Response-adapted consolidation therapy strategy for patients with metastatic high-risk neuroblastoma: Results of the SMC NB-2014 study.

BACKGROUND: Tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) and incorporation of 131I-metaiodobenzylguanidine (131I-MIBG) treatment have shown positive outcomes in high-risk neuroblastoma. However, more optimized treatment strategies are still needed. PROCEDURE: The NB-2014 study was a nonrandomized, prospective trial that examined survival outcomes in metastatic high-risk neuroblastoma patients using response-adapted consolidation therapy. We used post-induction residual 123I-MIBG status at metastatic sites as a treatment response marker. Patients achieving complete resolution of MIBG uptake at metastatic sites underwent a reduced first HDCT/auto-SCT with a 20% dose reduction in HDCT. After the first HDCT/auto-SCT, patients with remaining MIBG uptake received dose-escalated (18 mCi/kg) 131I-MIBG treatment. In contrast, those with complete resolution of MIBG at metastatic sites received a standard dose (12 mCi/kg) of 131I-MIBG. We compared survival and toxicity outcomes with a historical control group from the NB-2009. RESULTS: Of 65 patients treated, 63% achieved complete resolution of MIBG uptake at metastatic sites following induction chemotherapy, while 29% of patients still had MIBG uptake at metastatic sites after the first HDCT/auto-SCT. The 3-year event-free survival (EFS) and overall survival (OS) rates were 68.2% ± 6.0% and 86.5% ± 4.5%, respectively. Compared to NB-2009, EFS was similar (p = .855); however, NB-2014 had a higher OS (p = .031), a lower cumulative incidence of treatment-related mortality (p = .036), and fewer acute and late toxicities. CONCLUSIONS: Our results suggest that response-adaptive consolidation therapy based on chemotherapy response at metastatic sites facilitates better treatment tailoring, and appears promising for patients with metastatic high-risk neuroblastoma.

3D-PSSIM: Projective Structural Similarity for 3D Mesh Quality Assessment Robust to Topological Irregularities.

Despite acceleration in the use of 3D meshes, it is difficult to find effective mesh quality assessment algorithms that can produce predictions highly correlated with human subjective opinions. Defining mesh quality features is challenging due to the irregular topology of meshes, which are defined on vertices and triangles. To address this, we propose a novel 3D projective structural similarity index ( 3D- PSSIM) for meshes that is robust to differences in mesh topology. We address topological differences between meshes by introducing multi-view and multi-layer projections that can densely represent the mesh textures and geometrical shapes irrespective of mesh topology. It also addresses occlusion problems that occur during projection. We propose visual sensitivity weights that capture the perceptual sensitivity to the degree of mesh surface curvature. 3D- PSSIM computes perceptual quality predictions by aggregating quality-aware features that are computed in multiple projective spaces onto the mesh domain, rather than on 2D spaces. This allows 3D- PSSIM to determine which parts of a mesh surface are distorted by geometric or color impairments. Experimental results show that 3D- PSSIM can predict mesh quality with high correlation against human subjective judgments, across the presence of noise, even when there are large topological differences, outperforming existing mesh quality assessment models.

Sargassum horneri extract fermented by Lactiplantibacillus pentosus SH803 mediates adipocyte metabolism in 3T3-L1 preadipocytes by regulating oxidative damage and inflammation.

