Category Archives: ORIGINAL ARTICLE

Characterization of runs of homozygosity islands in American mink using whole‐genome sequencing data

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Abstract

The genome-wide analysis of runs of homozygosity (ROH) islands can be an effective strategy for identifying shared variants within a population and uncovering important genomic regions related to complex traits. The current study performed ROH analysis to characterize the genome-wide patterns of homozygosity, identify ROH islands and annotated genes within these candidate regions using whole-genome sequencing data from 100 American mink (Neogale vison). After sequence processing, variants were called using GATK and Samtools pipelines. Subsequent to quality control, 8,373,854 bi-allelic variants identified by both pipelines remained for further analysis. A total of 34,652 ROH segments were identified in all individuals, among which shorter segments (0.3–1 Mb) were abundant throughout the genome, approximately accounting for 84.39% of all ROH. Within these segments, we identified 63 ROH islands housing 156 annotated genes. The genes located in ROH islands were associated with fur quality (EDNRA, FGF2, FOXA2 and SLC24A4), body size/weight (MYLK4, PRIM2, FABP2, EYS and PHF3), immune capacity (IL2, IL21, PTP4A1, SEMA4C, JAK2, CCNA2 and TNIP3) and reproduction (ADAD1, KHDRBS2, INSL6, PGRMC2 and HSPA4L). Furthermore, Gene Ontology and KEGG pathway enrichment analyses revealed 56 and 9 significant terms (FDR-corrected p-value < 0.05), respectively, among which cGMP-PKG signalling pathway, regulation of actin cytoskeleton, and calcium signalling pathway were highlighted due to their functional roles in growth and fur characteristics. This is the first study to present ROH islands in American mink. The candidate genes from ROH islands and functional enrichment analysis suggest possible signatures of selection in response to the mink breeding targets, such as increased body length, reproductive performance and fur quality. These findings contribute to our understanding of genetic characteristics, and provide complementary information to assist with implementation of breeding strategies for genetic improvement in American mink.

Identification of genomic regions and pathways associated with traits related to rumen acidosis in feedlot Nellore cattle

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Abstract

There may be an increased risk of metabolic disorders, such as rumen acidosis, in cattle fed high-concentrate diets, particularly those from Bos taurus indicus genotypes, which have shown to be more sensitive to ruminal acidification. Therefore, this study aimed to estimate (co)variance components and identify genomic regions and pathways associated with ruminal acidosis in feedlot Nellore cattle fed high-concentrate diets. It was utilized a dataset containing a total of 642 Nellore bulls that were genotyped from seven feedlot nutrition studies. The GGP Indicus 35k panel was used with the single step genome-wide association study methodology in which the effects of the markers were obtained from the genomic values estimated by the GBLUP model. A bivariate model to estimate genetic correlations between the economically important traits and indicator traits for acidosis was used. The traits evaluated in this study that were nutritionally related to rumen acidosis included average daily gain (ADG), final body weight, time spent eating (TSE), time spent ruminating, rumenitis score (RUM), rumen absorptive surface area (ASA), rumen keratinized layer thickness (KER) and hot carcass weight (HCW). The identified candidate genes were mainly involved in the negative or non-regulation of the apoptotic process, salivary secretion, and transmembrane transport. The genetic correlation between HCW and ASA was low positive (0.27 ± 0.23), and between ADG and ASA was high moderate (0.58 ± 0.59). A positive genetic correlation between RUM and all performance traits was observed, and TSE correlated negatively with HCW (−0.33 ± 0.21), ASA (−0.75 ± 0.48), and KER (−0.40 ± 0.27). The genetic association between economically important traits and indicator traits for acidosis suggested that Nellore cattle may be more sensitive to acidosis in feedlot systems.

