Multidisciplinary Consensus for Rationalizing the Use of Acid Suppressants in Children and Adults: CONFOR.

The use of acid suppression therapy (AST) is a common approach for managing a wide spectrum of acid peptic disorders. Histamine type 2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) are the most widely prescribed AST in routine clinical practice. However, an exponential surge in the prescriptions of PPIs, such as Omeprazole, Esomeprazole, Pantoprazole, Lansoprazole in recent years and their associated adverse effects have raised concern about their inappropriate and overuse, both in children and adults. To address these issues, a three-step modified Delphi polling process was employed to establish best practice consensus statements for rationalizing the use of acid suppressants. A multidisciplinary expert panel of 13 health professionals across medical specialties, including gastroenterologists, hepatologists, pediatric gastroenterologists, pediatricians, otolaryngologists, cardiologists, nephrologists, gynecologist and orthopedists actively contributed to this collaborative process of consensus development. The expert panel proposed 21 consensus statements providing best practice points on the general use and safety of acid suppressants based on a comprehensive review of scientific literature and clinical expertise. The panel also collaboratively developed a PPI deprescribing algorithm. Altogether, this consensus paper offers evidence-based recommendations and guidance for the rational use of acid suppressants with a blueprint for deprescribing PPIs. This consensus paper contributes to aiding primary care practitioners in improving patient outcomes and minimizing healthcare costs. Additionally, it enhances patient safety and curtail inappropriate usage. How to cite this article: Prabhoo RY, Pai UA, Wadhwa A, et al. Multidisciplinary Consensus for Rationalizing the Use of Acid Suppressants in Children and Adults: CONFOR. Euroasian J Hepato-Gastroenterol 2024;14(1):99-119.

Regulation of a single inositol 1-phosphate synthase homeologue by HSFA6B contributes to fibre yield maintenance under drought conditions in upland cotton.

Drought stress substantially impacts crop physiology resulting in alteration of growth and productivity. Understanding the genetic and molecular crosstalk between stress responses and agronomically important traits such as fibre yield is particularly complicated in the allopolyploid species, upland cotton (Gossypium hirsutum), due to reduced sequence variability between A and D subgenomes. To better understand how drought stress impacts yield, the transcriptomes of 22 genetically and phenotypically diverse upland cotton accessions grown under well-watered and water-limited conditions in the Arizona low desert were sequenced. Gene co-expression analyses were performed, uncovering a group of stress response genes, in particular transcription factors GhDREB2A-A and GhHSFA6B-D, associated with improved yield under water-limited conditions in an ABA-independent manner. DNA affinity purification sequencing (DAP-seq), as well as public cistrome data from Arabidopsis, were used to identify targets of these two TFs. Among these targets were two lint yield-associated genes previously identified through genome-wide association studies (GWAS)-based approaches, GhABP-D and GhIPS1-A. Biochemical and phylogenetic approaches were used to determine that GhIPS1-A is positively regulated by GhHSFA6B-D, and that this regulatory mechanism is specific to Gossypium spp. containing the A (old world) genome. Finally, an SNP was identified within the GhHSFA6B-D binding site in GhIPS1-A that is positively associated with yield under water-limiting conditions. These data lay out a regulatory connection between abiotic stress and fibre yield in cotton that appears conserved in other systems such as Arabidopsis.

Biocompatible neem gum-modified polyvinyl alcohol composite as dielectric material for flexible energy devices.

