Systemic Delivery of an mRNA-Encoding, Tumor-Activated Interleukin-12 Lock to Eliminate Tumors and Avoid Immune-Related Adverse Events.

Interleukin-12 (IL-12) is a robust proinflammatory cytokine that activates immune cells, such as T cells and natural killer cells, to induce antitumor immunity. However, the clinical application of recombinant IL-12 has been limited by systemic immune-related adverse events (irAEs) and rapid degradation. To address these challenges, we employed mRNA technology to encode a tumor-activated IL-12 "lock" fusion protein that offers both therapeutic efficacy and systemic safety.

Genetic variants affecting RNA stability influence complex traits and disease risk.

Gene expression is modulated jointly by transcriptional regulation and messenger RNA stability, yet the latter is often overlooked in studies on genetic variants. Here, leveraging metabolic labeling data (Bru/BruChase-seq) and a new computational pipeline, RNAtracker, we categorize genes as allele-specific RNA stability (asRS) or allele-specific RNA transcription events. We identify more than 5,000 asRS variants among 665 genes across a panel of 11 human cell lines.

β-hydroxybutyrate dehydrogenase promotes pancreatic cancer cell proliferation through regulation of the NAD/NADH balance and mitochondrial acetylation.

Ketone bodies are a key alternative energy source during carbohydrate deficiency. In addition to their metabolic function, they regulate essential cellular processes, including metabolism, signal transduction, and protein post-translational modifications (PTMs). However, the role of ketone body metabolism in tumorigenesis remains poorly understood.

High-brightness PT-symmetric laser bars with exceptional point modulation via spectral beam combining.

PT-symmetric semiconductor laser bars are fabricated and experimentally harnessed via spectral beam combining. A 22.20% reduction in the PT-symmetry-breaking threshold current is observed, compared to that of free-running operation, which is justified by the numerical analysis, based on a three-mirror equivalent model and the gain-clamping effect.

Inequities in prenatal neonatology consultation in high-mortality neonatal populations.

Objectives: To explore inequities in prenatal consultation and parental resuscitation decisions across high-mortality conditions.

Study Design: We conducted a retrospective chart review of pregnant people whose liveborn neonates were diagnosed with high-mortality conditions. We examined two cohorts: periviable infants (22 0/7-24 6/7 weeks) and infants with severe congenital anomalies.

Topological robustness of a high-power narrow linewidth semiconductor laser based on the Su-Schrieffer-Heeger model.

Narrow-linewidth semiconductor lasers utilizing surface high-order Bragg gratings frequently encounter the issue of reduced output power. Many microstructures are used to improve the device output power, but correspondingly, more stringent requirements are put forward for the process tolerance. Fortunately, topology theory provides a new approach to robust laser design.

Finotonlimab (PD-1 inhibitor) plus bevacizumab (bevacizumab biosimilar) as first-tier therapy for late-stage hepatocellular carcinoma: a randomized phase 2/3 trial.

We aimed to assess the tolerability and efficacy of finotonlimab (an anti-programmed cell death protein-1 antibody) in combination with SCT510, a bevacizumab biosimilar, versus sorafenib in unresectable advanced HCC. This randomized phase 2 and 3 study (ClinicalTrials.gov, NCT04560894; Chinadrugtrials.

Effect of Pasteurization on Ghrelin and Resistin Hormone Concentrations in Human Breast Milk.

Donor breast milk (DBM) is often used to supplement maternal milk, especially for very low birth weight infants, a population vulnerable to suboptimal postnatal growth. The Holder pasteurization process used to ensure DBM safety reduces bioactive components, with unclear impact on preterm infant growth. Ghrelin and resistin are two hormones found in breast milk that may play roles in infant growth.

Refractive status and ocular biometric parameters in children undergoing the levator muscle-conjoint fascial sheath complex suspension.

Purpose: To evaluate the effect of the levator muscle-conjoint Fascial Sheath Complex Suspension on ocular biometric parameters and refractive status in children with congenital blepharoptosis.

Methods: We reviewed the clinical records of 68 patients with congenital blepharoptosis who attended our hospital from 2021 to 2023 and underwent ptosis surgery with detailed examination. The changes of corneal topography and refractive characteristics before and 1 month, 3 months, 6 months after surgery were compared and analyzed.

