A blood-based PT-LIFE (Pediatric Liver Transplantation-LIver Fibrosis Evaluation) biomarker panel for non-invasive evaluation of pediatric liver fibrosis after liver transplantation: a prospective derivation and validation study.

Allograft fibrosis is increasingly detected in graft biopsies as the postoperative period extends, potentially emerging as a pivotal determinant of long-term graft function and graft survival among pediatric recipients. Currently, there is a paucity of non-invasive diagnostic tools capable of identifying allograft fibrosis in pediatric recipients of liver transplants. This study involved 507 pediatric liver transplant patients and developed a novel blood-based diagnostic assay, PT-LIFE, to noninvasively distinguish allograft fibrosis using blood samples, clinical data, and biopsy outcomes. The PT-LIFE assay was derived from a matrix of 23 variables and validated in two independent cohorts. It integrates three biomarkers (LECT2, YKL-40, FBLN3) with an AUROC of 0.91. In the pooled analysis, a PT-LIFE score lower than 0.12 identified LAFSc 0-2 with a sensitivity of 91.9%, whereas scores above 0.29 indicated LAFSc 3-6, with a specificity of 88.4%. The PT-LIFE assay presents as a promising non-invasive diagnostic tool for the detection of allograft fibrosis in pediatric liver transplant recipients. The study is registered with ClinicalTrials.gov, identifier NCT05308628.

Immune remodulation in pediatric inherited metabolic liver diseases.

Inherited metabolic liver diseases arise from genetic mutations that lead to disruptions in liver metabolic pathways and are predominantly observed in pediatric populations. The spectrum of genetic metabolic liver disorders is diverse, encompassing a range of conditions associated with aberrations in iron, copper, carbohydrate, lipid, protein, and amino acid metabolism. Historically, research in the domain of genetic metabolic liver diseases has predominantly concentrated on hepatic parenchymal cell alterations. Nevertheless, emerging studies suggest that inherited metabolic liver diseases exert significant influences on the immune microenvironment, both within the liver and systemically. This review endeavors to encapsulate the immunological features of genetic metabolic liver diseases, aiming to expand the horizons of researchers in this discipline, and to elucidate the underlying pathophysiological mechanisms pertinent to hereditary metabolic liver diseases and to propose innovative therapeutic approaches.

Mapping Endocytic Vesicular Acidification with a pH-Responsive DNA Nanomachine.

Mapping the endocytic vesicular acidification process is of prior importance to better understand the health and pathological processes of cells. Herein, by integrating a pH-sensitive i-motif and a pair of fluorescence resonance energy transfer (FRET) into a tetrahedral DNA framework (TDF), we develop a pH-responsive DNA nanomachine, allowing for efficient sensing of pH from 7.0 to 5.5 via the pH-triggered spatial proximity modulation of FRET. The inheriting endo-lysosome-targeting ability of TDF enables spatiotemporal tracking of endocytic vesicle acidification during the endosomal maturation process. Analysis of pH-dependent FRET response at single fluorescent spot level reveals the significant difference of endocytic vesicular acidification between normal and cancer cells. The performance of pH-responsive DNA nanomachine underlines its potential for studies on vesicle acidification-related pathologies as a universal platform.

IMPDH2 suppression impedes cell proliferation by instigating cell cycle arrest and stimulates apoptosis in pediatric hepatoblastoma.

BACKGROUND: Hepatoblastoma (HB) is the most common pediatric liver tumor, presenting significant therapeutic challenges due to its high rates of recurrence and metastasis. While Inosine Monophosphate Dehydrogenase 2(IMPDH2) has been associated with cancer progression, its specific role and clinical implications in HB have not been fully elucidated. METHODS: This study utilized Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Tissue Microarray (TMA) for validation. Following this, IMPDH2 was suppressed, and a series of in vitro assays were conducted. Flow cytometry was employed to assess apoptosis and cell cycle arrest. Additionally, the study explored the synergistic therapeutic effects of mycophenolate mofetil (MMF) and doxorubicin (DOX) on HB cell lines. RESULTS: The study identified a marked overexpression of IMPDH2 in HB tissues, which was strongly correlated with reduced Overall Survival (OS) and Event-Free Survival (EFS). IMPDH2 upregulation was also found to be associated with key clinical-pathological features, including pre-chemotherapy alpha-fetoprotein (AFP) levels, presence of preoperative metastasis, and the pre-treatment extent of tumor (PRETEXT) staging system. Knockdown of IMPDH2 significantly inhibited HB cell proliferation and tumorigenicity, inducing cell cycle arrest at the G0/G1 phase. Notably, the combination of MMF, identified as a specific IMPDH2 inhibitor, with DOX, substantially enhanced the therapeutic response. CONCLUSION: The overexpression of IMPDH2 was closely linked to adverse outcomes in HB patients and appeared to accelerate cell cycle progression. These findings suggest that IMPDH2 may serve as a valuable prognostic indicator and a potential therapeutic target for HB. IMPACT: The present study unveiled a significant overexpression of inosine monophosphate dehydrogenase 2 (IMPDH2) in hepatoblastoma (HB) tissues, particularly in association with metastasis and recurrence of the disease. The pronounced upregulation of IMPDH2 was found to be intimately correlated with adverse outcomes in HB patients. This overexpression appears to accelerate the progression of the cell cycle, suggesting that IMPDH2 may serve as a promising candidate for both a prognostic marker and a therapeutic target in the context of HB.

