Liver-specific DICER1 syndrome model mice develop cystic liver tumors with defective primary cilia.

DICER1 syndrome is a tumor predisposition syndrome caused by familial genetic mutations in DICER1. Pathogenic variants of DICER1 have been discovered in many rare cancers, including cystic liver tumors. However, the molecular mechanisms underlying liver lesions induced by these variants remain unclear. In the present study, we sought to gain a better understanding of the pathogenesis of these variants by generating a mouse model of liver-specific DICER1 syndrome. The mouse model developed bile duct hyperplasia with fibrosis, similar to congenital hepatic fibrosis, as well as cystic liver tumors resembling those in Caroli's syndrome, intrahepatic cholangiocarcinoma, and hepatocellular carcinoma. Interestingly, the mouse model of DICER1 syndrome showed abnormal formation of primary cilia in the bile duct epithelium, which is a known cause of bile duct hyperplasia and cyst formation. These results indicated that DICER1 mutations contribute to cystic liver tumors by inducing defective primary cilia. The mouse model generated in this study will be useful for elucidating the potential mechanisms of tumorigenesis induced by DICER1 variants and for obtaining a comprehensive understanding of DICER1 syndrome. © 2024 The Pathological Society of Great Britain and Ireland.

Plateau-linear reaction norm model analysis of number born alive in purebred Landrace pigs using meteorological data in Japan.

We performed a plateau-linear reaction norm model (RNM) analysis of number born alive (NBA) in purebred Landrace pigs, where breeding value changes according to maximum temperature at mating day, using public meteorological observation data in Japan. We analysed 52,668 NBA records obtained from 10,320 Landrace sows. Pedigree data contained 99,201 animals. Off-farm daily temperature data at the nearest weather station from each of the farms were downloaded from the Japan Meteorological Agency website. A plateau-linear RNM analysis based on daily maximum temperature on mating day (threshold temperature of 16.6°C) was performed. The percentage of the records with daily maximum temperatures at mating days of ≤16.6, ≥25.0, ≥30.0 and ≥35.0°C were 34.3%, 33.6%, 14.0% and 0.8%, respectively. The value of Akaike's information criterion for the plateau-linear RNM was lower than that for a simple repeatability model (RM). With the plateau-linear RNM, estimated value of heritability ranged from 0.14 to 0.15, while that from the RM analysis was 0.15. Additive genetic correlation between intercept and slope terms was estimated to be -0.52 from the plateau-linear RNM analysis. Estimated additive genetic correlations were >0.9 between NBA at different temperatures ranging from 16.6 to 37.6°C. For the 10,320 sows, average values of prediction reliability of the intercept and slope terms for breeding values in the plateau-linear RNM were 0.47 and 0.16, respectively. Increasing weight for slope term in linear selection index could bring positive genetic gain in the slope part, but prediction accuracy would decrease. Our results imply that genetically improving heat tolerance in sows reared in Japan focusing on NBA using RNM is possible, while RNM is more complex to implement and interpret. Therefore, further study should be encouraged to make genetic improvement for heat tolerance in sows more efficient.

Comparing pedigree and genomic inbreeding coefficients, and inbreeding depression of reproductive traits in Japanese Black cattle.

