Excess melanin deposition causes hyperpigmentation, a common dermatological disorder that leads to skin discoloration and an uneven skin tone. Traditional therapies such as topical creams and chemical peels have limitations due to insufficient skin penetration, lengthy treatment durations, and potential adverse effects. Transdermal drug administration has emerged as a viable alternative, offering improved therapeutic effectiveness, sustained release, and enhanced drug absorption. Among transdermal systems, microneedle-based patches have gained significant interest because of their ability to deliver active compounds directly through the skin, bypassing the stratum corneum. This study examines recent advancements in transdermal delivery for hyperpigmentation treatment, with a focus on dissolving microneedle (DMN) patches. Research indicates that DMN patches containing niacinamide, glabridin, and tranexamic acid exhibit greater skin-lightening effects than traditional topical formulations. Clinical studies have validated their safety, efficacy, and ability to reduce melasma and post-inflammatory hyperpigmentation with minimal side effects. Furthermore, novel polymeric formulations enhance drug absorption and stability, optimizing therapeutic outcomes. The use of multifunctional components, targeting tyrosinase inhibition, oxidative stress reduction, and melanin transfer, further improves depigmentation efficacy. The paper also highlights how emerging carriers, such as tetrahedral framework nucleic acids (tFNAs), may enhance drug delivery efficiency. As transdermal technologies continue to advance, microneedlebased approaches hold strong potential to transform hyperpigmentation treatment by providing a highly effective, non-invasive, and patient-friendly therapeutic option. Future research should focus on expanding clinical applications and refining formulation parameters to maximize benefits across diverse skin types.

Dawn vs. Dusk: Yoga practice timing shapes sleep, mood and well-being in young adults - results of a randomized controlled trial.

Inspired by endogenous physiological electric fields, electro-mediated therapeutic strategies represent promising approaches for targeted cancer therapy owing to their deep tissue penetration and spatiotemporal precision. The integration of biomaterials and nanotechnology with electrotherapy has emerged as a key strategy to enhance tumor-specific electron delivery and improve therapeutic outcomes. This review summarizes recent advances in bioengineered electrotherapy, covering technologies like electroporation, triboelectric nanogenerators, electrochemical systems (including galvanic, electrocatalytic, and piezoelectric/pyroelectric mechanisms), and eddy currents. Rational biomedical engineering design enables three primary therapeutic mechanisms: 1) disrupting cancer cell proliferation through membrane modulation, ion channel interference, and metabolic perturbation; 2) enabling precise drug/cytokine delivery via biomaterial-enhanced electroporation; and 3) modulating the tumor microenvironment (TME) through electrically triggered generation of heat, therapeutic gases (such as H2, H2S, and NO), and reactive oxygen species. Nanomaterial engineering strategies, including heterojunction construction, defect engineering, and surface modification, optimize charge transfer kinetics to potentiate electrical effects. The development of intelligent biohybrid platforms further advances capabilities for localized energy delivery, immune modulation, and TME reprogramming. This review highlights the pivotal role of biomedical engineering in advancing electrotherapeutic technologies and proposes translational frameworks that integrate bioactive materials, biotechnological tools, and precision electrical paradigms to address oncology challenges.

Introduction: Antisense molecules are short synthetic nucleic acid strands designed to bind to complementary sequences of messenger RNA (mRNA) to regulate gene expression. This study focuses on understanding the chemistry, modifications, and therapeutic applications of antisense molecules. Method: A comprehensive literature review was conducted using scientific databases, including PubMed, Scopus, and Google Scholar. Relevant published articles were selected using keywords such as “antisense oligonucleotides,” “gene silencing,” “therapeutic applications,” “neurological disorders,” and “cancer.” Studies included in this review consisted of research focusing on the mechanisms, delivery methods, and therapeutic outcomes of antisense oligonucleotides. Result: The data obtained in this study indicate that third-generation ASOs exhibit greater therapeutic efficacy than first- and second-generation ASOs. Discussion: This review compiles and discusses the mechanisms of action, structural features, chemical modifications, recent advances, applications, challenges, and future directions of ASOs in genetic disorders and other diseases. Conclusion: Antisense oligonucleotides (ASOs) have been successfully approved by the FDA for the development of drugs such as Nusinersen (used for the treatment of spinal muscular atrophy) and Fomivirsen (used for treating Cytomegalovirus retinitis). ASOs offer a unique ability to target specific RNA sequences and help overcome limitations associated with traditional therapies.