In our pursuit of a flexible energy storage solution, we have developed biocompatible (bc)-NG/PVA composite polymers by combining neem tree gum (NG) with polyvinyl alcohol (PVA). This innovative bio-inspired approach harnesses NG's unique properties for both the bio-electrolyte and bio-electrode components. The resulting bc-NG/PVA composites exhibit superior dielectric strength and versatility, surpassing traditional inorganic ceramic dielectrics in advanced electronics and pulsed power systems. Our study investigates the dielectric characteristics, conductivities, electric modulus, and impedance parameters of Pure PVA and NG-doped PVA composites. Adding 5 % NG to PVA significantly boosts its conductivity from 10-8 S cm-1 to 10-4 S cm-1, while the dielectric constant of PVA/5 % NG composite jumps to 104.5 compared to pure PVA. These improvements position the composite films of 5 % NG added PVA as promising materials for diverse applications. The heightened performance of these NG-blended PVA composite materials underscores their potential as a valuable resource for flexible energy storage solutions.

Two-phase simulation of entropy optimized mixed convection flow of two different shear-thinning nanomaterials in thermal and mass diffusion systems with Lorentz forces.

This research compares the momentum, thermal energy, mass diffusion and entropy generation of two shear thinning nanofluids in an angled micro-channel with mixed convection, nonlinear thermal radiation, temperature jump boundary condition and variable thermal conductivity effects. The [Formula: see text] approach was used to solve the Buongiorno nonlinear governing model. The effect of different parameters on the flow, energy, concentration, and entropy generating fields have been graphically illustrated and explained. The hyperbolic tangent nanoliquid has a better velocity than the Williamson nanofluid. The Williamson nanofluid has higher thermal energy and concentration than the hyperbolic tangent nanoliquid in the microchannel. The Grashof number, both thermal and solutal, increases the fluid flow rate throughout the flow system. The energy of the nanoliquid is reduced by the temperature jump condition, while the energy field of the nanoliquid is enhanced by the improving thermal conductivity value. The nanoliquids concentration rises as the Schmitt number rises. The irreversibility rate of the channel system is maximized by the variable thermal conductivity parameter.

Amino acid and protein specificity of protein fatty acylation in C. elegans.

Protein lipidation plays critical roles in regulating protein function and localization. However, the chemical diversity and specificity of fatty acyl group utilization have not been investigated using untargeted approaches, and it is unclear to what extent structures and biosynthetic origins of S-acyl moieties differ from N- and O-fatty acylation. Here, we show that fatty acylation patterns in Caenorhabditis elegans differ markedly between different amino acid residues. Hydroxylamine capture revealed predominant cysteine S-acylation with 15-methylhexadecanoic acid (isoC17:0), a monomethyl branched-chain fatty acid (mmBCFA) derived from endogenous leucine catabolism. In contrast, enzymatic protein hydrolysis showed that N-terminal glycine was acylated almost exclusively with straight-chain myristic acid, whereas lysine was acylated preferentially with two different mmBCFAs and serine was acylated promiscuously with a broad range of fatty acids, including eicosapentaenoic acid. Global profiling of fatty acylated proteins using a set of click chemistry-capable alkyne probes for branched- and straight-chain fatty acids uncovered 1,013 S-acylated proteins and 510 hydroxylamine-resistant N- or O-acylated proteins. Subsets of S-acylated proteins were labeled almost exclusively by either a branched-chain or a straight-chain probe, demonstrating acylation specificity at the protein level. Acylation specificity was confirmed for selected examples, including the S-acyltransferase DHHC-10. Last, homology searches for the identified acylated proteins revealed a high degree of conservation of acylation site patterns across metazoa. Our results show that protein fatty acylation patterns integrate distinct branches of lipid metabolism in a residue- and protein-specific manner, providing a basis for mechanistic studies at both the amino acid and protein levels.

Untargeted Proteomics and Metabolomics Analysis of Plant Organ Development.

Our understanding of major developmental transitions in plants and animals has been transformed by the emergence of omics technologies. The majority of leaf growth research has been conducted at the transcriptional level. Although historically understudied, alterations at the protein and metabolite levels have begun to gain traction in recent years. Here, we present a protocol for metabolite and protein extraction followed by untargeted metabolomics and proteomics analysis of the growing leaves.

Proteinogenic dipeptides, an emerging class of small-molecule regulators.