BACKGROUND: Pedigree-based inbreeding coefficients have been generally included in statistical models for genetic evaluation of Japanese Black cattle. The use of genomic data is expected to provide precise assessment of inbreeding level and depression. Recently, many measures have been used for genome-based inbreeding coefficients; however, with no consensus on which is the most appropriate. Therefore, we compared the pedigree- ([Formula: see text]) and multiple genome-based inbreeding coefficients, which were calculated from the genomic relationship matrix with observed allele frequencies ([Formula: see text]), correlation between uniting gametes ([Formula: see text]), the observed vs expected number of homozygous genotypes ([Formula: see text]), runs of homozygosity (ROH) segments ([Formula: see text]) and heterozygosity by descent segments ([Formula: see text]). We quantified inbreeding depression from estimating regression coefficients of inbreeding coefficients on three reproductive traits: age at first calving (AFC), calving difficulty (CD) and gestation length (GL) in Japanese Black cattle. RESULTS: The highest correlations with [Formula: see text] were for [Formula: see text] (0.86) and [Formula: see text] (0.85) whereas [Formula: see text] and [Formula: see text] provided weak correlations with [Formula: see text], with range 0.33-0.55. Except for [Formula: see text] and [Formula: see text], there were strong correlations among genome-based inbreeding coefficients ([Formula: see text] 0.94). The estimates of regression coefficients of inbreeding depression for [Formula: see text] was 2.1 for AFC, 0.63 for CD and -1.21 for GL, respectively, but [Formula: see text] had no significant effects on all traits. Genome-based inbreeding coefficients provided larger effects on all reproductive traits than [Formula: see text]. In particular, for CD, all estimated regression coefficients for genome-based inbreeding coefficients were significant, and for GL, that for [Formula: see text] had a significant.. Although there were no significant effects when using overall genome-level inbreeding coefficients for AFC and GL, [Formula: see text] provided significant effects at chromosomal level in four chromosomes for AFC, three chromosomes for CD, and two chromosomes for GL. In addition, similar results were obtained for [Formula: see text]. CONCLUSIONS: Genome-based inbreeding coefficients can capture more phenotypic variation than [Formula: see text]. In particular, [Formula: see text] and [Formula: see text] can be considered good estimators for quantifying inbreeding level and identifying inbreeding depression at the chromosome level. These findings might improve the quantification of inbreeding and breeding programs using genome-based inbreeding coefficients.

Genetic parameter estimation for pork production and litter performance traits of Landrace, Large White, and Duroc pigs in Japan.

We estimated genetic parameters for two pork production and six litter performance traits of Landrace, Large White, and Duroc pigs reared in Japan. Pork production traits were average daily gain from birth to end of performance testing and backfat thickness at end of testing (46,042 records for Landrace, 40,467 records for Large White, and 42,920 records for Duroc). Litter performance traits were number born alive, litter size at weaning (LSW), number of piglets dead during suckling (ND), survival rate of piglets during suckling (SV), total piglet weight at weaning (TWW), and average piglet weight at weaning (AWW) (27,410, 26,716, and 12,430 records for Landrace, Large White, and Duroc, respectively). ND was calculated as the difference between LSW and litter size at start of suckling (LSS). SV was calculated as LSW/LSS. AWW was calculated as TWW/LSW. Pedigree data for Landrace, Large White, and Duroc breeds contained 50,193, 44,077, and 45,336 pigs, respectively. Trait heritability was estimated via single-trait analysis and genetic correlation between two traits was estimated via two-trait analysis. When considering the linear covariate of LSS in the statistical model for LSW and TWW, for all breeds, the heritability was estimated to be 0.4-0.5 for pork production traits and below 0.2 for litter performance traits. Estimated genetic correlation between average daily gain and backfat thickness was small, ranging from 0.057 to 0.112, and those between pork production traits and litter performance traits were negligible to moderate, ranging from -0.493 to 0.487. A wide range of genetic correlation values among the litter performance traits was estimated, while that between LSW and ND could not be obtained. The results of genetic parameter estimation were affected by whether the linear covariate of LSS was included in the statistical model for LSW and TWW or not. This finding implies the necessity of carefully interpreting the results according to the choice of statistical model. Our results could give fundamental information on simultaneously improving productivity and female reproductivity for pigs.

Genetic and genomic analysis of oxygen consumption in mice.