Sargassum horneri (S. horneri), a brown seaweed excessively proliferating along Asian coastlines, are damaging marine ecosystems. Thus, this study aimed to enhance nutritional value of S. horneri through lactic acid bacteria fermentation to increase S. horneri utilization as a functional food supplement, and consequently resolve coastal S. horneri accumulation. S. horneri supplemented fermentation was most effective with Lactiplantibacillus pentosus SH803, thus this product (F-SHWE) was used for further in vitro studies. F-SHWE normalized expressions of oxidative stress related genes NF-κB, p53, BAX, cytochrome C, caspase 9, and caspase 3, while non-fermented S. horneri (SHWE) did not, in a H2O2-induced HT-29 cell model. Moreover, in an LPS-induced HT-29 cell model, F-SHWE repaired expressions of inflammation marker genes ZO1, IL1ß, IFNγ more effectively than SHWE. For further functional assessment, F-SHWE was also treated in 3T3-L1 adipocytes. As a result, F-SHWE decreased lipid accumulation, along with gene expression of adipogenesis markers PPARγ, C/EBPα, C/EBPß, aP2, and Lpl; lipogenesis markers Lep, Akt, SREBP1, Acc, Fas; inflammation markers IFN-γ and NF-κB. Notably, gene expression of C/EBPß, IFN-γ and NF-κB were suppressed only by F-SHWE, suggesting the enhancing effect of fermentation on obesity-related properties. Compositional analysis attributed the protective effects of F-SHWE to acetate, an organic acid significantly higher in F-SHWE than SHWE. Therefore, F-SHWE is a novel potential anti-obesity agent, providing a strategy to reduce excess S. horneri populations along marine ecosystems.

Improved Reversibility of Thin-Film Solid Oxide Cells at 500 °C by Tailoring Sputtering Processes for Depositing Yttria-Stabilized Zirconia Electrolyte.

The present study investigates the impact of sputtering configurations on the microstructure and crystallinity of thin-film yttria-stabilized zirconia electrolytes for anodized aluminum oxide-supported all-sputtered thin-film reversible solid oxide cells. Employing various sputtering parameters, such as target-substrate distance and substrate rotation speed, the present study reveals distinct surface characteristics and crystalline structures of thin-film yttria-stabilized zirconia. The microstructure analysis includes scanning electron microscopy and atomic force microscopy examinations, uncovering the influence of the process parameters on the surface morphology, roughness, and grain size. X-ray diffraction data illustrate the texture preferences and crystallite characteristics. The electrochemical characterization of the reversible solid oxide cells demonstrates that the optimized sputtering configuration significantly outperforms the others in both SOFC and SOEC modes, showing exceptional current densities of 964 mA/cm2 at 1.3 V in electrolysis mode at 500 °C. Electrochemical impedance spectroscopy further reveals improved charge transfer reactions at the interface of the electrolyte. The enhanced electrochemical performance is attributed to the unique microstructure and crystallinity of the thin film of yttria-stabilized zirconia. The record-breaking electrolysis performance of this work at 500 °C underscores the potential of tailored sputtering parameters in optimizing the reversible solid oxide cell performance.

Current strategies using 3D organoids to establish in vitro maternal-embryonic interaction.

IMPORTANCE: The creation of robust maternal-embryonic interactions and implantation models is important for comprehending the early stages of embryonic development and reproductive disorders. Traditional two-dimensional (2D) cell culture systems often fail to accurately mimic the highly complex in vivo conditions. The employment of three-dimensional (3D) organoids has emerged as a promising strategy to overcome these limitations in recent years. The advancements in the field of organoid technology have opened new avenues for studying the physiology and diseases affecting female reproductive tract. OBSERVATIONS: This review summarizes the current strategies and advancements in the field of 3D organoids to establish maternal-embryonic interaction and implantation models for use in research and personalized medicine in assisted reproductive technology. The concepts of endometrial organoids, menstrual blood flow organoids, placental trophoblast organoids, stem cell-derived blastoids, and in vitro-generated embryo models are discussed in detail. We show the incorportaion of organoid systems and microfluidic technology to enhance tissue performance and precise management of the cellular surroundings. CONCLUSIONS AND RELEVANCE: This review provides insights into the future direction of modeling maternal-embryonic interaction research and its combination with other powerful technologies to interfere with this dialogue either by promoting or hindering it for improving fertility or methods for contraception, respectively. The merging of organoid systems with microfluidics facilitates the creation of sophisticated and functional organoid models, enhancing insights into organ development, disease mechanisms, and personalized medical investigations.

The obesogen bisphenol A promotes adipogenesis in canine adipose-derived stem cells: Potential implication in dog obesity.