Traumatic optic neuropathy (TON) is a devastating cause of irreversible vision loss for which no effective treatment currently exists. Its poor prognosis stems from two major challenges: the limited regenerative capacity of retinal ganglion cells (RGCs) and the hostile, inflammation-driven environment that follows injury. In this work, using transcriptomic bioinformatic and histopathological analysis, we discovered that mechanical trauma and subsequent neuroinflammation trigger microglial pyroptosis through the NLRP3/CASP1/GSDMD pathway. This process amplifies inflammatory cascades and exacerbates RGC degeneration via microglia-neuron interactions. To overcome these dual barriers, we engineered a microglia-targeted lipid nanoparticle (LNP) platform co-delivering disulfiram (DSF), a selective GSDMD inhibitor, together with self-amplifying mRNA (saRNA) encoding ciliary neurotrophic factor (CNTF). We found that this combinatorial strategy concurrently suppresses pyroptosis-driven neuroinflammation while providing sustained neurotrophic support. Through comprehensive in vitro and in vivo evaluations, the co-delivery system showed enhanced RGC survival, remarkable axonal regeneration, and eventually significant restoration of visual function. In summary, our results demonstrate that a coordinated strategy targeting both neuroinflammatory mechanisms and regenerative pathways yields superior therapeutic outcomes in TON. This work underscores the potential of integrated RNA-small molecule therapies as a promising multi-target treatment paradigm, with broad applicability for other neuroinflammatory and neurodegenerative diseases.

COST action CA22103 Net4Brain: Pan-European Network Advancing Translational Research in Brain Cancer.

Host genetic ancestry plays an important role in shaping somatic mutation landscapes and may influence therapeutic outcomes as well as the risk of developing treatment-related adverse events. As genetic ancestry has been associated with differential susceptibility to melanoma subtypes, distinct somatic mutation frequencies and variable responses to immune checkpoint inhibitors warrant further investigation. This study investigated the genetic ancestry of a North American melanoma population using banked biospecimens from 744 patients enrolled in the ECOG-ACRIN E1609 phase III clinical trial (stages IIIB, IIIC, M1a, or M1b). Peripheral blood samples were genotyped using the Illumina Infinium Global Screening Array v3.0 + Multi-Disease BeadChip, followed by quality control, integration with reference dataset, and linkage disequilibrium pruning (198 064 single nucleotide polymorphisms). Dimensionality reduction was performed with Uniform Manifold Approximation and Projection analysis, and genetic ancestry was inferred using unsupervised ADMIXTURE models. Most patients (728 of 744; 97.8%) had predominant European (EUR) ancestry, followed by minor representation from admixed American (12 of 744; 1.6%) and East Asian (4 of 744; 0.5%) populations. Moreover, based on ADMIXTURE model (K = 5), 96.9% of participants had an estimated EUR ancestry proportion exceeding 80%. Self-reported race and ethnicity demonstrated strong concordance with genetically inferred ancestry, although a small subset of participants exhibited discordant ancestry components. Participants who self-identified as Hispanic exhibited mixed EUR-Admixed American ancestry components. Most patients represented predominant EUR ancestry, with limited representation of non-EUR populations. Integrating ancestry-informed genomic analyses will enhance understanding of melanoma susceptibility, improve prediction of immune-related adverse events, and support the development of tailored immunotherapy strategies.

Platinum-based chemotherapeutics remain clinically indispensable for treating various malignancies despite causing severe side effects, with ototoxicity being particularly limiting. This study reports the synthesis and evaluation of platinum(IV) prodrugs incorporating the hearing-protective ligand RG108. Among the synthesized mono- and di-substituted cisplatin and oxaliplatin derivatives, compound 4 exhibited exceptional antitumor activity with an IC50 value of 0.07 ± 0.08µM in FaDu cells. Mechanistic investigations revealed that the enhanced anti-tumor effect was primarily mediated via the EZH2/SLC47A2 regulatory axis. These prodrugs significantly mitigated ototoxicity, preserving cochlear hair cell viability, stabilizing auditory brainstem response thresholds, and maintaining cochlear basement membrane morphology. Our findings establish a framework for designing dual-functional platinum agents that synergize antitumor efficacy with organoprotective properties, addressing critical hearing loss limitations of conventional platinum chemotherapy while maintaining robust therapeutic outcomes.