We estimated genetic parameters for oxygen consumption (OC), OC per metabolic body weight (OCMBW) and body weight at three through 8 weeks of age in divergently selected mice populations, with an animal model considering maternal genetic, common litter environmental and cytoplasmic inheritance effects. Cytoplasmic inheritance was considered based on maternal lineage information. With respect to OC, estimated direct heritability was moderate (0.32) and the estimated proportion of the variance of cytoplasmic inheritance effects to the phenotypic variance was very low (0.01), implying that causal genes for OC could be located on autosomes. To assess this hypothesis, we attempted to identify possible candidate causal genes through selective signature detection with the results of pooled whole-genome resequencing using pooled DNA samples from high and low OC mice. We made a list of possible candidate causal genes for OC, including those relating to electron transport chain and ATP-binding proteins (Ndufa12, Sdhc, Atp10b, etc.), Prr16 encoding Largen protein, Cry1 encoding a key component of the circadian core oscillator and so on. The results, although careful interpretation must be required, could contribute to elucidate the genetic mechanism of OC, an indicator for maintenance energy requirement, and therefore feed efficiency.

Performance of using opposing homozygotes for paternity testing in Japanese Black cattle.

Genome-wide single nucleotide polymorphism (SNP) markers in Japanese Black cattle enable genomic prediction and verifying parent-offspring relationships. We assessed the performance of opposing homozygotes (OH) for paternity testing in Japanese Black cattle, using SNP genotype information of 50 sires and 3,420 fattened animals, 1,945 of which were fathered by the 50 genotyped sires. The number of OH was counted for each sire-progeny pair in 28,764 SNPs with minor allele frequencies of ≥0.05 in this population. Across all pairs of animals, the number of OH tended to increase as the pedigree-based coefficient of relationship decreased. With a threshold of 288 (1% of SNPs) for paternity testing, most sire-progeny pairs were detected as true relationships. The frequency of Mendelian inconsistencies was 2.4%, reflecting the high accuracy of pedigree information in Japanese Black cattle population. The results indicate the utility of OH for paternity testing in Japanese Black cattle.

Maternal effect on body measurement and meat production traits in purebred Duroc pigs.

We investigated maternal effect on nine body measurement traits (body height, body length, front width (FW), chest width (CW), hind width (HW), chest depth, chest girth (CHG), front cannon circumference (FCC) and rear cannon circumference (RCC)) measured at the end of performance testing and five meat production traits (ages at the start and end of performance testing (D30 and D105), average daily gain (ADG), backfat thickness and loin muscle area) in purebred Duroc pigs. Genetic parameters for each trait were estimated by using six single-trait models with and without common litter environmental effect, maternal genetic effect and direct-maternal genetic correlation. The value of Akaike's information criterion was lowest with the model including direct additive genetic and common litter environmental effects for 10 traits. The estimated proportion of common litter environmental variance to phenotypic variance was approximately ≥0.1 for D30, D105, ADG, FW, CW, HW, CHG, FCC and RCC. Using a model without common litter environmental effect would overestimate the direct heritability of most traits. Standard errors of estimated genetic parameters tended to be larger in models including maternal genetic effect. The results indicate that a compromise could be made for accurate genetic parameter estimation for body measurement traits, as well as meat production traits, in pigs by considering common litter environmental effect.

Modelled plasma concentrations of pemafibrate with co-administered typical cytochrome P450 inhibitors clopidogrel, fluconazole or clarithromycin predicted by physiologically based pharmacokinetic modelling in virtual populations.