Proteinogenic dipeptides, with few known exceptions, are products of protein degradation. Dipeptide levels respond to the changes in the environment, often in a dipeptide-specific manner. What drives this specificity is currently unknown; what likely contributes is the activity of the different peptidases that cleave off the terminal dipeptide from the longer peptides. Dipeptidases that degrade dipeptides to amino acids, and the turnover rates of the "substrate" proteins/peptides. Plants can both uptake dipeptides from the soil, but dipeptides are also found in root exudates. Dipeptide transporters, members of the proton-coupled peptide transporters NTR1/PTR family, contribute to nitrogen reallocation between the sink and source tissues. Besides their role in nitrogen distribution, it becomes increasingly clear that dipeptides may also serve regulatory, dipeptide-specific functions. Dipeptides are found in protein complexes affecting the activity of their protein partners. Moreover, dipeptide supplementation leads to cellular phenotypes reflected in changes in plant growth and stress tolerance. Herein we will review the current understanding of dipeptides' metabolism, transport, and functions and discuss significant challenges and future directions for the comprehensive characterization of this fascinating but underrated group of small-molecule compounds.

Rewiring of the protein-protein-metabolite interactome during the diauxic shift in yeast.

In budding yeast Saccharomyces cerevisiae, the switch from aerobic fermentation to respiratory growth is separated by a period of growth arrest, known as the diauxic shift, accompanied by a significant metabolic rewiring, including the derepression of gluconeogenesis and the establishment of mitochondrial respiration. Previous studies reported hundreds of proteins and tens of metabolites accumulating differentially across the diauxic shift transition. To assess the differences in the protein-protein (PPIs) and protein-metabolite interactions (PMIs) yeast samples harvested in the glucose-utilizing, fermentative phase, ethanol-utilizing and early stationary respiratory phases were analysed using isothermal shift assay (iTSA) and a co-fractionation mass spectrometry approach, PROMIS. Whereas iTSA monitors changes in protein stability and is informative towards protein interaction status, PROMIS uses co-elution to delineate putative PPIs and PMIs. The resulting dataset comprises 1627 proteins and 247 metabolites, hundreds of proteins and tens of metabolites characterized by differential thermal stability and/or fractionation profile, constituting a novel resource to be mined for the regulatory PPIs and PMIs. The examples discussed here include (i) dissociation of the core and regulatory particle of the proteasome in the early stationary phase, (ii) the differential binding of a co-factor pyridoxal phosphate to the enzymes of amino acid metabolism and (iii) the putative, phase-specific interactions between proline-containing dipeptides and enzymes of central carbon metabolism.

OPDA, more than just a jasmonate precursor.

The oxylipin 12-oxo-phytodienoic acid (OPDA) is known as a biosynthetic precursor of the important plant hormone jasmonic acid. However, OPDA is also a signaling molecule with functions independent of jasmonates. OPDA involvement in diverse biological processes, from plant defense and stress responses to growth regulation and development, has been documented across plant species. OPDA is synthesized in the plastids from alpha-linolenic acid, and OPDA binding to plastidial cyclophilins activates TGA transcription factors upstream of genes associated with stress responses. Here, we summarize what is known about OPDA metabolism and signaling while briefly discussing its jasmonate dependent and independent roles. We also describe open questions, such as the OPDA protein interactome and biological roles of OPDA conjugates.

How does a small molecule bind at a cryptic binding site?

