Papers & Updates

This review comprehensively surveys recent advancements in the synthesis and structural diversification of chalcone derivatives, highlighting methods like Claisen–Schmidt condensation and the incorporation of various heterocyclic moieties. It thoroughly discusses their broad spectrum of biological activities, including anticancer, antimicrobial, and anti-inflammatory effects, along with their structure-activity relationships, demonstrating the potential for rational modification to improve therapeutic efficacy despite challenges in clinical translation.

This research developed a modular synthetic platform to create tuneable, amphiphilic polymer-metal hybrids by integrating ruthenium photoactive agents into diverse polymer architectures for antimicrobial photodynamic therapy (aPDT). The resulting polymers exhibited potent antibacterial activity against clinical strains, including multidrug-resistant *P. aeruginosa* biofilms, with low cytotoxicity, and specific structure-activity relationships were identified, guiding the development of rationally tuneable photoactive antimicrobials.

Immunomodulatory drugs (IMiDs) revolutionized multiple myeloma therapy by extending survival through their mechanism of Cereblon E3 ligase modulation and selective neosubstrate degradation. This mechanistic understanding drove the development of next-generation Cereblon E3 Ligase Modulators (CELMoDs) like iberdomide and mezigdomide, designed to overcome IMiD resistance and enhance efficacy, particularly in combination with emerging immunotherapies.

This study introduces a patient-specific, 3D-printed silicone mold system for repairing superior semicircular canal dehiscence (SSCD), addressing the limitations and vestibular function loss associated with conventional surgical methods. Designed from high-resolution CT scans, the mold facilitates ex-vivo casting of polymethyl methacrylate bone cement to precisely restore the canal's anatomy. Successfully validated in 3D-printed models and a first-in-human clinical case, this system achieved full symptom resolution and preserved vestibular function, marking a significant advance in precision inner-ear reconstruction.

Researchers employed a pharmacophore fusion strategy, integrating scaffolds from Napabucasin and curcumin, to design and identify LF39 as a novel, potent dual STAT3/TrxR1 inhibitor for colorectal cancer. LF39 exhibited significant antiproliferative activity against CRC cells by inducing apoptosis, directly inhibiting TrxR1, and abrogating STAT3 signaling, with validated dual-target binding and excellent biosafety, positioning it as a promising therapeutic lead compound.

This study chemogenetically excited or inhibited ventral dentate gyrus (vDG) PACAP neurons in PACAP-Cre mice to investigate their role in fear acquisition. The findings demonstrated that modulating these neurons did not impact fear learning at mild shock intensities, suggesting vDG PACAP neurons are not critical for fear acquisition under these specific conditions.

Plumieride (PR), an iridoid from *Plumeria rubra*, was demonstrated to ameliorate type 2 diabetes (T2D) by stimulating intestinal GLP-1 secretion and attenuate colitis by reducing intestinal oxidative stress and inflammation in mouse models. Pharmacokinetic analysis revealed PR's gut accumulation, and its metabolite, plumieride aglycone (PR-a), was identified as the active form, modulating intestinal functions via calcium signaling in L cells and NRF2/NLRP3 pathways in macrophages, thereby providing a mechanistic basis for its traditional uses.

This review highlights metallorganic compounds as a novel class of epigenetic therapeutics for cancer, designed to overcome the limitations of conventional epigenetic drugs like off-target toxicity and resistance. Their unique metal-center properties enable multi-target engagement with various epigenetic regulators (e.g., DNMTs, HDACs) and multimodal mechanisms, offering potential advantages for more durable antitumor responses and innovative precision oncology strategies.

This review presents ultrasound molecular imaging (USMI) as a novel, non-invasive, and real-time functional imaging paradigm for assessing tumor immunotherapy response. It details USMI's acoustic mechanisms and the design of immune-targeted microbubble/nanobubble probes, demonstrating its ability to dynamically track immune cell infiltration, quantify immune checkpoint expression, and predict therapeutic efficacy, offering superior spatiotemporal resolution over conventional methods.

This study developed a deep learning neural network, trained on extensive human transcriptomic data, to identify drug repurposing candidates. By applying this model to gene expression profiles from an *in vitro* cardiac hypertrophy model, researchers successfully correlated disease signals with known drug targets, identifying potential drugs like lapatinib and amiodarone for mitigating cardiac hypertrophy.