Association between tumor morphology and efficacy of atezolizumab plus bevacizumab for advanced hepatocellular carcinoma

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Association between tumor morphology and efficacy of atezolizumab plus bevacizumab for advanced hepatocellular carcinoma

This study showed that atezolizumab plus bevacizumab for hepatocellular carcinoma might be increasingly effective in patients with non-simple nodular (non-SN) intrahepatic lesions, which had a higher potential for aggressive features. A treatment strategy focusing on conversion therapy may be important in patients with non-SN lesions.


Abstract

Aim

The IMbrave150 trial revealed that atezolizumab plus bevacizumab (AtezoBv) showed a higher objective response rate (ORR) in patients with advanced hepatocellular carcinoma (HCC). Although conversion therapy after AtezoBv has been recently reported, markers predictive of its efficacy, particularly radiological imaging markers, have not yet been identified. The present study focused on tumor morphological appearance on radiological imaging and evaluated whether it could be associated with AtezoBv efficacy.

Methods

Ninety-five intrahepatic lesions in 74 patients who were given AtezoBv for advanced HCC were recruited for evaluation. The lesions were divided into two groups, simple nodular (SN group) and non-simple nodular (non-SN group), based on the gross morphology on pretreatment imaging, and retrospectively evaluated for treatment response and other relevant clinical outcomes.

Results

Assessing the size of individual tumors after treatment, waterfall plots showed that tumor shrinkage in the non-SN group including 56 lesions was higher than that in the SN group comprising 39 lesions. The ORR was significantly higher in the non-SN group (39.3% vs. 15.4%, p = 0.012). Additionally, the median time to nodular progression was longer in the non-SN group (21.0 months vs. 8.1 months, p = 0.119) compared to the SN group. Six patients with non-SN lesions underwent sequential local therapy.

Conclusions

Atezolizumab plus bevacizumab may show increased therapeutic efficacy in patients with tumors with a higher potential for aggressive oncological behavior, such as non-SN lesions. Treatment strategies focusing on conversion therapy may be crucial in patients with non-SN lesions.

Estimation of genetic parameters for reproductive indices in sheep

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Abstract

This study aimed to estimate two reproductive efficiency indices in sheep based on the ratio between litter weight (at birth and weaning) and dam weight, as well as their genetic parameters. Phenotypic and pedigree data comprising the period from 1990 to 2018 were obtained from the Santa Inês sheep database of Embrapa Tabuleiros Costeiros. For estimation of the genetic parameters of the indices, a repeatability model was applied in single- and two-trait analyses by a Bayesian approach. The mean reproductive efficiency index was 0.069 ± 0.0163 and 0.43 ± 0.0955 at birth and weaning, respectively. These values indicate that, on average, ewes give birth to 69 g of lamb per kg body weight and wean 430 g of lamb per kg body weight. Described here for the first time, the heritability estimate obtained in single- and two-trait analyses was 0.24 for the index based on birth weights and ranged from 0.13 to 0.15 for the index based on weaning weights. The estimates indicate the possibility of genetic gain by selection and are similar to those reported for reproductive traits in sheep, representing an option for selection criterion. The genetic correlation between indices was positive and moderate (0.26). The repeatability estimates were high (0.49 for the birth weight index and 0.71 for the weaning weight index). These values indicate good prediction of future performance with few observations. The weaning weight index might be a good culling criterion of females.

Genetic correlation estimates between calving ease in primiparous cows and economically important traits in Nellore cattle