Protein-protein interactions (PPIs) are ubiquitous biomolecular processes that are central to virtually all aspects of cellular function. Identifying small molecules that modulate specific disease-related PPIs is a strategy with enormous promise for drug discovery. The design of drugs to disrupt PPIs is challenging, however, because many potential drug-binding sites at PPI interfaces are "cryptic": When unoccupied by a ligand, cryptic sites are often flat and featureless, and thus not readily recognizable in crystal structures, with the geometric and chemical characteristics of typical small-molecule binding sites only emerging upon ligand binding. The rational design of small molecules to inhibit specific PPIs would benefit from a better understanding of how such molecules bind at PPI interfaces. To this end, we have conducted unbiased, all-atom MD simulations of the binding of four small-molecule inhibitors (SP4206 and three SP4206 analogs) to interleukin 2 (IL2)-which performs its function by forming a PPI with its receptor-without incorporating any prior structural information about the ligands' binding. In multiple binding events, a small molecule settled into a stable binding pose at the PPI interface of IL2, resulting in a protein-small-molecule binding site and pose virtually identical to that observed in an existing crystal structure of the IL2-SP4206 complex. Binding of the small molecule stabilized the IL2 binding groove, which when the small molecule was not bound emerged only transiently and incompletely. Moreover, free energy perturbation (FEP) calculations successfully distinguished between the native and non-native IL2-small-molecule binding poses found in the simulations, suggesting that binding simulations in combination with FEP may provide an effective tool for identifying cryptic binding sites and determining the binding poses of small molecules designed to disrupt PPI interfaces by binding to such sites.

Thermal treatments reduce rancidity and modulate structural and digestive properties of starch in pearl millet flour.

Pearl millet is a nutrient dense and gluten free cereal, however it's flour remains underutilized due to the onset of rancidity during its storage. To the best of our knowledge, processing methods, which could significantly reduce the rancidity of the pearl millet flour during storage, are non-existent. In this study, pearl millet grains were subjected to a preliminary hydro-treatment (HT). Subsequently, the hydrated grain-wet flour have undergone individual and combined thermal treatments viz., hydrothermal (HTh) and thermal near infrared rays (thNIR). Effects of these thermal treatments on the biochemical process of hydrolytic and oxidative rancidity were analyzed in stored flour. A significant (p < 0.05) decrease in the enzyme activities of lipase (47.8%), lipoxygenase (84.8%), peroxidase (98.1%) and polyphenol oxidase (100%) in HT-HTh-thNIR treated flour compared to the individual treatments was documented. Upon storage (90 days), decline of 67.84% and 66.4% of free fatty acid and peroxide contents were observed in flour under HT-HTh-thNIR treatment without altering starch and protein digestibility properties. HT-HTh treated flour exhibited the highest (7.6%) rapidly digestible starch, decreased viscosity and increased starch digestibility (67.17%). FTIR analysis of HT-HTh treated flour divulged destabilization of short-range ordered crystalline structure and altered protein structures with decreased in vitro digestibility of protein. Overall, these results demonstrated the effectiveness of combined thermal treatment of HT-HTh-thNIR in reducing rancidity and preserving the functional properties of the stored flour.

A structural model of a Ras-Raf signalosome.

The protein K-Ras functions as a molecular switch in signaling pathways regulating cell growth. In the human mitogen-activated protein kinase (MAPK) pathway, which is implicated in many cancers, multiple K-Ras proteins are thought to assemble at the cell membrane with Ras effector proteins from the Raf family. Here we propose an atomistic structural model for such an assembly. Our starting point was an asymmetric guanosine triphosphate-mediated K-Ras dimer model, which we generated using unbiased molecular dynamics simulations and verified with mutagenesis experiments. Adding further K-Ras monomers in a head-to-tail fashion led to a compact helical assembly, a model we validated using electron microscopy and cell-based experiments. This assembly stabilizes K-Ras in its active state and presents composite interfaces to facilitate Raf binding. Guided by existing experimental data, we then positioned C-Raf, the downstream kinase MEK1 and accessory proteins (Galectin-3 and 14-3-3σ) on and around the helical assembly. The resulting Ras-Raf signalosome model offers an explanation for a large body of data on MAPK signaling.

Autophagy complements metalloprotease FtsH6 in degrading plastid heat shock protein HSP21 during heat stress recovery.

