Standards

The advancement of mRNA-based immunotherapies for cancer is highly dependent on the effective delivery of RNA payloads using ionizable lipid nanoparticles (LNPs). However, the clinical application of these therapies is hindered by variable mRNA expression among different cancer types and the risk of systemic toxicity. The transient expression profile of mRNA further complicates this issue, necessitating frequent dosing and thus increasing the potential for adverse effects. Addressing these challenges, we utilized a high-throughput combinatorial method to synthesize and screen LNPs that efficiently deliver circular RNA (circRNA) to lung tumors...

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) represents a high-risk B-lineage ALL subtype characterized by adverse clinical features and poor relapse-free survival despite risk-adapted multi-agent chemotherapy regimens. The advent of next-generation sequencing has unraveled the diversity of kinase-activating genetic drivers in Ph-like ALL that are potentially amenable to 'personalized' molecularly-targeted therapies. Based upon robust preclinical data and promising case series of clinical activity of tyrosine kinase inhibitor (TKI)-based treatment in adults and children with relevant genetic Ph-like ALL subtypes, several clinical trials have investigated the efficacy of JAK- or ABL-directed TKIs in CRLF2/JAK pathway-mutant or ABL-class Ph-like ALL, respectively...

Disruption of DNA damage repair via impaired homologous recombination is characteristic of Ewing sarcoma (EWS) cells. We hypothesize that this disruption results in increased reliance on non-homologous end joining (NHEJ) to repair DNA damage. In this study, we investigated if pharmacological inhibition of the enzyme responsible for NHEJ, the DNA-PK holoenzyme, alters the response of EWS cells to genotoxic standard of care chemotherapy. We used analyses of cell viability and proliferation to investigate the effects of clinical DNA-PK inhibitors (DNA-PKi) in combination with six therapeutic or experimental agents for EWS...

PURPOSE: To analyze the available evidence and assess the effect of different implant coatings on healing outcomes. MATERIALS AND METHODS: Using the PICOS strategy, a structured question was formed. A protocol was agreed upon and registered with PROSPERO (no. CRD42022321926). The MEDLINE, Embase, Cochrane Database of Systematic Reviews, Scopus, Web of Science, Pubmed, and ScienceDirect databases were searched using a structured strategy. Study selection was independently carried out in duplicate, first by title and abstract, then by full-text assessment...

Cellulose nanofiber (CNF) holds great promise in applications such as surface-enhanced Raman scattering (SERS), catalysis, esthesia, and detection. This study aimed to build novel CNF-based SERS substrates through a facile synthetic method. Citrate-reduced gold nanoparticles (AuNPs) were adsorbed on the cationized CNF surface due to electrostatic interactions, and uniform AuNPs@(2,3-epoxypropyl trimethylammonium chloride)EPTMAC@CNF flexible SERS substrates were prepared by a simple vacuum-assisted filtration method...

BACKGROUND: Primary prevention patients with ischemic cardiomyopathy and chronic total occlusion of an infarct-related coronary artery (IRA-CTO) are at a particularly high risk of implantable cardioverter-defibrillator (ICD) therapy occurrence. AIM: To evaluate the efficacy of preventive CTO-related substrate ablation strategy in ischaemic cardiomyopathy patients undergoing primary prevention ICD implantation. METHODS: The PREVENTIVE VT study was a prospective, multicenter, randomized trial including ischaemic patients with ejection fraction ≤40%, no documented VAs, and evidence of scar related to the coronary CTO...

Bone tissue engineering strategies incorporating mesenchymal stromal cells (MSC), hydrogels and osteoinductive signals offer great promise for bone repair and regeneration. Commonly used osteoinductive signals such as growth factors face challenges in clinical translation due to their high cost, low stability and potential immunogenicity. Therefore, interest is growing in the delivery of microRNAs as a simple, inexpensive and powerful alternative to modulate MSC osteogenesis. Nevertheless, challenges associated with the selection of appropriate miRNA candidates and their efficient delivery must be overcome to make this a reality...

This study examines the synthesis and evaluation of 11 newly developed compounds as potential anti-Alzheimer's agents that occur via cholinesterase and β-secretase inhibition. The compounds were tested for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using the modified Ellman method. The results showed that several compounds exhibited significant inhibition of AChE, particularly compounds 6d, 7a, and 7e, which demonstrated high inhibitory activity at lower concentrations, with IC50 values of 0...

Patellofemoral instability (PFI) is a common disorder in children and adolescents. Surgical stabilization of the patella poses challenges in skeletally immature patients due to anatomical peculiarities at this stage, leading to the absence of an established standard reconstruction technique. Recently, there has been a notable interest in the medial patellofemoral complex (MPFC), encompassing the medial patellofemoral ligament (MPFL) and the medial quadriceps tendon femoral ligament (MQTFL), owing to their role in restricting lateral patellar displacement...

