Development of a Cationic Polymeric Micellar Structure with Endosomal Escape Capability Enables Enhanced Intramuscular Transfection of mRNA-LNPs.

The endosomal escape of lipid nanoparticles (LNPs) is crucial for efficient mRNA-based therapeutics. Here, we present a cationic polymeric micelle (cPM) as a safe and potent co-delivery system with enhanced endosomal escape capabilities. We synthesized a cationic and ampholytic di-block copolymer, poly (poly (ethylene glycol) methacrylate--hexyl methacrylate)--poly(butyl methacrylate--dimethylaminoethyl methacrylate--propyl acrylate) (p(PEGMA--HMA)--p(BMA--DMAEMA--PAA)), via reversible addition-fragmentation chain transfer polymerization.

ROCK Inhibitor Enhances Resilience Against Metabolic Stress Through Increasing Bioenergetic Capacity in Corneal Endothelial Cells.

Purpose: To investigate the effect of Rho-associated protein kinase (ROCK) inhibitor Y27632 on bioenergetic capacity and resilience of corneal endothelial cells (CECs) under metabolic stress.

Methods: Bovine CECs (BCECs) were treated with Y27632 and subjected to bioenergetic profiling using the Seahorse XFp Analyzer. The effects on adenosine triphosphate (ATP) production through oxidative phosphorylation and glycolysis were measured.

Safety and immunogenicity of an optimized self-replicating RNA platform for low dose or single dose vaccine applications: a randomized, open label Phase I study in healthy volunteers.

Self-replicating RNA (srRNA) technology, in comparison to mRNA vaccines, has shown dose-sparing by approximately 10-fold and more durable immune responses. However, no improvements are observed in the adverse events profile. Here, we develop an srRNA vaccine platform with optimized non-coding regions and demonstrate immunogenicity and safety in preclinical and clinical development.

A new class of penicillin-binding protein inhibitors to address drug-resistant .

β-Lactams are the most widely used antibiotics for the treatment of bacterial infections because of their proven track record of safety and efficacy. However, susceptibility to β-lactam antibiotics is continually eroded by resistance mechanisms. Emerging multidrug-resistant (MDR) strains possessing altered alleles (encoding PBP2) pose a global health emergency as they threaten the utility of ceftriaxone, the last remaining outpatient antibiotic.

Deficiency of Endothelial Impairs Pulmonary Vascular Angiogenesis and Predisposes Pulmonary Hypertension.

Background: Mechanosensitive Piezo1 channel plays a key role in pulmonary hypertension (PH). However, the role of Piezo2 in PH remains unclear.

Methods: Endothelial cell (EC)-specific knockout (, Tek-Cre; ) rats and primarily cultured pulmonary microvascular ECs were used to determine the role of Piezo2 in PH.

Clinical assessment of urinary prostate cancer antigen 3 in Chinese population: a large-scale, prospective and multicenter study.

Background: To assess the clinical utility of PCA3 in the diagnostic accuracy, the correlation between PCA3 and biopsy or pathological characteristics and the performance of PCA3 to reduce the unnecessary biopsies in Chinese population.

Methods: A prospective study including patients with indication of prostate biopsies from 4 centers was conducted. All patients underwent PCA3 urine tests and prostate biopsies.

Dual Antiplatelet Treatment up to 72 Hours After Ischemic Stroke Stratified by Risk Profile: A Post Hoc Analysis.

Background: Risk profile of recurrence may influence the effect of antiplatelet therapy. This study aimed to evaluate the efficacy and safety of clopidogrel-aspirin initiated within 72 hours after symptom onset for acute mild stroke or high-risk transient ischemic attack stratified by risk profile.

Methods: This is a secondary post hoc analysis of the INSPIRES (Intensive Statin and Antiplatelet Therapy for Acute High-risk Intracranial or Extracranial Atherosclerosis) randomized clinical trial that enrolled patients 35 to 80 years old with acute mild ischemic stroke or high-risk transient ischemic attack between 2018 and 2022.

Diagnostic Efficacy of Ventilation-Perfusion Single Photo Emission Computed Tomography/Computed Tomography for Pulmonary Hypertension due to Fibrinous Mediastinitis.