Moderate and temporary heat stresses (HS) prime plants to tolerate, and survive, a subsequent severe HS. Such acquired thermotolerance can be maintained for several days under normal growth conditions, and create a HS memory. We recently demonstrated that plastid-localized small heat shock protein HSP21 is a key component of HS memory in Arabidopsis thaliana. A sustained high abundance of HSP21 during the HS recovery phase extends HS memory. The level of HSP21 is negatively controlled by plastid-localized metalloprotease FtsH6 during HS recovery. Here, we demonstrate that autophagy, a cellular recycling mechanism, exerts additional control over HSP21 degradation. Genetic and chemical disruption of both, metalloprotease activity and autophagy trigger superior HSP21 accumulation, thereby improving memory. Furthermore, we provide evidence that autophagy cargo receptor ATG8-INTERACTING PROTEIN1 (ATI1) is associated with HS memory. ATI1 bodies colocalize with both autophagosomes and HSP21, and their abundance and transport to the vacuole increase during HS recovery. Together, our results provide new insights into the control module for the regulation of HS memory, in which two distinct protein degradation pathways act in concert to degrade HSP21, thereby enabling cells to recover from the HS effect at the cost of reducing the HS memory.

Long-term outcomes in patients with advanced adrenocortical carcinoma after image-guided locoregional ablation or embolization.

BACKGROUND: To evaluate outcomes and survival rates in patients with metastatic adrenocortical carcinoma (ACC) who were treated with image-guided locoregional treatments (IGLTs). PURPOSE: To evaluate the overall survival (OS) and clinical impact of IGLT in the management of patients with advanced metastatic ACC. METHODS: Retrospective review of 39 patients treated with IGLT between 1999 and 2018 was performed. Short- and long-term efficacy of treatments were defined based upon imaging and clinical data. Subgroup survival analysis was performed on patients with metastatic disease at diagnosis (N = 17) and compared with the same stage group from the most recent National Cancer Database (NCDB) report. Statistical analysis was performed using Cox proportional hazards model. RESULTS: Treatments were performed at different anatomic sites including liver (N = 46), lung (N = 14), retroperitoneum (N = 5), bone (N = 4), subcutaneous (N = 2), and intracaval (N = 1). Radiofrequency, microwave, cryoablation, or a combination of two modalities (45, 18, 3, 3, respectively) were used in 69 ablation sessions. Intra-arterial procedures were performed in 12 patients in 18 treatment cycles (range 1-3 per patient). As of a 2019 analysis, 11 patients were alive with a mean follow-up of 169 months (range 63-292 months) from diagnosis. Two- and 5-year OS rates for all patients were 84.5% and 51%, respectively, and 76.5% and 59% for patients with metastatic disease at diagnosis (N = 17). This compares favorably with an NCDB report of 35% 5-year survival rate for patients with metastatic disease. Female gender and longer time from diagnosis to first IGLT were found to be predictors of prolonged survival with hazard ratios of 0.23 (p < 0.001) and 0.66 (p = 0.001), respectively. CONCLUSION: IGLT may be associated with prolonged life expectancy in select patients with metastatic ACC.

Comparison of Smartphone Augmented Reality, Smartglasses Augmented Reality, and 3D CBCT-guided Fluoroscopy Navigation for Percutaneous Needle Insertion: A Phantom Study.