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Abstract

This study aimed to estimate (co)variance components and genetic parameters for calving ease (CE) and their genetic correlations with growth, reproductive, carcass, and feed efficiency traits in Nellore cattle. Phenotypes for CE are scored in two categories: normal calving and assisted calving. The traits considered were probability of precocious calving, age at first calving, stayability, adjusted scrotal circumference at 365 days of age, accumulated cow productivity, age at puberty of males, gestation length, birth weight, adjusted weights at 210 and 450 days of age, adult cow weight, frame score, hip height, rib eye area, subcutaneous backfat thickness, rump fat thickness, intramuscular fat percentage, residual feed intake and dry matter intake. The estimation of genetic parameters was performed using a two-trait threshold-linear animal model, except for CE, stayability, and probability of precocious calving, which were evaluated through a two-trait threshold animal model. The direct (0.27) and maternal (0.19) heritability estimates for CE in heifers primiparous Nellore indicated that selecting for this trait is feasible. The selection to improve the female sexual precocity should consider CE during the selection and mating decisions to reduce calving problems. Genetic correlation estimates between CE and BW suggest that selecting low birth weight to reduce calving problems is not an appropriate strategy to improve calving ease in heifers Nellore. Therefore, adopting a multi-trait selection model with CE and BW in the Nellore breed would reduce calving difficulties, particularly in sexually precocious heifers, without impairing the growth, reproductive, feed efficiency conversion, and carcass indicator traits.

Hepatitis B surface antigen glycan isomer is a predictor of the development of hepatocellular carcinoma during nucleoside/nucleotide analog therapy

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Hepatitis B surface antigen glycan isomer is a predictor of the development of hepatocellular carcinoma during nucleoside/nucleotide analog therapy

The baseline platelet count and on-treatment hepatitis B surface antigen glycan isomer/hepatitis B surface antigen (HBsAgGi/HBsAg) ratio were useful predictors of hepatocellular carcinoma (HCC) development during nucleoside/nucleotide analog (NA) therapy. In addition, it suggests that a combination of on-treatment HBsAgGi and HBsAg may lead to an increase in the accuracy of predictions of the development of HCC during NA therapy compared with HBsAg alone.


Abstract

Aim

A recombinant monoclonal antibody against the hepatitis B surface antigen glycan isomer (HBsAgGi) was newly developed using the O-glycosylated PreS2 peptide in M-HBsAg of hepatitis B virus (HBV) genotype C. However, the association between HBsAgGi and the development of hepatocellular carcinoma (HCC) during nucleoside/nucleotide analog (NA) therapy remains unknown.

Methods

A total of 112 HBV genotype C-infected patients who were treated with NA were included in this study. We assessed the association between HBV markers, including HBsAgGi and other conventional markers, and the development of HCC during NA therapy.

Results

Ten patients developed HCC during the follow-up period. Of the HBV markers, HBsAg (≤3.53 log IU/mL; p = 0.047), HBsAgGi/HBsAg ratio (≥1.10; p = 0.035), and HBV DNA (≤6.3 log copies/mL; p = 0.012) at baseline and HBsAg (≤3.19 log IU/mL; p = 0.033) and HBsAgGi/HBsAg ratio (≥1.09; p = 0.003) at 48 weeks after NA therapy were significantly associated with the development of HCC according to the log rank test. In contrast, no significant association was observed between HBsAgGi and the development of HCC. Multivariate analysis revealed that a platelet count at baseline ≤88 × 103/mm3 (p = 0.026; hazard ratio [HR], 10.577) and an HBsAgGi/HBsAg ratio at 48 weeks after NA therapy ≥1.09 (p = 0.040; HR, 10.099) were independently and significantly associated with the development of HCC.

Conclusions

Our findings suggest that a combination of on-treatment HBsAgGi and HBsAg predicts the development of HCC during NA therapy.

Validation of Japanese indication criteria for deceased donor liver transplantation for hepatocellular carcinoma: Analysis of US national registry data

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Abstract

Aim

The Japanese indication criteria for liver transplantation (LT) for hepatocellular carcinoma (HCC) have been updated based on living donor LT data to include either the Milan criteria (MC) or the 5-5-500 rule, which requires a nodule size of ≤5 cm, ≤5 nodules, and an alpha-fetoprotein (AFP) level ≤500 ng/mL. We aimed to validate the 5-5-500 rule and the MC for deceased donor LT (DDLT).