Rationale And Objectives: Comprehensive data on the use of ventilation-perfusion single-photo emission computed tomography/computed tomography (V/Q SPECT/CT), an established diagnostic tool for chronic thromboembolic pulmonary hypertension, in identifying pulmonary hypertension secondary to fibrinous mediastinitis (PH-FM) is scarce. This study aimed to assess its diagnostic efficacy for PH-FM.

Materials And Methods: Patients with PH due to pulmonary artery stenosis were assessed using V/Q SPECT/CT, computed tomography pulmonary angiography (CTPA), and digital subtraction pulmonary angiography (PAG).

Scalable production of ultraflat and ultraflexible diamond membrane.

Diamond is an exceptional material with great potential across various fields owing to its interesting properties. However, despite extensive efforts over the past decades, producing large quantities of desired ultrathin diamond membranes for widespread use remains challenging. Here we demonstrate that edge-exposed exfoliation using sticky tape is a simple, scalable and reliable method for producing ultrathin and transferable polycrystalline diamond membranes.

A robust benchmark for detecting low-frequency variants in the HG002 Genome In A Bottle NIST reference material.

Somatic mosaicism is an important cause of disease, but mosaic and somatic variants are often challenging to detect because they exist in only a fraction of cells. To address the need for benchmarking subclonal variants in normal cell populations, we developed a benchmark containing mosaic variants in the Genome in a Bottle Consortium (GIAB) HG002 reference material DNA from a large batch of a normal lymphoblastoid cell line. First, we used a somatic variant caller with high coverage (300x) Illumina whole genome sequencing data from the Ashkenazi Jewish trio to detect variants in HG002 not detected in at least 5% of cells from the combined parental data.

Autofluorescence Virtual Staining System for H&E Histology and Multiplex Immunofluorescence Applied to Immuno-Oncology Biomarkers in Lung Cancer.

We extend the capabilities of virtual staining from AF to a different disease and stain modality. Our work includes newly developed virtual stains for H&E and a multiplex immunofluorescence panel (DAPI, PanCK, PD-L1, CD3, and CD8) for non-small cell lung cancer, which reproduce the key features of real stains.

Clinical and Genomic Prediction of Coronary Artery Disease Subtypes.

Background: Coronary artery disease (CAD) is a complex, heterogeneous disease with distinct etiological mechanisms. These different etiologies may give rise to multiple subtypes of CAD that could benefit from alternative preventions and treatments. However, so far, there have been no systematic efforts to predict CAD subtypes using clinical and genetic factors.

Assessing CD36 and CD47 expression levels in solid tumor indications to stratify patients for VT1021 treatment.

Despite the development of cancer biomarkers and targeted therapies, most cancer patients do not have a specific biomarker directly associated with effective treatment options. We have developed VT1021 that induces the expression of thrombospondin-1 (TSP-1) in myeloid-derived suppressor cells (MDSCs) recruited to the tumor microenvironment (TME). Our studies identified CD36 and CD47 as dual biomarkers that can be used as patient stratifying tools and prognostic biomarkers for VT1021 treatment.

Circulating tumor-reactive KIRCD8 T cells suppress anti-tumor immunity in patients with melanoma.

Effective anti-tumor immunity is driven by cytotoxic CD8 T cells with specificity for tumor antigens. However, the factors that control successful tumor rejection are not well understood. Here we identify a subpopulation of CD8 T cells that are tumor-antigen-specific and can be identified by KIR expression but paradoxically impair anti-tumor immunity in patients with melanoma.

Unraveling the Diffusion MRI-Based Glymphatic System Alterations in Children with Rolandic Epilepsy.

Rationale And Objectives: Although dysfunction of the glymphatic system in adult epilepsy has been extensively studied, there is a lack of research on the changes in this system during childhood development, particularly in children with Rolandic epilepsy (RE). This study aimed to investigate the changes in diffusion MRI measures related to the glymphatic function in children with RE.

Materials And Methods: A total of thirty-eight children with RE and thirty-six demographically matched healthy children were enrolled in the study.