Intraoral injection techniques have been reported in various countries, with their advantages well documented. Drawing upon existing literature on intraoral injections, we developed a novel intraoral submucosal zonal injection technique that has demonstrated promising therapeutic outcomes. However, its efficacy and safety require further validation through standardized clinical practice. The aim is compare the efficacy and safety of traditional extra-oral with novel intraoral submucosal zonal injection technique for improving perioral contour and assess the clinical applicability of the intraoral technique. Fifty-two female patients (aged 24-43) with perioral aging were randomized to receive either the traditional extra-oral injection group (Group A, n=26) or the intraoral submucosal zonal injection group (Group B, n=26). Efficacy was assessed using blinded digital photographic analysis, Global Aesthetic Improvement Scale, and Wrinkle Severity Rating Scale. Patient satisfaction, procedural pain, and adverse events were monitored. Intraoral submucosal zonal injection demonstrated clinical efficacy equivalent to extra-oral injection on GAIS and WSRS assessments, while significantly improving procedural comfort. This technique showed enhanced patient-rated acceptability in perioral regions including nasolabial folds, accompanied by significantly reduced VAS pain scores and decreased adverse event incidence. Compared to traditional extra-oral injection, intraoral submucosal zonal injection shows certain clinical advantages: significantly enhanced patient satisfaction and reducing the incidence of adverse reactions such as procedural pain. It can serve as an alternative option for improving perioral contour, particularly suitable for patients prioritizing comfort and minimal downtime. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Plant derived exosome-like nanoparticles (PELNs) are emerging as a powerful tool for treating cancers. Among them, PELNs derived from traditional Chinese medicines have shown great potential in treating various cancers. However, many Chinese medicines remain to be explored, and currently, there are no reports on the use of PELNs for treating prostate cancer. In this study, we extracted Huangqi derived exosome-like nanoparticles (HELNs) from fresh Huangqi (Astragalus membranaceus) and systematically explored the effects and mechanisms of HELNs in treating prostate cancer through an integrated approach of single-cell sequencing, 16S rDNA sequencing, and bulk-RNA sequencing. We found that HELNs demonstrated robust cytotoxic effects against prostate cancer both in vitro and in vivo. HELNs reverse the polarization of M2 macrophages, promote their M1-like polarization, and increase the abundance of anti-tumor probiotics in the gut to exert anti-tumor effects. In terms of direct effects, HELNs downregulate the expression level of GPX4 protein in prostate cancer cells, thereby inducing ferroptosis. Finally, we loaded siGPX4 into HELNs to construct a new nanoparticle siGPX4@HELNs. siGPX4@HELNs induce more pronounced ferroptosis in prostate cancer cells, achieving better therapeutic outcomes while maintaining safety.

Lipid nanoparticles (LNPs) play a critical role in the delivery of therapeutic messenger RNA (mRNA). Despite extensive efforts to optimize lipid formulations for in vivo delivery, efficacy of mRNA by LNPs remains suboptimal in many organs. Here, we demonstrate that LNP delivery efficacy is influenced by cellular metabolism, with the physiologic metabolome imposing constraints on mRNA expression from LNPs. Using an in vitro system, we found that simulated physiologic metabolic conditions led to the down-regulation of certain amino acid metabolic programs. Supplementation with an optimized formulation of methionine, arginine, and serine as an amino acid supplement (AAS) enhanced the uptake of LNPs and the expression of delivered mRNA cargo in epithelial cells in vitro. Coadministration of AAS with LNPs led to a 5- to 20-fold improvement in mRNA expression across various cell types and lipid formulations in vitro by promoting clathrin-independent carrier-mediated endocytosis. Delivery of mRNA by LNPs coadministered with AAS by multiple routes enhanced in vivo mRNA expression in preclinical models. Delivery of mRNA encoding growth hormone by LNPs with coadministration of AAS improved the liver growth hormone expression and the therapeutic outcomes in a model of inflammatory liver damage. Delivery of gene editing materials by LNP and AAS through an intratracheal route increased lung-targeted in vivo gene editing efficiency compared with LNP alone. The addition of an optimized AAS as a codelivered agent with LNPs may provide a simple strategy to broadly improve the efficacy of mRNA-based cell and gene therapies.