BACKGROUND: Reducing proton treatment time improves patient comfort and decreases the risk of error from intrafractional motion, but must be balanced against clinical goals and treatment plan quality. PURPOSE: To improve the delivery efficiency of spot scanning proton therapy by simultaneously reducing the number of spots and energy layers using the reweighted <mml:math xmlns:mml="https://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:msub><mml:mi>l</mml:mi> <mml:mn>1</mml:mn></mml:msub> <mml:annotation>$l_1$</mml:annotation></mml:semantics> </mml:math> regularization method...

Background: Bariatric surgery is a frequently performed procedure in the United States, accounting for ∼40,000 procedures annually. Patients undergoing bariatric surgery are at high risk for postoperative thrombosis, with a venous thromboembolism (VTE) rate of up to 6.4%. Despite this risk, there is a lack of guidelines recommending postoperative VTE prophylaxis and it is not routine practice at most hospitals. The postoperative bleeding rate after bariatric surgery is only 1.5%; however, the risk of bleeding may lead to hesitancy for more liberal VTE prophylaxis...

BACKGROUND.: Aeration heterogeneity affects lung stress and influences outcomes in adults with acute respiratory distress syndrome (ARDS). We hypothesize that aeration heterogeneity may differ between neonatal respiratory disorders and is associated with oxygenation, so its evaluation may be relevant in managing respiratory support. METHODS.: Observational, prospective study. Neonates with respiratory distress syndrome (RDS), transient tachypnea (TTN), evolving bronchopulmonary dysplasia (BPD) and neonatal ARDS (NARDS) were enrolled...

Tumor mutation burden (TMB) has profound implications for personalized cancer therapy, particularly immunotherapy. However, the size of the panel and the cutoff values for an accurate determination of TMB are still controversial. In this study, a pan-cancer analysis was performed on 22 cancer types from The Cancer Genome Atlas. The efficiency of gene panels of different sizes and the effect of cutoff values in accurate TMB determination was assessed on a large cohort using Whole Exome Sequencing data ( n  = 9929 patients) as the gold standard...

The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Individuals with a Fontan circulation (FC) exhibit central venous hypertension and face life-threatening complications of hepatic fibrosis, known as Fontan-associated liver disease (FALD). The fundamental biology and mechanisms of FALD are little understood. Here, we generated a transcriptomic and epigenomic atlas of human FALD at single-cell resolution using multiomic snRNA-ATAC-seq. We found profound cell type-specific transcriptomic and epigenomic changes in FC livers...

Target-mediated drug disposition (TMDD) is a phenomenon characterized by a drug's high-affinity binding to a target molecule, which significantly influences its pharmacokinetic profile within an organism. The comprehensive TMDD model delineates this interaction, yet it may become overly complex and computationally demanding in the absence of specific concentration data for the target or its complexes. Consequently, simplified TMDD models employing quasi-steady state approximations (QSSAs) have been introduced; however, the precise conditions under which these models yield accurate results require further elucidation...

We developed a motivational interviewing (MI) counselling training and support program for lay counsellors in South Africa-branded "Thusa-Thuso-helping you help", commonly referred to as Thusa-Thuso. We present the results of a pilot study to determine the program's impact on MI technical skills and qualitatively assess the feasibility of a training-of-trainers (TOT) scale-up strategy among counselling staff of non-governmental (NGO) support partners of the human immunodeficiency virus (HIV) treatment program in South Africa...

Glycerol tributyrate as a low-density lipoprotein plays a crucial role in drug development and food safety. In this work, a novel high-stability fiber optic sensor for glyceryl tributyrate based on the poly(acrylic acid) (PAA) and chitosan (CS) composite hydrogel embedding method is first proposed. Compared with traditional functionalization, the lipase in a polymer network structure used in this article can not only avoid chemical reactions that cause damage to the enzyme structure but also avoid the instability of ionic bonds and physical adsorption...

Adjuvant endocrine therapy represents the standard of care for almost all HR+/HER2- breast cancers and different agents and durations are currently available. In this context, the tailoring and optimization of adjuvant endocrine treatment by reducing unnecessary toxic treatment while taking into account the biological heterogeneity of HR+/HER2- breast cancer represents a clinical priority. There is therefore a significant need for the integration of biological biomarkers in the choice of adjuvant endocrine therapy beyond currently used clinicopathological characteristics...

The Thomas splint, the first practical traction splint for femoral fractures, revolutionized the capabilities of military medicine. Its usage in WWI lowered the mortality rate from 80% to nearly 15%. Its development not only shaped modern orthopedics but also established the splint as standard equipment in hospitals worldwide.

BACKGROUND: Adjuvant therapy (AT) and neoadjuvant therapy (NAT) are standard treatments for pancreatic ductal adenocarcinoma (PDAC) depending on the status of the disease. However, whether AT improves survival after NAT and radical resection in all TNM stages remains unclear. RESEARCH DESIGN AND METHODS: We utilized the Surveillance, Epidemiology, and End Results (SEER) database (2010-2019) for PDAC patients who underwent radical surgery and applied Pearson's chi-square test, multivariate and univariate Cox regression, Kaplan-Meier plot, Log-rank tests, and propensity score matching (PSM) for analysis...