The growing number of companion dogs has contributed to a rapidly growing market for pet products, including dog toys. However, little is known about the hazardous substances released from dog toys. This study aims to examine the potential presence of obesogens, a subset of endocrine-disrupting chemicals (EDCs) that are widely utilized as raw materials in the manufacture of dog toy components, and their effects on dog health. To achieve this, we adapted and employed a migration method typically used for children's products to simulate obesogen exposure in dogs through sucking or chewing toys. We demonstrated that out of various obesogens, bisphenol A (BPA) was released from dog toys into synthetic saliva, whereas phthalates and azo dyes were not detected in any of the leachates. Additionally, we found that BPA induced adipogenic differentiation in canine adipose-derived stem cells (cADSCs). Our RNA sequencing experiments revealed that BPA alters the adipogenesis-related gene signature in cADSCs by elevating the expression levels of ADIPOQ, PLIN1, PCK1, CIDEC, and FABP4. The associated transcriptional changes are involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, which may contribute to the promotion of adipogenesis by BPA. Our findings suggest that companion dogs are at risk of BPA exposure, which may contribute to obesity in dogs. Therefore, the implementation of precautionary measures is crucial.

MolPLA: a molecular pretraining framework for learning cores, R-groups and their linker joints.

MOTIVATION: Molecular core structures and R-groups are essential concepts in drug development. Integration of these concepts with conventional graph pre-training approaches can promote deeper understanding in molecules. We propose MolPLA, a novel pre-training framework that employs masked graph contrastive learning in understanding the underlying decomposable parts in molecules that implicate their core structure and peripheral R-groups. Furthermore, we formulate an additional framework that grants MolPLA the ability to help chemists find replaceable R-groups in lead optimization scenarios. RESULTS: Experimental results on molecular property prediction show that MolPLA exhibits predictability comparable to current state-of-the-art models. Qualitative analysis implicate that MolPLA is capable of distinguishing core and R-group sub-structures, identifying decomposable regions in molecules and contributing to lead optimization scenarios by rationally suggesting R-group replacements given various query core templates. AVAILABILITY AND IMPLEMENTATION: The code implementation for MolPLA and its pre-trained model checkpoint is available at https://github.com/dmis-lab/MolPLA.

iGenSig-Rx: an integral genomic signature based white-box tool for modeling cancer therapeutic responses using multi-omics data.

Multi-omics sequencing is poised to revolutionize clinical care in the coming decade. However, there is a lack of effective and interpretable genome-wide modeling methods for the rational selection of patients for personalized interventions. To address this, we present iGenSig-Rx, an integral genomic signature-based approach, as a transparent tool for modeling therapeutic response using clinical trial datasets. This method adeptly addresses challenges related to cross-dataset modeling by capitalizing on high-dimensional redundant genomic features, analogous to reinforcing building pillars with redundant steel rods. Moreover, it integrates adaptive penalization of feature redundancy on a per-sample basis to prevent score flattening and mitigate overfitting. We then developed a purpose-built R package to implement this method for modeling clinical trial datasets. When applied to genomic datasets for HER2 targeted therapies, iGenSig-Rx model demonstrates consistent and reliable predictive power across four independent clinical trials. More importantly, the iGenSig-Rx model offers the level of transparency much needed for clinical application, allowing for clear explanations as to how the predictions are produced, how the features contribute to the prediction, and what are the key underlying pathways. We anticipate that iGenSig-Rx, as an interpretable class of multi-omics modeling methods, will find broad applications in big-data based precision oncology. The R package is available: https://github.com/wangxlab/iGenSig-Rx .

Electrophysiological Analysis of Retinal Organoid Development Using 3D Microelectrodes of Liquid Metals.