Immune checkpoint blockade (ICB) shows therapeutic promise in hepatocellular carcinoma (HCC) but is associated with suboptimal responses in patients. Progenitor exhausted T (Tpex) cells are key responders to ICB, but the regulatory mechanisms regarding Tpex maintenance in HCC remain elusive. Through an integrated analysis of HCC single-cell RNA-sequencing datasets, we constructed an exhausted CD8+ T cell atlas and identified FYN as a marker of Tpex cells in ICB responders. FYN deficiency in CD8+ T cells induced LCK hyperactivation, which drove terminal exhaustion under high-affinity antigen stimulation. Mechanistically, LCK hyperactivation disrupted metabolic homeostasis by triggering excessive glycolysis and impairing mitochondrial function in Tpex cells. Conversely, LCK inhibition elevated compensatory FYN activity, restored mitochondrial fitness and preserved Tpex cell stemness. In preclinical HCC models, transient LCK inhibition during T cell expansion enhanced adoptive cell therapy efficacy by increasing Tpex cell persistence and stemness. Besides, preemptive low-dose LCK inhibition prior to anti-PD1 therapy expanded the Tpex cell pool, reduced terminal exhaustion, and improved therapeutic outcomes. This study establishes the balance between SRC kinases FYN and LCK as a critical regulator of the terminal exhaustion of Tpex cell through metabolic reprogramming. The finding suggests that modulating the FYN/LCK kinase balance is a promising strategy to overcome immunotherapy resistance in HCC.

CC8, a heterodimeric disintegrin from Cerastes cerastes snake venom, triggers apoptosis and restrains the dissemination of human glioblastoma cells.

Tacrolimus (TAC) is recognized as a promising therapy for Dry Eye Disease (DED). Recent experimental studies indicate that TAC formulations, such as nanoemulsions and liposomes, notably improve tear production, stabilize the tear film, and reduce corneal damage in animal models. TAC achieves these effects by inhibiting T-cell activation and suppressing the production of inflammatory cytokines, primarily through the NF-κB signaling pathway. Clinical trials report that topical TAC, especially at 0.03% concentration, significantly alleviates both symptoms and signs in patients with Sjögren's syndrome and ocular graft-versushost disease. Critical clinical improvements include higher Schirmer test values, prolonged tear film break-up time, and decreased ocular surface staining. Comparative analyses suggest that TAC is at least as effective as cyclosporine and offers a favorable safety profile. Combining TAC with agents such as sodium hyaluronate may further enhance therapeutic outcomes. Despite the need for further studies to optimize dose and longterm safety, current evidence supports the use of TAC as an effective solution for individuals with refractory or severe DED, providing a vital option where conventional treatments may fail.

Chimeric antigen receptor (CAR)-T cell therapy targeting CD19 has transformed the treatment of hematologic malignancies. The costimulatory domain (CSD) of CAR constructs plays a crucial role in determining T cell metabolism, persistence, and antitumor function. We previously developed a novel CSD combining CD79A and CD40, which conferred superior proliferation and antitumor efficacy compared with CD28-based or 4-1BB-based CAR-T cells. The metabolic mechanisms underlying these effects remain to be elucidated. We compared CD28, 4-1BB, and CD79A/CD40 CAR-T cells using transcriptomic analysis, metabolic flux assays, and metabolomics. Patient samples treated with 4-1BB-based or CD28-based CAR-T therapies were analyzed to assess correlations between serum lipids and CAR-T expansion. Transcriptomic profiling revealed that CD79A/CD40 CAR-T cells shared gene expression patterns with 4-1BB CAR-T cells, particularly in pathways related to oxidative phosphorylation (OXPHOS) and T cell memory differentiation, but were distinct from CD28 CAR-T cells. Both 4-1BB and CD79A/CD40 CAR-T cells relied on OXPHOS and exhibited greater mitochondrial fitness, as evidenced by higher spare respiratory capacity and mitochondrial mass. Notably, CD79A/CD40 CAR-T cells displayed significantly enhanced glycolysis during the early phase following antigen stimulation, distinguishing them from 4-1BB CAR-T cells and supporting rapid initial expansion. Metabolomic profiling showed upregulation of cholesterol biosynthesis enzymes in both CD79A/CD40 and 4-1BB CAR-T cells, suggesting a shared reliance on cholesterol metabolism. Importantly, in patients treated with 4-1BB-based CAR-T therapy, higher serum low-density lipoprotein cholesterol levels positively correlated with CAR-T expansion in the late phase, particularly within CD4+T cell subsets. This relationship was not observed in patients receiving CD28-based CAR-T therapy. These findings indicate that cholesterol availability may influence CAR-T persistence in vivo, and that the metabolic phenotype of CD79A/CD40 CAR-T cells is optimized for both early proliferation and long-term survival. CD79A/CD40 CAR-T cells exhibit unique metabolic adaptations, including early glycolytic activation, sustained OXPHOS, and upregulated cholesterol metabolism, which together may underpin their enhanced proliferation and persistence. Targeting cholesterol metabolism may represent a novel strategy to optimize CAR-T cell function and improve therapeutic outcomes.