PURPOSE: To compare needle placement performance using an augmented reality (AR) navigation platform implemented on smartphone or smartglasses devices to that of CBCT-guided fluoroscopy in a phantom. MATERIALS AND METHODS: An AR application was developed to display a planned percutaneous needle trajectory on the smartphone (iPhone7) and smartglasses (HoloLens1) devices in real time. Two AR-guided needle placement systems and CBCT-guided fluoroscopy with navigation software (XperGuide, Philips) were compared using an anthropomorphic phantom (CIRS, Norfolk, VA). Six interventional radiologists each performed 18 independent needle placements using smartphone (n = 6), smartglasses (n = 6), and XperGuide (n = 6) guidance. Placement error was defined as the distance from the needle tip to the target center. Placement time was recorded. For XperGuide, dose-area product (DAP, mGy*cm2) and fluoroscopy time (sec) were recorded. Statistical comparisons were made using a two-way repeated measures ANOVA. RESULTS: The placement error using the smartphone, smartglasses, or XperGuide was similar (3.98 ± 1.68 mm, 5.18 ± 3.84 mm, 4.13 ± 2.38 mm, respectively, p = 0.11). Compared to CBCT-guided fluoroscopy, the smartphone and smartglasses reduced placement time by 38% (p = 0.02) and 55% (p = 0.001), respectively. The DAP for insertion using XperGuide was 3086 ± 2920 mGy*cm2, and no intra-procedural radiation was required for augmented reality. CONCLUSIONS: Smartphone- and smartglasses-based augmented reality reduced needle placement time and radiation exposure while maintaining placement accuracy compared to a clinically validated needle navigation platform.

Autophagy is responsible for the accumulation of proteogenic dipeptides in response to heat stress in Arabidopsis thaliana.

Proteogenic dipeptides are intermediates of proteolysis as well as an emerging class of small-molecule regulators with diverse and often dipeptide-specific functions. Herein, prompted by differential accumulation of dipeptides in a high-density Arabidopsis thaliana time-course stress experiment, we decided to pursue an identity of the proteolytic pathway responsible for the buildup of dipeptides under heat conditions. By querying dipeptide accumulation versus available transcript data, autophagy emerged as a top hit. To examine whether autophagy indeed contributes to the accumulation of dipeptides measured in response to heat stress, we characterized the loss-of-function mutants of crucial autophagy proteins to test whether interfering with autophagy would affect dipeptide accumulation in response to the heat treatment. This was indeed the case. This work implicates the involvement of autophagy in the accumulation of proteogenic dipeptides in response to heat stress in Arabidopsis.

Selective autophagy regulates heat stress memory in Arabidopsis by NBR1-mediated targeting of HSP90.1 and ROF1.

In nature, plants are constantly exposed to many transient, but recurring, stresses. Thus, to complete their life cycles, plants require a dynamic balance between capacities to recover following cessation of stress and maintenance of stress memory. Recently, we uncovered a new functional role for macroautophagy/autophagy in regulating recovery from heat stress (HS) and resetting cellular memory of HS in Arabidopsis thaliana. Here, we demonstrated that NBR1 (next to BRCA1 gene 1) plays a crucial role as a receptor for selective autophagy during recovery from HS. Immunoblot analysis and confocal microscopy revealed that levels of the NBR1 protein, NBR1-labeled puncta, and NBR1 activity are all higher during the HS recovery phase than before. Co-immunoprecipitation analysis of proteins interacting with NBR1 and comparative proteomic analysis of an nbr1-null mutant and wild-type plants identified 58 proteins as potential novel targets of NBR1. Cellular, biochemical and functional genetic studies confirmed that NBR1 interacts with HSP90.1 (heat shock protein 90.1) and ROF1 (rotamase FKBP 1), a member of the FKBP family, and mediates their degradation by autophagy, which represses the response to HS by attenuating the expression of HSP genes regulated by the HSFA2 transcription factor. Accordingly, loss-of-function mutation of NBR1 resulted in a stronger HS memory phenotype. Together, our results provide new insights into the mechanistic principles by which autophagy regulates plant response to recurrent HS.Abbreviations: AIM: Atg8-interacting motif; ATG: autophagy-related; BiFC: bimolecular fluorescence complementation; ConA: concanamycinA; CoIP: co-immunoprecipitation; DMSO: dimethyl sulfoxide; FKBP: FK506-binding protein; FBPASE: fructose 1,6-bisphosphatase; GFP: green fluorescent protein; HS: heat stress; HSF: heat shock factor; HSFA2: heat shock factor A2; HSP: heat shock protein; HSP90: heat shock protein 90; LC-MS/MS: Liquid chromatography-tandem mass spectrometry; 3-MA: 3-methyladenine; NBR1: next-to-BRCA1; PQC: protein quality control; RFP: red fluorescent protein; ROF1: rotamase FKBP1; TF: transcription factor; TUB: tubulin; UBA: ubiquitin-associated; YFP: yellow fluorescent protein.