Methods

Using national registry data from the United States from 2010 to 2014, we separated DDLT patients into four groups based on the MC and the 5-5-500 rule. The AFP values were stratified into categories: ≤100, 101–300, 301–500, and >500 ng/mL.

Results

The 5-year survival rate was significantly lower for patients in the groups within MC/beyond 5-5-500 (56.3%) or beyond MC/5-5-500 (60.7%) than for patients in the groups within MC/5-5-500 (76.2%) and beyond MC/within 5-5-500 (72.3%) (p < 0.01). Hepatocellular carcinoma recurrence at 5 years was highest for the within MC/beyond 5-5-500 (25.4%) group, followed by the beyond MC/within 5-5-500 (13.1%), beyond MC/5-5-500 (9.6%), and within MC/5-5-500 (7.4%) groups. The stratified 5-year survival rates after DDLT were 76.5%, 72.4%, 58.4%, and 55.6% in the AFP ≤100, 101–300, 301–500, and >500 categories, respectively (p < 0.01).

Conclusion

The 5-5-500 rule guides the appropriate selection of patients with HCC for DDLT. Patients with AFP levels from 300 to 500 ng/mL had inferior outcomes even when they met the 5-5-500 rule, so further investigation is needed to guide their treatment.

Impact of the COVID‐19 pandemic on the number and short‐term outcomes in hepatectomy for hepatocellular carcinoma: Results from the Japanese National Clinical Database, 2018–2021

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Impact of the COVID-19 pandemic on the number and short-term outcomes in hepatectomy for hepatocellular carcinoma: Results from the Japanese National Clinical Database, 2018–2021

This national survey using the National Clinical Database in Japan showed a decreasing number of resected cases for hepatocellular carcinoma (HCC). However, our study also revealed the surgical safety of hepatectomy for HCC during the COVID-19 pandemic using risk-adjusted metrics.


Abstract

Aim

The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted the allocation of medical resources, including cancer screening, diagnosis, and treatment. We aimed to investigate the effects of the pandemic on morbidity and mortality following hepatectomy for hepatocellular carcinoma (HCC).

Methods

We identified patients who underwent hepatectomy for HCC between 2018 and 2021 from the Japanese National Clinical Database (NCD). The number of surgical cases, the use of intensive care units, and the incidence of morbidity were assessed. The standardized morbidity / mortality ratio (SMR) was used to evaluate the rates of morbidity (bile leakage and pneumonia) and mortality in each month, which compares the observed incidence to the expected incidence calculated by the NCD's risk calculator.

Results

The study included a total of 10 647 cases. The number of patients undergoing hepatectomy for HCC gradually decreased. The proportion of patients aged 80 years or older increased and that of cases with T1 stage decreased. The proportion of patients who were admitted to the intensive care unit did not change between the pre- and postpandemic period. The mean actual incidence rates of bile leakage, pneumonia, 30-day mortality, and surgical mortality were 9.2%, 2.3%, 1.4%, and 2.1%, respectively. The SMR for the mortalities and morbidities in each month did not increase mostly throughout the COVID-19 pandemic.

Conclusions

The present study showed the decreasing number of resected cases for HCC, while the surgical safety for hepatectomy was enough to be maintained by managing medical resources in Japan.

Sex‐specific genetic parameter estimates of body weight in Mazandaran indigenous chickens