Oral antidyslipidaemic drug pemafibrate is cleared from human plasma via hepatic uptake by organic anion transporting polypeptide (OATP) 1B1 and oxidation by cytochromes P450 (P450) 2C8, 2C9 and 3A4. The pharmacokinetic profiles of pemafibrate with virtual administrations of P450 inhibitors and/or disease interactions were generated using a physiologically based pharmacokinetic (PBPK) model previously established for co-administration of pemafibrate with OATP1B1 inhibitors. This PBPK model was validated in the current study using reported maximum pemafibrate plasma concentrations and areas under the curve from interaction studies in healthy subjects co-administered with clopidogrel (P450 2C8 inhibitor), fluconazole (P450 2C9/3A4 inhibitor) or clarithromycin (P450 3A4 inhibitor). Virtual co-administrations of pemafibrate with clopidogrel, fluconazole or clarithromycin increased the predicted plasma exposures of pemafibrate 1.4-1.7-fold, 1.2-1.4-fold and 2.9-11-fold, respectively, in subjects with or without moderate or severe renal impairment or Child-Pugh A or B liver cirrhosis. Some of the exposure-enhancing effects of clarithromycin may originate from its inhibitory potential toward OATP1B1, because the estimated effects of itraconazole (a P450 3A4 inhibitor) were only minor. Simulations using the current PBPK model in groups of virtual subjects with or without renal or hepatic impairment revealed modified pharmacokinetic profiles for pemafibrate following co-administration of typical P450 inhibitors.

Plasma concentrations of pemafibrate with co-administered drugs predicted by physiologically based pharmacokinetic modeling in virtual populations with renal/hepatic impairment.

Pharmacokinetic profiles of pemafibrate with virtual drug and/or disease interactions were assessed by creating a detailed physiologically based pharmacokinetic (PBPK) model.Passive diffusion clearance in liver was experimentally determined as 0.013 mL/min/106 human hepatocytes. In vitro intrinsic clearance values for pemafibrate by cytochromes P450 2C8, 2C9, and 3A4 were 54, 26, and 16 µL/min/mg protein, respectively. Values for the effective permeability and the intrinsic clearance of hepatic uptake by organic anion transporting polypeptide (OATP) 1B1 were optimized in a simulator platform.This PBPK model was subsequently validated using reported maximum pemafibrate plasma concentration and area under the curve values in reported interaction studies in healthy subjects co-administered with rifampicin.For subjects with Child-Pugh A and B liver cirrhosis, the intrinsic clearance of hepatic uptake of pemafibrate by OATP1B1 were modeled using 53% and 31% of that of healthy subjects, respectively. Virtual co-administrations of rifampicin and sacubitril (OATP1B inhibitors) in subjects with renal impairment and liver cirrhosis resulted in 11- to 13-folds (rifampicin) and 1.1- to 1.3-folds (sacubitril) increased plasma exposures of pemafibrate.The current PBPK model and simulations revealed different pharmacokinetic profiles for pemafibrate following co-administration of rifampicin or sacubitril in virtual subjects with or without renal/hepatic impairment.

Prediction of circulating human metabolites of pemafibrate, a novel antidyslipidemic drug, using chimeric mice with humanized liver.

Pharmacokinetics and metabolism of recently launched antidyslipidemic drug pemafibrate ((2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid) was investigated in chimeric mice with humanized liver in the present study.The plasma unbound fractions of [14C]pemafibrate in mice (0.0046-0.0048) were higher than those in monkeys and humans (0.0015-0.0022).In chimeric mice with humanized liver intravenously treated with pemafibrate at 1.0 mg/kg body weight, the pharmacokinetic parameters (CLtotal, Vss and AUC0-inf) of unbound pemafibrate in chimeric mice with humanized liver were more similar to those reported in monkeys and humans than those in control mice.High concentrations of N-dealkylated form (M4) and benzoxazole 6-hydroxylated form (M6) of pemafibrate in plasma were observed as the main circulating metabolites in chimeric mice with humanized liver treated with pemafibrate. Moreover, the concentrations of other specified metabolites of pemafibrate were much higher in chimeric mice with humanized liver than in control mice.These results suggest that there are species differences in the pharmacokinetics of pemafibrate in vivo between mice tested and humans reported. Moreover, chimeric mice with humanized liver seem to be a beneficial animal model for further studies to predict the circulating human metabolites of pemafibrate and their pharmacokinetics.