Despite of the substantial potential of human-derived retinal organoids, the degeneration of retinal ganglion cells (RGCs) during maturation limits their utility in assessing the functionality of later-born retinal cell subtypes. Additionally, conventional analyses primarily rely on fluorescent emissions, which limits the detection of actual cell functionality while risking damage to the 3D cytoarchitecture of organoids. Here, an electrophysiological analysis is presented to monitor RGC development in early to mid-stage retinal organoids, and compare distinct features with fully-mature mouse retina. This approach utilizes high-resolution 3D printing of liquid-metal microelectrodes, enabling precise targeting of specific inner retinal layers within organoids. The adaptable distribution and softness of these microelectrodes facilitate the spatiotemporal recording of inner retinal signals. This study not only demonstrates the functional properties of RGCs in retinal organoid development but also provides insights into their synaptic connectivity, reminiscent of fetal native retinas. Further comparison with fully-mature mouse retina in vivo verifies the organoid features, highlighting the potential of early-stage retinal organoids in biomedical research.

Selecting serum-free hepatocyte cryopreservation stage and storage temperature for the application of an "off-the-shelf" bioartificial liver system.

The bioartificial liver (BAL) system can potentially rescue acute liver failure (ALF) patients by providing partial liver function until a suitable donor liver can be found or the native liver has self-regenerated. In this study, we established a suitable cryopreservation process for the development of an off-the-shelf BAL system. The viability of hepatocyte spheroids cryopreserved in liquid nitrogen was comparable to that of fresh primary hepatocyte spheroids. When hepatocyte spheroids were subjected to cryopreservation in a deep freezer, no statistically significant differences were observed in ammonia removal rate or urea secretion rate based on the cryopreservation period. However, the functional activity of the liver post-cryopreservation in a deep freezer was significantly lower than that observed following liquid nitrogen cryopreservation. Moreover, cryopreserving spheroid hydrogel beads in a deep freezer resulted in a significant decrease (approximately 30%) in both ammonia removal and urea secretion rates compared to the group cryopreserved in liquid nitrogen. The viabilities of spheroid hydrogel beads filled into the bioreactor of a BAL system were similar across all four groups. However, upon operating the BAL system for 24 h, the liver function activity was significantly higher in the group comprising hydrogel beads generated after thawing hepatocyte spheroids cryopreserved in liquid nitrogen. Consequently, the manufacturing of beads after the cryopreservation of hepatocyte spheroids is deemed the most suitable method, considering efficiency, economic feasibility, and liver function activity, for producing a BAL system.

Recent Advancement in Diagnosis of Biliary Tract Cancer through Pathological and Molecular Classifications.

Biliary tract cancers (BTCs), including intrahepatic, perihilar, and distal cholangiocarcinomas, as well as gallbladder cancer, are a diverse group of cancers that exhibit unique molecular characteristics in each of their anatomic and pathological subtypes. The pathological classification of BTCs compromises distinct growth patterns, including mass forming, periductal infiltrating, and intraductal growing types, which can be identified through gross examination. The small-duct and large-duct types of intrahepatic cholangiocarcinoma have been recently introduced into the WHO classification. The presentation of typical clinical symptoms, as well as the extensive utilization of radiological, endoscopic, and molecular diagnostic methods, is thoroughly detailed in the description. To overcome the limitations of traditional tissue acquisition methods, new diagnostic modalities are being explored. The treatment landscape is also rapidly evolving owing to the emergence of distinct subgroups with unique molecular alterations and corresponding targeted therapies. Furthermore, we emphasize the crucial aspects of diagnosing BTC in practical clinical settings.

Trapping mechanism by di-d-psicose anhydride with methylglyoxal for prevention of diabetic nephropathy.

Di-d-psicose anhydride (DPA), derived from functional rare saccharide as d-psicose, is investigated for its strong chelating ability. Methylglyoxal (MGO), an important precursor of advanced glycation end-products (AGEs), promotes obesity, and causes complications such as diabetic nephropathy. On mesangial cells, DPA can substantially reduce the negative effects of MGO. DPA effectively trapping MGO in mesangial cells. The bonding properties of the DPA-MGO adduct were discussed by mass spectrometry and nuclear magnetic resonance (NMR). The NMR spectra of the DPA-MGO adduct provide evidence for chelation bonding. The inhibition of AGE formation and the mass spectrometry results of the DPA-MGO adduct indicate that DPA can scavenge MGO at a molar ratio of 1:1. DPA suppressed 330 % of the up-regulated receptor for an AGEs protein expression to a normal level and restored the suppressed glyoxalase 1 level to 86 % of the normal group. This research provides important evidence and theoretical basis for the development of AGE inhibitors derived from rare saccharide.