Monopolar Radiofrequency Energy Delivered by a Conductive Endovascular Basket or Guidewire Leads to Thermal Occlusion in a Swine Model.

PURPOSE: To assess the feasibility of inducing vascular occlusion by application of radiofrequency (RF) energy via conductive endovascular wires or baskets. MATERIALS AND METHODS: A retrievable nitinol basket and stainless steel guidewire with a platinum tip were evaluated as conductors for endovascular application of RF energy. Tissue-mimicking thermochromic gel phantoms that change color with heating were cast with 2-, 5-, and 7-mm-diameter lumens and filled with 37 oC saline. After ablation, the phantoms were sectioned, and the thermal footprints were evaluated. Six castrated male domestic swine underwent endovascular ablation using the basket in iliac arteries and guidewires in renal arteries. Post-procedural angiography was performed, and postmortem arterial segments were resected for histopathologic analysis. RESULTS: In the phantom, the depth of thermal change in the 5- and 7-mm lumens averaged 6.3 and 6.0 mm along the basket, respectively, and in the 2- and 5-mm lumens, the depth of thermal change averaged 1.9 and 0.5 mm along the wire, respectively. In the swine, RF energy delivery led to angiographic occlusion at 12 of 13 sites. Thermal injury and occlusion were similar at the proximal, middle, and distal basket treatment zone, whereas injury and occlusion decreased from the proximal to the distal end of the 5-cm wire treatment zone. CONCLUSIONS: Endovascular delivery of RF energy via a conductive basket in medium-sized arteries or a guidewire in small arteries led to acute angiographic and histologic occlusion. The potential to induce stasis might be useful in settings where rapid occlusion is desirable.

Safety and Tolerability of Topotecan-Eluting Radiopaque Microspheres for Hepatic Chemoembolization in a Rabbit Preclinical Model.

PURPOSE: Topotecan is a camptothecin analogue with potential advantages over irinotecan for transarterial chemoembolization (TACE) of hepatic colorectal metastases including greater anti-neoplastic activity without enzymatic activation. The purpose of this study was to assess safety and tolerability of topotecan-loaded radiopaque microspheres (ROMTOP) administered by TACE in a rabbit model and to compare the in vitro elution of topotecan from microspheres to irinotecan. MATERIALS AND METHODS: Topotecan was loaded into radiopaque microspheres (70-150 µm, DC Bead LUMI™, Biocompatibles UK Ltd-Boston Scientific Corporation) to the maximum capacity of 80 mg/mL of microspheres. Six healthy New Zealand White rabbits underwent hepatic TACE with ROMTOP under fluoroscopic guidance until angiographic stasis. Assessment of toxicities included regular liver function tests and complete blood counts until euthanasia 28 days post-TACE. In vitro topotecan elution from the microspheres was assessed using an open-loop flow-through system and compared to irinotecan. RESULTS: The mean bead volume and topotecan dose delivered were 0.086 mL (0.076-0.105 mL) and 1.99 mg/kg (1.51-2.55 mg/kg), respectively. Aspartate aminotransferase and alanine aminotransferase were elevated post-embolization but resolved within 2 weeks. One rabbit died two days after TACE with pyloric duodenal perforation observed at necropsy, potentially due to non-target embolization. In vitro elution of topotecan from ROMTOP was complete in 10 h compared to 3 h for irinotecan-loaded microspheres. CONCLUSION: Selective embolization with ROMTOP was tolerated at a dose of 2 mg/kg (24 mg/m2) in rabbits. In vitro topotecan elution from microspheres was more prolonged compared to irinotecan.