Pharmacokinetics and metabolism of pemafibrate, a novel selective peroxisome proliferator-activated receptor-alpha modulator, in rats and monkeys.

The metabolic profiles and pharmacokinetics of pemafibrate, a novel selective peroxisome proliferator activated receptor-alpha modulator currently launched as an antidyslipidemic drug, were investigated in vitro using hepatocytes from rats, monkeys and humans and in vivo in rats and monkeys. Hepatocytes from rats, monkeys and humans all biotransformed pemafibrate to its demethylated form (M1). The bioavailabilities of pemafibrate in Sprague-Dawley rats and cynomolgus monkeys were 15% and 87%, respectively, after a single oral administration of pemafibrate (1 mg/kg). In rat plasma, unmetabolized pemafibrate was the major form, accounting for 29% of the area under the curve (AUC) of total radioactivity. In monkey plasma, in contrast, the major circulating metabolites were M2/3 (dearylated/dicarboxylic acid forms, 15%), M4 (N-dealkylated form, 21%) and M5 (benzylic oxidative form, 9%), but pemafibrate was the notable minor form (3%). These results, in combination with the reported findings in humans, suggest that the metabolite profile of pemafibrate in plasma was different for rats and monkeys, and that monkeys could be a suitable animal model for further pharmacokinetic studies of pemafibrate in humans.

New markers for tracking endoderm induction and hepatocyte differentiation from human pluripotent stem cells.

The efficient generation of hepatocytes from human pluripotent stem cells (hPSCs) requires the induction of a proper endoderm population, broadly characterized by the expression of the cell surface marker CXCR4. Strategies to identify and isolate endoderm subpopulations predisposed to the liver fate do not exist. In this study, we generated mouse monoclonal antibodies against human embryonic stem cell-derived definitive endoderm with the goal of identifying cell surface markers that can be used to track the development of this germ layer and its specification to a hepatic fate. Through this approach, we identified two endoderm-specific antibodies, HDE1 and HDE2, which stain different stages of endoderm development and distinct derivative cell types. HDE1 marks a definitive endoderm population with high hepatic potential, whereas staining of HDE2 tracks with developing hepatocyte progenitors and hepatocytes. When used in combination, the staining patterns of these antibodies enable one to optimize endoderm induction and hepatic specification from any hPSC line.

Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis.

We report the fabrication of a scaffold (hereafter referred to as AngioChip) that supports the assembly of parenchymal cells on a mechanically tunable matrix surrounding a perfusable, branched, three-dimensional microchannel network coated with endothelial cells. The design of AngioChip decouples the material choices for the engineered vessel network and for cell seeding in the parenchyma, enabling extensive remodelling while maintaining an open-vessel lumen. The incorporation of nanopores and micro-holes in the vessel walls enhances permeability, and permits intercellular crosstalk and extravasation of monocytes and endothelial cells on biomolecular stimulation. We also show that vascularized hepatic tissues and cardiac tissues engineered by using AngioChips process clinically relevant drugs delivered through the vasculature, and that millimetre-thick cardiac tissues can be engineered in a scalable manner. Moreover, we demonstrate that AngioChip cardiac tissues implanted with direct surgical anastomosis to the femoral vessels of rat hindlimbs establish immediate blood perfusion.

Three-dimensional culture and cAMP signaling promote the maturation of human pluripotent stem cell-derived hepatocytes.

Human pluripotent stem cells (hPSCs) represent a novel source of hepatocytes for drug metabolism studies and cell-based therapy for the treatment of liver diseases. These applications are, however, dependent on the ability to generate mature metabolically functional cells from the hPSCs. Reproducible and efficient generation of such cells has been challenging to date, owing to the fact that the regulatory pathways that control hepatocyte maturation are poorly understood. Here, we show that the combination of three-dimensional cell aggregation and cAMP signaling enhance the maturation of hPSC-derived hepatoblasts to a hepatocyte-like population that displays expression profiles and metabolic enzyme levels comparable to those of primary human hepatocytes. Importantly, we also demonstrate that generation of the hepatoblast population capable of responding to cAMP is dependent on appropriate activin/nodal signaling in the definitive endoderm at early stages of differentiation. Together, these findings provide new insights into the pathways that regulate maturation of hPSC-derived hepatocytes and in doing so provide a simple and reproducible approach for generating metabolically functional cell populations.