Enhanced plant-derived vesicles for nucleotide delivery for cancer therapy.

Small RNAs (microRNAs [miRNAs] or small interfering RNAs [siRNAs]) are effective tools for cancer therapy, but many of the existing carriers for their delivery are limited by low bioavailability, insufficient loading, impaired transport across biological barriers, and low delivery into the tumor microenvironment. Extracellular vesicle (EV)-based communication in mammalian and plant systems is important for many physiological and pathological processes, and EVs show promise as carriers for RNA interference molecules. However, some fundamental issues limit their use, such as insufficient cargo loading and low potential for scaling production. Plant-derived vesicles (PDVs) are membrane-coated vesicles released in the apoplastic fluid of plants that contain biomolecules that play a role in several biological mechanisms. Here, we developed an alternative approach to deliver miRNA for cancer therapy using PDVs. We isolated vesicles from watermelon and formulated a hybrid, exosomal, polymeric system in which PDVs were combined with a dendrimer bound to miRNA146 mimic. Third generation PAMAM was chosen due to its high branching structure and versatility for loading molecules of interest. We performed several in vivo experiments to demonstrate the therapeutic efficacy of our compound and explored in vitro biological mechanisms underlying the anti-tumor effects of miRNA146, which are mostly related to its anti-angiogenic activity.

Optimal Dietary Intake of Riboflavin Associated with Lower Risk of Cervical Cancer in Korea: Korean National Health and Nutrition Examination Survey 2010-2021.

BACKGROUND: This study aimed to evaluate the association between the dietary intake of vitamin B complex (thiamine, riboflavin, and niacin) and cervical cancer in Korea. METHODS: The data from the Korean National Health and Nutrition Examination Survey (KNHANES) from 2010 to 2021 were analyzed, which included 28,306 participants who were categorized into non-cervical cancer and cervical cancer groups. The following dietary intake threshold levels of thiamine, riboflavin, and niacin were identified based on the recommended daily allowances (RDAs): thiamine, 1.1 mg/day; riboflavin, 1.2 mg/day; and niacin, 14 mg/day. RESULTS: Among 28,306 participants, 27,976 were in the non-cervical cancer group and 330 were in the cervical cancer group. Riboflavin intakes of more than 1.2 mg/day but less than 2.4 mg/day were associated with a significantly reduced risk of cervical cancer, whereas intakes of above 2.4 mg/day were not associated with cervical cancer. Thiamine and niacin intakes were not significantly related to the risk of cervical cancer. CONCLUSIONS: The results of this study suggest that an intake of riboflavin of 1.2-2.4 mg/day may contribute to a lower risk of cervical cancer.

Isolation and characterization of novel 3,3'-iminodipropionitrile biodegrading Paracoccus communis, from an industrial wastewater treatment bioreactor.

Until now, bacteria able to degrade, 3,3'-iminodipropionitrile (IDPN), a neurotoxin that destroys vestibular hair cells, causing ototoxicity, culminating in irreversible movement disorders, had never been isolated. The aim of this study was to isolate a novel IDPN-biodegrading microorganism and characterize its metabolic pathway. Enrichment was performed by inoculating activated sludge from a wastewater treatment bioreactor that treated IDPN-contaminated wastewater in M9 salt medium, with IDPN as the sole carbon source. A bacterial strain with a spherical morphology that could grow at high concentrations was isolated on a solid medium. Growth of the isolated strain followed the Monod kinetic model. Based on the 16S rRNA gene, the isolate was Paracoccus communis. Whole-genome sequencing revealed that the isolated P. communis possessed the expected full metabolic pathway for IDPN biodegradation. Transcriptome analyses confirmed the overexpression of the gene encoding hydantoinase/oxoprolinase during the exponential growth phase under IDPN-fed conditions, suggesting that the enzyme involved in cleaving the imine bond of IDPN may promote IDPN biodegradation. Additionally, the newly discovered P. communis isolate seems to metabolize IDPN through cleavage of the imine bond in IDPN via nitrilase, nitrile hydratase, and amidase reactions. Overall, this study lays the foundation for the application of IDPN-metabolizing bacteria in the remediation of IDPN-contaminated environments.