TLR3-overexpressing umbilical cord mesenchymal stromal cells suppress immune responses to attenuate high-risk corneal transplantation rejection.

Background: The success rates of high-risk corneal transplantation are significantly hindered by immunological rejection. Umbilical cord mesenchymal stem cells (UC-MSCs) have emerged as a potential solution to improve graft outcomes. Toll-like receptors (TLRs) play pivotal roles in the immune response, however, their specific functions in UC-MSC-based treatments for corneal graft rejection requires further investigation.

FXR overexpression alleviates cholestasis via NLRC4 inflammasome suppression and bile acid homeostasis regulation.

Cholestasis, a major driver of liver disease progression, is characterized by toxic bile acid accumulation due to impaired bile flow, potentially leading to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. To date, the pathogenesis of cholestasis has remained incompletely understood. In the present study, we investigated the role of farnesoid X receptor (FXR) in modulating the NLR family CARD domain-containing protein 4 (NLRC4) inflammasome activity using in vitro (AML-12 hepatocytes) and in vivo (C57BL/6 mice) models of lithocholic acid (LCA)-induced cholestasis.

High efficiency and a narrow spectrum spectral beam combining a module with a single grating external cavity.

A single grating multiple diffraction spectral beam combining (SBC) structure is proposed and demonstrated, which keeps high efficiency by using the methods of polarization separation and full feedback. The maximum combining efficiency is 81.1%, which leads to an output power of 12.

High-power semiconductor laser with a narrow linewidth based on transverse photonic crystal.

Broad-area lasers (BA) are practical for producing high output power. However, under a high current operation, high-order modes are easily excited, resulting in the broadened linewidth. Here, based on mode engineering of double-side transverse photonic crystals (TPCs) combined with a longitudinal high-order surface grating, a narrow-linewidth electrically-pumped broad-area laser with high power emission only using I-line lithography is demonstrated.

CXCL12 expression and the survival of patients with gastric cancer: a meta-analysis.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide. CXCL12, a chemokine involved in tumor progression and metastasis, has been inconsistently associated with GC survival. This meta-analysis aimed to evaluate the prognostic significance of CXCL12 expression in GC patients.

The Biliary Stenting Strategy for the Unresectable Hilar Type of Intrahepatic Cholangiocarcinoma: A Single-Center Experience.

Objectives: Hilar-type intrahepatic cholangiocarcinoma (H-ICC), which originates from the large bile ducts, tends to invade the hepatic hilus and results in malignant hilar biliary obstruction (MHBO). Compared with hilar cholangiocarcinoma (HC), H-ICC exhibits a more aggressive biological behavior and a dismal prognosis. We aimed to investigate the optimal biliary stenting strategy for the treatment of unresectable H-ICC.

Research on Collaborative Delivery Path Planning for Trucks and Drones in Parcel Delivery.

With the rapid development of e-commerce, the logistics industry faces multiple challenges, including high delivery costs, long delivery times, and a shortage of delivery personnel. Truck-drone collaborative delivery combines the high load capacity of trucks with the flexibility and speed of drones, offering an innovative and practical solution. This paper proposes the Truck-Drone Collaborative Delivery Routing Problem (TDCRPTW) and develops a multi-objective optimization model that minimizes delivery costs and maximizes time reliability under capacity and time window constraints in multi-truck, multi-drone scenarios.

Unveiling the Multifaceted Role of HP6: A Critical Regulator of Humoral Immunity in (Lepidoptera: Saturniidae).

Serine proteases are widely distributed in both invertebrates and vertebrates, playing critical roles in the regulation of innate immunity. In the insect innate immune system, two pivotal pathways-the prophenoloxidase (PPO) activation cascade and Toll pathway-mediated antimicrobial peptide (AMP) synthesis-are both tightly regulated by serine protease cascades. This study focuses on serine protease-hemolymph protease 6 of (-HP6).

Novel Phenoxyacetic Acid (4-Aminophenoacetic Acid) Shikonin Ester Kills KRAS Mutant Colon Cancer Cells via Targeting the Akt Allosteric Site.

