Opposing roles of p38α-mediated phosphorylation and PRMT1-mediated arginine methylation in driving TDP-43 proteinopathy.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation of p38 mitogen-activated protein kinase (MAPK) is implicated in ALS.

Acute Myeloid Leukemia Skews Therapeutic WT1-specific CD8 TCR-T Cells Towards an NK-like Phenotype that Compromises Function and Persistence.

Acute myeloid leukemia (AML) that is relapsed and/or refractory post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. In a prior study, we demonstrated that AML relapse in high-risk patients was prevented by post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8 T cells engineered to express a high-affinity Wilms Tumor Antigen 1 (WT1)-specific T-cell receptor (T). However, in the present study, infusion of EBV- or Cytomegalovirus (CMV)-specific T did not clearly improve outcomes in fifteen patients with active disease post-HCT.

Prediction of checkpoint inhibitor immunotherapy efficacy for cancer using routine blood tests and clinical data.

Predicting whether a patient with cancer will benefit from immune checkpoint inhibitors (ICIs) without resorting to advanced genomic or immunologic assays is an important clinical need. To address this, we developed and evaluated SCORPIO, a machine learning system that utilizes routine blood tests (complete blood count and comprehensive metabolic profile) alongside clinical characteristics from 9,745 ICI-treated patients across 21 cancer types. SCORPIO was trained on data from 1,628 patients across 17 cancer types from Memorial Sloan Kettering Cancer Center.

Somatic PTEN and ARID1A loss and endometriosis disease burden: a longitudinal study.

Study Question: Is there an association between the somatic loss of PTEN (phosphatase and tensin homolog) and ARID1A (AT-rich interaction domain 1A) and endometriosis disease severity and worse clinical outcomes?

Summary Answer: Somatic PTEN loss in endometriosis epithelium was associated with greater disease burden and subsequent surgical complexity.

What Is Known Already: Somatic cancer-driver mutations including those involving the PTEN and ARID1A genes exist in endometriosis without cancer; however, their clinical impact remains unclear.

Study Design, Size, Duration: This prospective longitudinal study involved endometriosis tissue and clinical data from 126 participants who underwent surgery at a tertiary center for endometriosis (2013-2017), with a follow-up period of 5-9 years.

Dopamine-conjugated extracellular vesicles induce autophagy in Parkinson's disease.

The application of extracellular vesicles (EVs) as vehicles for anti-Parkinson's agents represents a significant advance, yet their clinical translation is hampered by challenges in efficient brain delivery and complex blood-brain barrier (BBB) targeting strategies. In this study, we engineered dopamine onto the surface of adipose-derived stem cell EVs (Dopa-EVs) utilizing a facile, two-step cross-linking approach. This engineering enhanced neuronal uptake of the EVs in primary neurons and neuroblastoma cells, a process shown to be competitively inhibited by dopamine pretreatment and dopamine receptor antibodies.

Plasma Protein Biomarkers of Spirometry Measures of Impaired Lung Function.

Background: Impaired pulmonary function carries significant risks for lung, cardiovascular, and metabolic disorders.

Research Question: Can circulating protein biomarkers of pulmonary function provide insight into the pathophysiologic features of lung function impairment and links to comorbidities?.

Study Design And Methods: We analyzed plasma levels of 2,922 proteins in 32,493 UK Biobank participants (53% female; mean [SD] age, 57 [8] years) to investigate their associations with spirometry measures of lung function (FEV, FVC, FEV to FVC ratio), and with obstructive (n = 4,713) and restrictive (n = 3,886) spirometry patterns.

Accuracy of Financial Disclosures by Scientific Presenters/Authors at the ASNR 2024 annual meeting.

Physician-industry financial relationships can drive research and innovation, improving patient care and outcomes, but potentially raise ethical concerns if not disclosed appropriately. This study shows high rates of non-disclosures by authors/presenters at the ASNR 2024 annual meeting, despite strict requirements. 86.

Mitochondrial Genomes of Korean Native Black Goats Reveal Shared Phylogeographic Patterns and Demographic History.

This study explores the phylogeny of Korean native black goats through analysis of their complete mitochondrial DNA. The National Institute of Animal Science has gathered genetic material on purebred goats from isolated regions such as Tongyeong, Dangjin, and Jangsu, and is actively breeding them on a national level. These populations, however, are small and exhibit high inbreeding rates, highlighting the urgent need to preserve genetic diversity.

PEDF-Enriched Extracellular Vesicle for Vessel Normalization to Potentiate Immune Checkpoint Blockade Therapy.