Cancer-cell derived S100A11 promotes macrophage recruitment in ER+ breast cancer.

Macrophages are pivotal in driving breast tumor development, progression, and resistance to treatment, particularly in estrogen receptor-positive (ER+) tumors, where they infiltrate the tumor microenvironment (TME) influenced by cancer cell-secreted factors. By analyzing single-cell RNA-sequencing data from 25 ER+ tumors, we elucidated interactions between cancer cells and macrophages, correlating macrophage density with epithelial cancer cell density. We identified that S100A11, a previously unexplored factor in macrophage-cancer crosstalk, predicts high macrophage density and poor outcomes in ER+ tumors. We found that recombinant S100A11 enhances macrophage infiltration and migration in a dose-dependent manner. Additionally, in 3D models, we showed that S100A11 expression levels in ER+ cancer cells predict macrophage infiltration patterns. Neutralizing S100A11 decreased macrophage recruitment, both in cancer cell lines and in a clinically relevant patient-derived organoid model, underscoring its role as a paracrine regulator of cancer-macrophage interactions in the protumorigenic TME. This study offers novel insights into the interplay between macrophages and cancer cells in ER+ breast tumors, highlighting S100A11 as a potential therapeutic target to modulate the macrophage-rich tumor microenvironment.

Costotransverse joint ankylosis and their association with syndesmophyte progression in patients with radiographic axial spondyloarthritis.

Background: Abnormal new bone formation can occur not only in the vertebral body but also can occur in facet, costovertebral, and costotransverse joints in radiographic axial spondyloarthritis (r-axSpA) patients. Little is known about the association between syndesmophyte progression and paravertebral joint ankylosis in r-axSpA. Objectives: Costotransverse joint ankylosis in r-axSpA patients was measured. Furthermore, the association between syndesmophyte progression for 2 years assessed by computed tomography syndesmophyte score (CTSS) and facet, costovertebral, and costotransverse joints ankylosis were evaluated. Design: Single-center, prospective, cohort study. Methods: Whole spine CT images taken at baseline and 2-year follow-up were used to calculate the CTSS of the vertebral body. In addition, ankylosis of the facet/costovertebral/costotransverse joints was scored. CTSS (range, 0-552) and facet joint ankylosis (range, 0-46) were assessed at 23 vertebral units. Costovertebral joints at T1-T12 (range, 0-48) and costotransverse joints at T1-T10 (range, 0-20) were also assessed by independent two readers. Intraclass correlation coefficients (ICC) were calculated to determine inter-reader reliability. Odds ratios (OR) were calculated to identify the associations between syndesmophyte progression and the baseline status of facet, costovertebral, and costotransverse joints. Results: In all, 50 patients with r-axSpA were included. Readers 1 and 2 identified C7-T3 (facet joints), T5-T7 and T12 (costovertebral joints), and T8-T9 (costotransverse joints), as common sites of ankylosis at baseline and at 2-year follow-up. The ICCs for the facet, costovertebral, and costotransverse joints at baseline were 0.876, 0.952, and 0.753, respectively. OR of baseline costovertebral and costotransverse joint ankylosis for predicting syndesmophyte progression of the vertebral body was 4.644 [95% confidence interval (CI), 2.295-9.398] and 1.524 (95% CI, 1.036-2.244), respectively. Conclusion: Costotransverse joint ankylosis in r-axSpA patients can be measured semi-quantitatively on whole spine CT, and ankylosis of the costotransverse and costovertebral joints predicts the progression of syndesmophytes.Trial registration: Not applicable.