The PI3K-Akt axis is abnormally activated in KRAS-mutated colorectal cancer and is considered to be a potential therapeutic target. A novel series of phenoxyacetic acid (4-aminophenoacetic acid) shikonin esters was designed by computer-aided drug design (CADD) and synthesized as Akt allosteric inhibitors. Most compounds exhibited greater anti-proliferative activity compared to the positive control MK2206, while also demonstrating lower cytotoxicity against normal cells than shikonin.

Aptamer-Signatured Nanoparticle Protein Corona for Size-Dependent Fluorescent Barcoding Diagnosis.

Cancer-specific nanoparticl protein corona (NPC) opens a new avenue for biomarker discovery and diagnosis. However, the simultaneous detection of multiplex protein biomarkers from NPC is very challenging owing to ultra-low abundance and limited detection probes. Here, an aptamer-signatured NPC (ASNC)-based size-dependent fluorescence barcode is developed for flow cytometry profiling (FBFC) sensing platform to diagnose hepatocellular carcinoma (HCC).

Transferrin Receptor-Targeted Aptamer-Drug Conjugate Overcomes Blood-Brain Barrier for Potent Glioblastoma Therapy.

Glioblastoma (GBM) is the leading primary malignant tumor in the central nervous system. Current clinical therapeutics for treating GBM patients yield limited benefits. However, the development of new therapeutic methods is hindered because the blood-brain barrier (BBB) restricts drug penetration.

Identifying brain-penetrant small-molecule modulators of human microglia using a cellular model of synaptic pruning.

Microglia dysregulation is implicated across a range of neurodevelopmental and neurodegenerative disorders, making their modulation a promising therapeutic target. Using PBMC-derived induced microglia-like cells (piMGLCs) in a scalable assay, we screened 489 CNS-penetrant compounds for modulation of microglial phagocytosis of human synaptosomes in a validated assay for microglia-mediated synaptic pruning. Compounds from the library that reduced phagocytosis by ≥2 standard deviations across the library without cytotoxicity were validated in secondary screens, with 28 of them further confirmed to reduce phagocytosis by 50% or more.

Maternal Hypertension and Adverse Neurodevelopment in a Cohort of Preterm Infants.

Importance: Whether maternal hypertensive disorders of pregnancy (HDP) confer independent neurodevelopmental deficit risks in premature infants is controversial. Previous studies are limited by inadequate confounding variable control and other biases.

Objective: To evaluate the associations between maternal HDP, especially preeclampsia, and neurodevelopmental outcomes of preterm infants at 2 years' corrected age.

Engineering aptamer-directed phosphatase recruiting chimeras: a strategy for modulating receptor function and overcoming drug resistance.

Receptor tyrosine kinases (RTKs) play a crucial role in the regulation of intracellular signal transduction, underscoring their significance as targets for drug therapy. Despite the widespread clinical use of kinase inhibitors, the increasing occurrence of off-target effects and drug resistance makes it urgent to explore alternative approaches to modulate RTKs functions. Here, we propose an approach for attenuating cell-surface receptor signaling, termed Aptamer-directed Phosphatase Recruiting Chimeras (Apt-PRCs).

Knockdown TNF family prognosis index crucial gene PDE4B promoted PANoptosis of ovarian carcinoma cell:Based in vitro and in vivo experiments.

Ovarian cancer represents a malignancy characterized by high incidence and mortality rates, necessitating further elucidation of its underlying mechanisms. We conducted an analysis using bulk transcriptomic data of ovarian cancer and normal ovarian tissues, as well as single-cell sequencing data according to publicly available databases. Through calculation of Gene Set Variation Analysis (GSVA) scores for TNF family genes, weighted gene co-expression network analysis (WGCNA) for hub genes identification, and subsequent Gene Ontology (GO) enrichment analysis, we delineated pathways crucial in ovarian cancer pathogenesis.

Corneal Sensory Nerve Injury Disrupts Lacrimal Gland Function by Altering Circadian Rhythms in Mice.

Purpose: To investigate the impact of corneal sensory nerve injury on lacrimal gland function, focusing on mechanisms involving the superior salivatory nucleus (SSN), circadian rhythm disruption, immune microenvironment alterations, and the potential for neural regeneration.

Methods: A murine model of corneal sensory nerve injury was used to assess lacrimal gland function, with tear secretion measured using the phenol red thread test. Transcriptomic analysis of lacrimal glands examined circadian rhythm and immune-related gene expression.