Minimally invasive glaucoma surgery (MIGS) is characterized by minimal injuries and complications, with its surgical volume increasing annually in China. It encompasses a diverse range of surgical techniques. To accurately understand and select appropriate surgical indications and ensure optimal therapeutic outcomes, this article emphasizes the necessity of proposing a new classification system for MIGS. By discussing the structural and functional complexity of the trabecular meshwork and Schlemm's canal and comparing the efficacy of MIGS with different design principles, we introduce the MIGS 4R classification system based on the structural and functional integrity of the trabecular meshwork and Schlemm's canal, along with a sequential surgical selection approach, to provide reference for ophthalmologists in clinical practice.

Since the dawn of the 21st century, the convergence of interdisciplinary fields─including life sciences, nanotechnology, and information technology─propels pharmaceuticals and healthcare into a period of rapid transformation. This paradigm shift catalyzes the emergence of innovative medical technologies. Immuno-oncology plays a pivotal role in cancer therapeutics. However, most patients derive limited benefits from currently available immunotherapies, while many experience immune-related adverse events (irAEs). Consequently, significant research efforts focus on developing nanomedicines that attenuate immunosuppression within the tumor microenvironment (TME) or enhance immune-cell-mediated tumor recognition and cytotoxicity. This review outlines nanomedicine-mediated immunotherapeutic strategies against tumors. Such novel approaches function as monotherapies or synergize with conventional oncology treatments to achieve superior therapeutic outcomes. Nanomedicine offers a transformative framework for precision cancer therapy through rational design principles that integrate tumor-specific characteristics and in vivo kinetics of drug transport. These advances hold promise for augmenting existing treatments and expanding therapeutic options for cancer patients. Finally, we critically analyze current challenges and depict the future directions in nanomedicine-driven immunotherapy, aiming to harness the immune system effectively against malignancies and ultimately expand the oncologist's armamentarium.

Parent-therapist therapeutic alliance - a neglected factor in pediatric speech-language intervention: A longitudinal study.

The prognosis for hepatocellular carcinoma remains grim. Combining radiotherapy with immune checkpoint blockade (ICB) has shown potential to enhance therapeutic outcomes, yet there is a pressing need for further advancements. Our previous research demonstrated that this combined approach suppresses ALKBH5 gene expression and increases m6A modification levels in hepatocellular carcinoma tissues. High-throughput sequencing and detailed molecular analysis revealed that inhibiting ALKBH5 amplifies CIITA m6A modifications post-therapy. This modulation triggers MHC II molecule expression in tumors, facilitating the presentation of tumor-associated antigens to CD4 + T lymphocytes and the recruitment of CD8 + T cells for an anti-tumor immune response. Building on these findings, we engineered a CIITA vector with a specific site mutation to confirm that the regulation of CIITA by the combined radiotherapy and immunotherapy is mediated through m6A methylation. Consequently, we established a comprehensive network involving ALKBH5, CIITA, MHC II, and CD4+ and CD8 + T cells. To elucidate the role and underlying molecular mechanisms of this combined therapy in reshaping the tumor immune microenvironment for hepatocellular carcinoma, we employed multi-omics approaches across in vitro, animal model, and clinical multi-dimensional studies, offering novel insights for enhancing treatment efficacy.

Optimizing mercaptopurine therapy in indian pediatric ALL: The role of TPMT and NUDT15 genetic polymorphisms.