Stage-specific signaling through TGFß family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells.

The generation of insulin-producing ß-cells from human pluripotent stem cells is dependent on efficient endoderm induction and appropriate patterning and specification of this germ layer to a pancreatic fate. In this study, we elucidated the temporal requirements for TGFß family members and canonical WNT signaling at these developmental stages and show that the duration of nodal/activin A signaling plays a pivotal role in establishing an appropriate definitive endoderm population for specification to the pancreatic lineage. WNT signaling was found to induce a posterior endoderm fate and at optimal concentrations enhanced the development of pancreatic lineage cells. Inhibition of the BMP signaling pathway at specific stages was essential for the generation of insulin-expressing cells and the extent of BMP inhibition required varied widely among the cell lines tested. Optimal stage-specific manipulation of these pathways resulted in a striking 250-fold increase in the levels of insulin expression and yielded populations containing up to 25% C-peptide+ cells.

Effects of single nucleotide polymorphism marker density on degree of genetic variance explained and genomic evaluation for carcass traits in Japanese Black beef cattle.

BACKGROUND: Japanese Black cattle are a beef breed whose meat is well known to excel in meat quality, especially in marbling, and whose effective population size is relatively low in Japan. Unlike dairy cattle, the accuracy of genomic evaluation (GE) for carcass traits in beef cattle, including this breed, has been poorly studied. For carcass weight and marbling score in the breed, as well as the extent of whole genome linkage disequilibrium (LD), the effects of equally-spaced single nucleotide polymorphisms (SNPs) density on genomic relationship matrix (G matrix), genetic variance explained and GE were investigated using the genotype data of about 40,000 SNPs and two statistical models. RESULTS: Using all pairs of two adjacent SNPs in the whole SNP set, the means of LD (r2) at ranges 0-0.1, 0.1-0.2, 0.2-0.5 and 0.5-1 Mb were 0.22, 0.13, 0.10 and 0.08, respectively, and 25.7, 13.9, 10.4 and 6.4% of the r2 values exceeded 0.3, respectively. While about 90% of the genetic variance for carcass weight estimated using all available SNPs was explained using 4,000-6,000 SNPs, the corresponding percentage for marbling score was consistently lower. With the conventional linear model incorporating the G matrix, correlation between the genomic estimated breeding values (GEBVs) obtained using 4,000 SNPs and all available SNPs was 0.99 for carcass weight and 0.98 for marbling score, with an underestimation of the former GEBVs, especially for marbling score. CONCLUSIONS: The Japanese Black is likely to be in a breed group with a relatively high extent of whole genome LD. The results indicated that the degree of marbling is controlled by only QTLs with relatively small effects, compared with carcass weight, and that using at least 4,000 equally-spaced SNPs, there is a possibility of ranking animals genetically for these carcass traits in this breed.

Reaction-norm animal model analysis of average daily gain heat tolerance in purebred Duroc pigs.

The present study aimed to genetically improve growth performance under high-heat environments by specifically designing a reaction-norm animal model (RNAM) for purebred Duroc pigs in Japan. A total of 54,750 records of average daily gain (ADG) measured for pigs reared at four farms in different prefectures were analyzed. Estimated maximum daily temperatures at the respective farm locations were used to calculate the average cumulative thermal load (TL). The TL values served as an indicator of high-heat environments for pigs. The plausible cumulative period length and threshold temperature for calculating TL were determined to be 8 weeks until just before shipping and 25°C, respectively. Variance components were estimated via RNAM analysis using TL as a linear covariate. The estimated additive genetic variances under both responsive and non-responsive to TL were found to be significant. Moreover, the estimated heritability of ADG ranged from 0.38 to 0.73 for TL values of 0-8. These results suggest that the RNAM developed holds the potential for improving the genetic ability of growth under high-heat environments in pigs.