Pembrolizumab in combination with lenvatinib in participants with hepatocellular carcinoma (HCC) before liver transplant as neoadjuvant therapY-PLENTY pilot study.

BACKGROUND: The high recurrent rate after liver transplantation (LT) remains a clinical challenge, especially for those exceeding the Milan criteria (MC) and with high RETREAT scores. Therefore, the authors aim to investigate whether neoadjuvant systemic therapy allows safely administered and effectively reduces post-LT recurrence for those patients. METHODS: In this prospective, randomized, open-label, pilot study, patients with HCC exceeding the MC were randomly assigned to PLENTY or control group before LT. The primary endpoint of the study was the recurrence-free survival after LT. RESULTS: Twenty-two patients were enrolled and randomly assigned: 11 to the PLENYT group and 11 to the control group. The 30-month tumor-specific RFS was 37.5% in the PLENTY group and 12.5% in the control group. The 12-month tumor-specific RFS after LT was significantly improved in the PLENTY group (87.5%) compared to the control group (37.5%) (P=0·0022). The objective response rate in the PLENTY group was 30 and 60% when determined by RECIST 1.1 and mRECIST, respectively. Six patients (60%) had significant tumor necrosis, including three (30%) who had complete tumor necrosis at histopathology. No acute allograft rejection after LT occurred in the PLENTY and Control group. CONCLUSION: Neoadjuvant pembrolizumab plus lenvatinib before LT appears to be safe and feasible, associated with significantly better RFS for patients exceeding the MC. Despite the limitations of small sample size, this is the first RCT to evaluate neoadjuvant PD-1 blockade combined with tyrosine kinase inhibitors in LT recipients, the results of this study will inform future research.

Programmable DNA Hydrogel Assisting Microcrystal Formulations for Sustained Locoregional Drug Delivery in Surgical Residual Tumor Lesions and Lymph Node Metastasis.

Surgical residual tumor lesions (R1 resection of surgical procedures (e.g., liver cancer infiltrating the diaphragm, surgical residual breast cancer, postoperative residual ovarian cancer) or boundary residual after ablation) and lymph node metastasis that cannot be surgically resected (retroperitoneal lymph nodes) significantly affect postoperative survival of tumor patients. This clinical conundrum poses three challenges for local drug delivery systems: stable and continuous delivery, good biocompatibility, and the ability to package new targeted drugs that can synergize with other treatments. Here, a drug-laden hydrogel generated from pure DNA strands and highly programmable in adjusting its mesh size is reported. Meanwhile, the DNA hydrogel can assist the microcrystallization of novel radiosensitizing drugs, ataxia telangiectasia and rad3-related protein (ATR) inhibitor (Elimusertib), further facilitating its long-term release. When applied to the tumor site, the hydrogel system demonstrates significant antitumor activity, minimized systemic toxicity, and has a modulatory effect on the tumor-immune cell interface. This drug-loaded DNA-hydrogel platform represents a novel modality for adjuvant therapy in patients with surgical residual tumor lesions and lymph node metastasis.

DNA Framework-Based Topological Cell Sorters.

Molecular recognition in cell biological process is characterized with specific locks-and-keys interactions between ligands and receptors, which are ubiquitously distributed on cell membrane with topological clustering. Few topologically-engineered ligand systems enable the exploration of the binding strength between ligand-receptor topological organization. Herein, we generate topologically controlled ligands by developing a family of tetrahedral DNA frameworks (TDFs), so the multiple ligands are stoichiometrically and topologically arranged. This topological control of multiple ligands changes the nature of the molecular recognition by inducing the receptor clustering, so the binding strength is significantly improved (ca. 10-fold). The precise engineering of topological complexes formed by the TDFs are readily translated into effective binding control for cell patterning and binding strength control of cells for cell sorting. This work paves the way for the development of versatile design of topological ligands.

A new class of electrolytes based on magnesium bis(diisopropyl)amide for magnesium-sulfur batteries.

We present a new class of electrolytes, which has relatively high anodic stability on stainless steel (2.65 V, vs. Mg RE), low over-potential for Mg plating/stripping and close to 100% coulombic efficiency, for Mg-S batteries prepared by a facile in situ reaction of commercial magnesium bis(diisopropyl)amide (MBA) with AlCl3, The resulting Mg-S battery shows a highly stable discharge capacity of approximately 540 mA h g-1 for 30 cycles and one well-defined voltage plateau of about 1.1 V vs. Mg.