The Value of Necrotic Area Features in Contrast-Enhanced Ultrasound for Distinguishing Between Benign and Malignant Subpleural Pulmonary Lesions.

Objective: To analyze Necrotic Area Features of subpleural pulmonary lesions (SPLs) demonstrated by contrast-enhanced ultrasound (CEUS) and investigate their value in differentiating between malignant and benign SPLs.

Methods: Patients with SPLs who underwent CEUS at our hospital from January to May 2021. The following patient information was recorded: (i) age, (ii) sex, (iii) lesion size, (iv) lesion location, (v) size of necrotic areas and (vi) necrotic area morphology, including sieve-like necrosis, necrotic area with septal enhancement, necrotic area with annular enhancement margins, and necrotic area with burr-like enhancement margins.

Prognostic value of extracellular volume fraction in myocardial infarction and myocardial infarction with nonobstructive coronary arteries: A multicenter study.

Rationale And Objectives: The aim of the present retrospective study was to evaluate the prognostic role of the extracellular volume fraction (ECV) in patients with myocardial infarction (MI) and myocardial infarction with nonobstructive coronary arteries (MINOCA). The present study hypothesized that ECV is associated with major adverse cardiovascular events (MACEs) in MI and MINOCA patients.

Materials And Methods: Cardiac magnetic resonance (CMR) imaging was performed on 351 consecutive patients (mean age: 58 ± 12 years; 252 [71.

Discovery of a single-subunit oligosaccharyltransferase that enables glycosylation of full-length IgG antibodies in .

Human immunoglobulin G (IgG) antibodies are one of the most important classes of biotherapeutic agents and undergo glycosylation at the conserved N297 site in the C2 domain, which is critical for IgG Fc effector functions and anti-inflammatory activity. Hence, technologies for producing authentically glycosylated IgGs are in high demand. While attempts to engineer for this purpose have been described, they have met limited success due in part to the lack of available oligosaccharyltransferase (OST) enzymes that can install linked glycans within the QYNST sequon of the IgG C2 domain.

Health Economic Evaluation of Antimicrobial Stewardship, Procalcitonin Testing, and Rapid Blood Culture Identification in Sepsis Care: A 90-Day Model-Based, Cost-Utility Analysis.

Objective: We evaluated the cost-effectiveness of a bundled intervention including an antimicrobial stewardship program (ASP), procalcitonin (PCT) testing, and rapid blood culture identification (BCID), compared with pre-implementation standard care in critically ill adult patients with sepsis.

Methods: We conducted a decision tree model-based cost-effectiveness analysis alongside a previously published pre- and post-implementation quality improvement study. We adopted a public Canadian healthcare payer's perspective.

Association of Vascular Risk With Severe vs Non-Severe Stroke: An Analysis of the INTERSTROKE Study.

Background And Objectives: Acute stroke is associated with a spectrum of functional deficits. The objective of this analysis was to explore whether the importance of individual risk factors differ by stroke severity, which may be of relevance to public health strategies to reduce disability.

Methods: INTERSTROKE is an international case-control study of risk factors of first acute stroke (recruitment 2007-August 2015) in 32 countries.

Outcomes of Community-Acquired Acute Kidney Injury: A Cohort Study of US Veterans.

Background: Community-acquired acute kidney injury (CA-AKI) occurs outside of the hospital and is the most common form of AKI. CA-AKI is not well understood, which hinders efforts to prevent, identify, and manage CA-AKI.

Objective: Examine 30-day outcomes following CA-AKI using national administrative and lab data from the Veterans Health Administration (VA).

mRNA delivery enabled by metal-organic nanoparticles.

mRNA therapeutics are set to revolutionize disease prevention and treatment, inspiring the development of platforms for safe and effective mRNA delivery. However, current mRNA delivery platforms face some challenges, including limited organ tropism for nonvaccine applications and inflammation induced by cationic nanoparticle components. Herein, we address these challenges through a versatile, noncationic nanoparticle platform whereby mRNA is assembled into a poly(ethylene glycol)-polyphenol network stabilized by metal ions.