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Abstract

Body weight is an economically important trait in poultry that shows sexual dimorphism (SD). In the present study, variation in SD in Mazandaran native chickens was investigated in terms of the (Co) variance components and genetic parameters of body weight between males and females. Studied traits were body weights at hatch (BW1), 8 weeks (BW8) and 12 weeks of age (BW12). Also, for weight at sexual maturity (WSM) covariance components were only estimated in females. Cross-sex direct and maternal correlations were also estimated for studied traits except for WSM. For this purpose, a deep 21-generation pedigree and body weight data (57,576 BW1, 72,925 BW8, 62,727 BW12 and, 42,496 WSM) were used. Evaluation of SD of body weight was performed using six bivariate animal models with and without considering the genetic and permanent maternal environmental effects under the restricted maximum likelihood method in WOMBAT software. Model with direct additive genetic effects and maternal genetic effects without covariance between them was identified as the best model for BW1 and BW8. The Model including direct additive genetic effects and permanent maternal environmental effects was the best model for BW12 and WSM. Direct heritability (h 2) estimates for BW1, BW8 and, BW12 were, respectively, 0.05 ± 0.013, 0.17 ± 0.02 and, 0.25 ± 0.03 in males and, 0.05 ± 0.012, 0.15 ± 0.01 and 0.21 ± 0.01 in females. Also, the direct heritability of WSM based on univariate analysis in females was estimated to be 0.40 ± 0.01. Maternal heritability (hm2$$ {h}_m^2 $$) varied from 0.39 ± 0.01 (BW1) to 0.04 ± 0.009 (BW8) in males, and 0.36 ± 0.10 (BW1) to 0.04 ± 0.006 (BW8) in females. The correlation between direct genetic effects between males and females for BW1 was not significantly different from one. The direct genetic correlation between the two sexes for BW8 and BW12 was significantly different from 1 concluding that these traits are dimorphic in terms of direct genetic effects and therefore independent selection in both sexes is possible.

Inbreeding depression and runs of homozygosity islands in Asturiana de los Valles cattle breed after 30 years of selection

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Abstract

Inbreeding depression results in a decrease in the average phenotypic values of affected traits. It has been traditionally estimated from pedigree-based inbreeding coefficients. However, with the development of single-nucleotide polymorphism arrays, novel methods were developed for calculating the inbreeding coefficient, and consequently, inbreeding depression. The aim of the study was to analyse inbreeding depression in 6 growth and 2 reproductive traits in the Asturiana de los Valles cattle breed using both genealogical and molecular information. The pedigree group comprised 225,848 records and an average equivalent number of complete generations of 2.3. The molecular data comprised genotypes of 2693 animals using the Affymetrix medium-density chip. Using the pedigree information, three different inbreeding coefficients were estimated for the genotyped animals: the full pedigree coefficient (FPED), and the recent and ancient inbreeding coefficients based on the information of the last three generations (FPED<3G) and until the last three generations (FPED>3G), respectively. Using the molecular data, seven inbreeding coefficients were calculated. Four of them were estimated based on runs of homozygosity (ROH), considering (1) the total length (FROH), (2) segments shorter than 4 megabases (FROH<4), (3) between 4 and 17 megabases (FROH4-17), and (4) longer than 17 Mb (FROH>17). Additionally, the three inbreeding coefficients implemented in the Plink software (FHAT1-3) were estimated. Inbreeding depression was estimated using linear mixed-effects model with inbreeding coefficients used as covariates. All analysed traits (birth weight, preweaning average daily gain, weaning weight adjusted at 180 days, carcass weight, calving ease, age at first calving, calving interval) showed a statistically significant non-zero effect of inbreeding depression estimated from the pedigree group, except for the Postweaning Average Daily Gain trait. When inbreeding coefficients were based on the genomic group, statistically significant inbreeding depression was observed for two traits, Preweaning Average Daily Gain and Weaning Weight based on FROH, FROH>17, and FHAT3 inbreeding coefficients. Nevertheless, similar to inbreeding depression estimated based on pedigree information, estimates of inbreeding depression based on genomic information had no relevant economic impact. Despite this, from a long-term perspective, genotyped data could be included to maximize genetic progress in genetic programs following an optimal genetic contribution strategy and to consider individual inbreeding load instead global inbreeding. ROH islands were identified on chromosomes 2, 3, 8, 10, and 16. Such regions contain several candidate genes for growth development, intramuscular fat, body weight and lipid metabolism that are related to production traits selected in Asturiana de los Valles breed.