The abnormal tumor vasculature acts as the physical and functional barrier to the infiltration and activity of effector T cells, leading to the low response rate of immune checkpoint inhibitors (ICIs). Herein, antiangiogenic extracellular vesicles that enable normalization of the tumor-associated vasculature were prepared to potentiate the efficacy of ICIs. Small extracellular vesicles were exploited as the delivery platform to protect the antiangiogenic protein, pigment epithelium-derived factor (PEDF), from proteolytic degradation.

The reovirus variant RP116 is oncolytic in immunocompetent models and generates reduced neutralizing antibodies to Type 3 Dearing.

The mammalian reovirus Type 3 Dearing (T3D) is a naturally occurring oncolytic virus. We previously identified a T3D variant isolated from persistently infected cancer cells that has a premature stop codon mutation in the gene, generating a truncated σ1-attachment protein that lacks the globular head. We now report on the molecular characterization of this variant, named RP116, and assess its antitumor potential in human cancer cells and syngeneic mouse models.

A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders.

Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set of Mendelian disorders altering cMN development. We generate single cell epigenomic profiles for ~86,000 cMNs and related cell types, identifying ~250,000 accessible regulatory elements with cognate gene predictions for ~145,000 putative enhancers.

Mining nucleic acid "omics" to boost liquid biopsy in cancer.

Treatments for cancer patients are becoming increasingly complex, and there is a growing desire from clinicians and patients for biomarkers that can account for this complexity to support informed decisions about clinical care. To achieve precision medicine, the new generation of biomarkers must reflect the spatial and temporal heterogeneity of cancer biology both between patients and within an individual patient. Mining the different layers of 'omics in a multi-modal way from a minimally invasive, easily repeatable, liquid biopsy has increasing potential in a range of clinical applications, and for improving our understanding of treatment response and resistance.

Therapeutic silencing in TREM2 cardiac macrophages suppresses atrial fibrillation.

Atrial fibrillation (AFib) and the risk of its lethal complications are propelled by fibrosis, which induces electrical heterogeneity and gives rise to reentry circuits. Atrial TREM2 macrophages secrete osteopontin (encoded by ), a matricellular signaling protein that engenders fibrosis and AFib. Here we show that silencing in TREM2 cardiac macrophages with an antibody-siRNA conjugate reduces atrial fibrosis and suppresses AFib in mice, thus offering a new immunotherapy for the most common arrhythmia.

Age-related epithelial defects limit thymic function and regeneration.

The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states.

Long-term Remissions Following CD20-Directed Chimeric Antigen Receptor-Adoptive T-cell Therapy.

Chimeric antigen receptor (CAR) T-cell therapy produces high response rates in refractory B-cell non-Hodgkin lymphoma, but long-term data are minimal to date. In this study, we present long-term follow-up of a pilot trial testing a CD20-targeting third-generation CAR in patients with relapsed B-cell lymphomas following cyclophosphamide-only lymphodepletion. Two of the three patients in the trial, with mantle cell lymphoma and follicular lymphoma, had remissions lasting more than 7 years, though they ultimately relapsed.

Mechanical Ventilation in Older Adults With Dementia: Opportunities to Promote Goal-Concordant Care.

Context: Recent studies show increasing use of mechanical ventilation among people living with dementia. There are concerns that this trend may not be driven by patient preferences.

Objectives: To better understand decision-making regarding mechanical ventilation in people living with dementia.

Precision off-the-shelf natural killer cell therapies for oncology with logic-gated gene circuits.

Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis (5-year survival rate of 30.5% in the United States). Designing cell therapies to target AML is challenging because no single tumor-associated antigen (TAA) is highly expressed on all cancer subpopulations.

Posttranscriptional regulation of by miR-124-3p at rs3512 underlies onset-delaying genetic modification in Huntington's disease.

Many Mendelian disorders, such as Huntington's disease (HD) and spinocerebellar ataxias, arise from expansions of CAG trinucleotide repeats. Despite the clear genetic causes, additional genetic factors may influence the rate of those monogenic disorders. Notably, genome-wide association studies discovered somewhat expected modifiers, particularly mismatch repair genes involved in the CAG repeat instability, impacting age at onset of HD.

p53 promotes revival stem cells in the regenerating intestine after severe radiation injury.

Ionizing radiation induces cell death in the gastrointestinal (GI) epithelium by activating p53. However, p53 also prevents animal lethality caused by radiation-induced acute GI syndrome. Through single-cell RNA-sequencing of the irradiated mouse small intestine, we find that p53 target genes are specifically enriched in regenerating epithelial cells that undergo fetal-like reversion, including revival stem cells (revSCs) that promote animal survival after severe damage of the GI tract.