Comparing Methods to Select Candidates for Re-Genotyping to Impute Higher-Density Genotype Data in a Japanese Black Cattle Population: A Case Study.

As optimization methods to identify the best animals for dense genotyping to construct a reference population for genotype imputation, the MCA and MCG methods, which use the pedigree-based additive genetic relationship matrix (A matrix) and the genomic relationship matrix (G matrix), respectively, have been proposed. We assessed the performance of MCA and MCG methods using 575 Japanese Black cows. Pedigree data were provided to trace back up to five generations to construct the A matrix with changing the pedigree depth from 1 to 5 (five MCA methods). Genotype information on 36,426 single-nucleotide polymorphisms was used to calculate the G matrix based on VanRaden's methods 1 and 2 (two MCG methods). The MCG always selected one cow per iteration, while MCA sometimes selected multiple cows. The number of commonly selected cows between the MCA and MCG methods was generally lower than that between different MCA methods or between different MCG methods. For the studied population, MCG appeared to be more reasonable than MCA in selecting cows as a reference population for higher-density genotype imputation to perform genomic prediction and a genome-wide association study.

Estimation of off-farm temperatures and temperature-humidity index from meteorological observation records.

The objective of this study was to devise an optimal method for estimating air temperatures outside pig farms to be able to evaluate the genetic performance of pigs. Using daily temperature data from Japan Meteorological Agency meteorological stations, we investigated the optimal number of observation weather stations (number of records), and methods of estimating outside temperature when temperature records are missing. We also considered the possibility of using relative humidity data. Our results showed that it is possible to use records from the three nearest weather stations to estimate off-farm ambient temperatures. We also concluded that estimates of outside temperatures when records are missing can be made by using data from at least one weather station that holds a full set of data. The correlation coefficients between the true THI (temperature-humidity index) and the estimated THI and the average daily temperature were almost the same, indicating that the daily average temperature can be used instead of estimated THI.

Angioplasty of the inferior vena cava with a bovine pericardial patch by the modified open-chest dorsal approach for Budd-Chiari syndrome: A case report.

INTRODUCTION AND IMPORTANCE: Surgical treatment of Budd-Chiari syndrome (BCS) includes endovenectomy followed by angioplasty of the inferior vena cava (IVC). Herein, we report a case of surgery using an open-chest approach in a patient with BCS. We modified the technique reported by Kuniyoshi et al. CASE PRESENTATION: A 45-year-old male, was diagnosed with BCS and referred to our hospital. We used an open-chest approach to remove stenosis in the IVC and angioplasty with a bovine pericardial patch. Endovenectomy and angioplasty were performed by clamping the stenosis above and below it with Pringle's clamping under extracorporeal circulation. The patient is currently undergoing outpatient follow-up 14 months after the surgery, and his liver function and blood test results were normal, with no symptoms. CLINICAL DISCUSSION: The main advantage of this technique is that the liver is not mobilized from the diaphragm, which allows for the preservation of collateral blood flow between the diaphragm and liver, reducing the amount of intraoperative blood loss and damage to the liver parenchyma due to intraoperative congestion. In addition, no mobilization of the liver from the diaphragm will prevent future surgical difficulties due to adhesions during total hepatectomy when liver transplantation becomes necessary. CONCLUSION: The techniques described in this article include procedures that cardiovascular surgeons usually perform such as thoracotomy, pericardiotomy, and extracorporeal circulation. Collaborative work by hepatobiliary surgeons and cardiovascular surgeons can achieve successful outcomes with this procedure in patients with BCS.