This paper identifies the retromer complex as a master regulator of the endosomal-lysosomal system, influencing shared neurodegenerative mechanisms like proteostasis, mitochondrial function, neurotransmission, and neuroinflammation in Alzheimer's, Parkinson's, and ALS. Findings indicate that enhancing retromer function improves these cellular processes and reduces disease pathology in model systems. Consequently, novel pharmacological agents designed to enhance retromer activity are being explored as a promising therapeutic strategy to slow the progression of these neurodegenerative diseases.

This study engineered an improved transformer base editor (tBE), named "etBE," by rational deaminase engineering and UGI fusion, to overcome the modest editing efficiency of previous tBEs while retaining their reduced off-target mutation rates. The etBE demonstrated up to a 35-fold improvement in editing efficiency compared to tBE, without increasing off-target mutations. As a therapeutic proof-of-concept, AAV-mediated etBE delivery in a humanized mouse model efficiently edited PCSK9 (up to 35.13%), leading to significant reductions in plasma PCSK9 (24%) and LDL-C (33%) with minimal off-target effects.

To overcome the limited affinity and selectivity of wild-type YTH domains for m6A-modified RNAs, this research utilized genetic code expansion to site-specifically incorporate noncanonical tryptophan derivatives into the m6A-binding pocket of the YTHDF1 domain. This strategy successfully yielded two YTH variants with enhanced m6A binding affinity and selectivity, demonstrating genetic code expansion as a promising method for engineering improved epitranscriptomic readers and highlighting the critical role of CH-π interactions in m6A recognition.

This theoretical and experimental study investigated small cationic antimicrobial peptides, revealing that their activity is critically influenced by the precise balance and spatial distribution of net positive charges and hydrophobic residues. It demonstrated these peptides require distinct positively charged and hydrophobic faces for proper interaction with bacterial membranes, supporting a unique three-step mechanism of action for small AMPs, distinct from their larger counterparts.

This first-in-human FIELD-PULSE trial evaluated a novel subsecond, high-voltage focal pulsed-field ablation (PFA) catheter designed for "instantaneous" point-by-point ablation in 35 atrial fibrillation patients. The study achieved acute pulmonary vein isolation in all participants, with an optimized waveform demonstrating 94.2% per-vein durability at 90 days and a favorable safety profile. These findings highlight the catheter's efficiency for creating individualized lesion sets without requiring prolonged catheter stability.

Utilizing DFT calculations, this study investigated CO oxidation on Pt single-atom and diatomic catalysts supported on CeO2 nanotubes with varying curvatures. It identified a novel curvature-induced reaction pathway switching for the critical OCOO intermediate, which proceeds via the Mars-van Krevelen mechanism. The Pt@(6, 6) nanotube, featuring high curvature and a single Pt atom, showed optimal catalytic performance (0.43 eV barrier) due to strong confinement and unique Pt coordination, offering theoretical guidance for designing efficient catalysts.

This first-in-human, Phase 1 randomized controlled trial assessed the safety and immunogenicity of two novel Group A Streptococcus peptide vaccine candidates, J8-K4S2 and p*17-K4S2, in 30 volunteers. Both vaccines were well tolerated with mild, transient adverse events comparable to a rabies vaccine comparator, and consistently induced robust, sustained antibody responses, achieving 100% seroconversion to key antigens that persisted for at least six months and recognized live *S. pyogenes*. These favorable safety and immunogenicity profiles support ongoing development of these promising candidates.

This first-in-human, multicentre Stage I study evaluated the novel non-adhesive liquid embolic agent, Amber 20, for peripheral vascular embolization in 15 patients. Results showed 100% technical success in achieving vascular occlusion and no device-related serious adverse events within 24 hours, indicating a favorable safety profile and potential as an effective agent.

This research introduces viroVbot, a novel in vivo CAR-T platform designed for enhanced safety and redosability by employing predictive de-immunization and precision targeting. The platform leverages an engineered Piry virus glycoprotein with low immunogenicity and optimized genetic controls to restrict CAR expression specifically to T lymphocytes. In humanized xenograft models, viroVbot demonstrated potent, specific, and redosable anti-tumor efficacy against B cell malignancies and solid tumors with minimal off-target effects.

This review comprehensively examined repurposed drugs and investigational therapeutics targeting six key pathological hallmarks of Parkinson's disease, such as alpha-synuclein aggregation and neuroinflammation. It revealed that agents like ambroxol, N-acetylcysteine, and metformin show promising mechanistic engagement and some clinical activity; however, late intervention timing and patient heterogeneity pose significant translational challenges that necessitate precision stratification and early biomarkers for successful future drug development.