miR-15b expression, consistent with the reported clustered genomic location of both miRNAs. Notably, functional studies identified the miR-15b/16-2 cluster as a negative regulator of early thymocyte proliferation and demonstrated that overexpression of miR-15b/16-2 in T-ALL cells impaired leukemic growth in vitro and tumor progression in patient-derived xenotransplantation assays. Mechanistically, miR-15b/16-2 represses the expression of the genes encoding BCL-2 and cyclin D3, thereby promoting apoptosis and cell cycle dysregulation in T-ALL cells, characterized by an accumulation of G0-phase cells and a defective transition to the G2/M phase. Overall, these findings support a novel tumor-suppressive function for miR-15b/16-2 in T-ALL and highlight its potential as a promising therapeutic target.

Comparative assessment of municipal solid waste management and community vulnerability in peri-urban India

Drugging smart: molecular glue degraders rise in T-ALL

Enhancing scene text super-resolution via dense residual reconstruction and asymmetric recurrent modeling

Lysozyme-associated nephropathy heralding leukemic transformation in myelofibrosis

Elevated circulating growth differentiation factor-15 in asthma is associated with fixed airway obstruction and future exacerbations

Chrono-atlas of cell-type specific daily gene expression rhythms in the regenerating colon

Diagnostic performance of plasma pTau217 in genetically admixed South American populations

Abstract Plasma pTau217 is a leading biomarker for Alzheimer’s disease, but evidence from genetically admixed populations in low- and middle-income countries remains limited. We evaluated the diagnostic performance of pTau217 and pTau217/Aβ42 measured using Simoa technology in memory-clinic cohorts from Brazil (Cog-Aging-Study, n  = 353) and Argentina (GeNED.ar, n  = 134). Here we show that both biomarkers accurately identified cerebrospinal fluid (CSF)-defined amyloid pathology in Cog-Aging-Study-Brazil and showed high concordance with clinical diagnosis across both cohorts. Classification performance was improved using two-cut-off approaches that account for diagnostic uncertainty. We further show that APOE-ε4 , lower body mass index, and reduced kidney function were associated with higher pTau217 in Cog-Aging-Study-Brazil, whereas education also influenced biomarker levels in GeNED.ar-Argentina. African ancestry modified APOE-ε4 effect on CSF but not plasma biomarkers. These findings support the use of plasma pTau217-based biomarkers in genetically admixed South American populations and in settings with limited access to CSF testing and brain imaging.

Select earthquake forecasting models demonstrate consistency with prospective decadal observations in California

Abstract Earthquake forecasting systems are now operationalized by agencies in several countries, providing situational awareness to at-risk communities. To ensure that forecasts follow the best science available, the underlying models require rigorous testing against prospective data and benchmarking. Between August 2007 and August 2018, 27 forecasting models, including the types used for operational earthquake forecasting, were prospectively operated as part of a multi-institutional project by the Collaboratory for the Study of Earthquake Predictability, generating 51,625 next-day M w  ≥ 3.95 seismicity forecasts for California. Here, we comprehensively evaluate their predictive skills against 597 M w  ≥ 3.95 earthquakes using community-vetted statistical methods. We show that approximately 95%, two-thirds, and 95% of the models produced forecasts consistent with the number, locations, and magnitudes of observed earthquakes, respectively. Individually, select versions of well-established, operational-type models demonstrated sustained consistency with prospective observations. We provide detailed recommendations, software tools, and benchmarking data to support the development of operational earthquake forecasting systems worldwide.

Nuclear exosome targeting complexes modulate cohesin binding and enhancer-promoter interactions in 3D

Abstract Three-dimensional long-range contacts between enhancers and promoters are thought to be largely determined by loop extrusion driven by the cohesin complex and insulator factors. However, recent evidence also suggests a role for noncoding RNAs, such as enhancer-associated RNAs and promoter upstream transcripts, in shaping enhancer-promoter connectivity. While the nuclear RNA exosome, together with targeting complexes, poly(A) tail exosome targeting connection and nuclear exosome targeting complex, controls the decay of noncoding RNAs, it remains unclear whether these complexes regulate three-dimensional chromatin contacts. Chromatin recruitment maps of the nuclear exosome targeting complex subunit ZCCHC8, the poly(A) tail exosome targeting connection subunit ZFC3H1, and the RNA helicase MTR4 in human cells reveal that these factors associate with sites of enhancer–promoter interactions. Depletion of these factors leads to the accumulation of ncRNAs, notably enhancer-associated RNAs and promoter upstream transcripts, and increases cohesin occupancy at these sites. Chromatin conformation capture analysis reveals that MTR4 modulates long-range enhancer-promoter contacts. Upon loss of MTR4, enhancer-promoter contacts increase while intraloop contacts decrease, suggesting that MTR4 facilitates loop extrusion. These data highlight a key interplay between cohesin-mediated enhancer-promoter interactions and the regulation of noncoding RNAs by nuclear RNA exosome targeting complexes that is consistent with a role for RNA in genome folding.

Explainable AI: learning from the learners

Surviving Pediatric Cardiogenic Shock: Clinical Approach, Improving Outcomes, and Future Directions: A Scientific Statement From the American Heart Association

Pediatric heart failure–related cardiogenic shock carries high morbidity and mortality but is understudied. Improving outcomes in pediatric cardiogenic shock hinges on timely diagnosis and appropriate triage, medical management tailored to the cause and phenotype of cardiogenic shock, and optimal timing of escalation to appropriate mechanical circulatory support. This scientific statement provides a diagnostic framework for the bedside clinician, in addition to proposing a pediatric cardiogenic shock definition and severity staging aligned with systems previously validated in other studies. It outlines the initial approach to diagnosis and stabilization of a child with suspected cardiogenic shock and offers guidance on optimal noninvasive and invasive monitoring strategies to determine clinical trajectory because a significant proportion of children with cardiogenic shock will continue to deteriorate in the first 24 hours. Last, it identifies future directions for the field, including educational interventions for the frontline clinicians seeing these patients, studying the role of a multidisciplinary shock team, evaluating the prognostic and clinical relevance of known and novel biomarkers, and leveraging all these to develop clinical decision tools or algorithms to guide nuanced management of these patients.

Decomposition and separation of vibration waves from blasting demolition of tall buildings and their component characteristics