Value of autotaxin for hepatocellular carcinoma risk assessment in chronic hepatitis B patients treated with nucleos(t)ide analogs

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Abstract

Aim

Autotaxin (ATX) is a newly identified liver fibrosis biomarker; however, its clinical usefulness remains unclear. Therefore, we analyzed the changes in patients with chronic hepatitis B virus infection treated with nucleos(t)ide analogs (NAs) to evaluate its usefulness. We also investigated the predictors of hepatocellular carcinoma development, including ATX, in patients with chronic hepatitis B based on their clinical characteristics.

Methods

This retrospective study included 179 patients with hepatitis B virus infection treated with NAs for >2 years. First, we measured the ATX levels before and up to 10 years after initiating entecavir (therapy for 88 patients whose serial ATX levels could be measured before and during entecavir therapy. Subsequently, for 179 patients whose ATX levels could be measured at the commencement of NAs, we examined the factors involved in developing hepatocellular carcinoma, including ATX.

Results

The ATX levels showed a gradual and significant decrease during the observation period of up to 10 years. Multivariable analysis showed that a baseline ATX/upper limits of normal ratio ≥1.214, age, and alkaline phosphatase levels were independent risk factors for hepatocellular carcinoma development. The combination of age and ATX/upper limits of normal ratio was used to stratify the high-risk groups for liver carcinogenesis.

Conclusions

A decrease in ATX levels up to 10 years after the commencement of therapy suggested that ATX is a helpful biomarker in evaluating fibrosis in patients undergoing long-term NA therapy. Furthermore, this study showed that combining age and the baseline ATX/upper limits of normal ratio may help identify high-risk carcinogenesis groups.

Natural killer group 2D‐major histocompatibility complex class I polypeptide‐related sequence A activation enhances natural killer cell‐mediated immunity against hepatocellular carcinoma: A review

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Natural killer group 2D-major histocompatibility complex class I polypeptide-related sequence A activation enhances natural killer cell-mediated immunity against hepatocellular carcinoma: A review

A recent meta-analysis showed that the percentage of infiltrating natural killer cells in hepatocellular carcinoma correlates with a better patient outcome. On the surface of stressed hepatocyte or hepatocellular carcinoma, membrane-bound major histocompatibility complex class I polypeptide-related sequence A (MICA) is cleaved by a disintegrin and metalloproteases, releasing soluble MICA, which acts as an immunological decoy in serum, preventing natural killer-driven antitumor activity. In this review, we summarize the mechanisms underlying the regulation of MICA and describe a recent promising approach for immunosurveillance through the use of a MICA shedding inhibitor.


Abstract

The recent clinical introduction of immune checkpoint inhibitors has improved therapeutic outcomes in patients with advanced hepatocellular carcinoma. However, these therapies targeting CD8+ T lymphocytes have a response rate of approximately 30%. In addition to CD8+ T lymphocytes, natural killer (NK) cells represent promising therapeutic targets for hepatocellular carcinoma, because they comprise 30%–50% of all lymphocytes in the liver and contribute to antitumor immunity. A recent meta-analysis revealed that the percentage of infiltrating NK cells in hepatocellular carcinoma correlates with a better patient outcome. Similarly, our previous genome-wide association study on chronic viral hepatitis showed that a single-nucleotide polymorphism of major histocompatibility complex class I polypeptide-related sequence A (MICA), a ligand to the NK activating receptor, plays a critical role in hepatocarcinogenesis. In this review, we summarize the mechanisms underlying the regulation of MICA and NK group 2D expression in chronic hepatitis. Furthermore, we describe recent reports on MICA single-nucleotide polymorphism-driven hepatocarcinogenesis. The suppression of MICA shedding could represent a promising approach for immunosurveillance, as increased expression of membrane-bound MICA achieved through the use of a MICA shedding inhibitor also enhances NK cell-mediated cytotoxicity.

Sexual selection in Thaumatotibia leucotreta (Meyrick) is shaped by contrasting geographic adaptations, but does it matter for area‐wide sex pheromone control tools?

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Sexual selection in Thaumatotibia leucotreta (Meyrick) is shaped by contrasting geographic adaptations, but does it matter for area-wide sex pheromone control tools?

Geographically isolated populations of Thaumatotibia leucotreta (Meyrick) (Lepidoptera: Tortricidae) occur in South Africa, causing speculations of loss of sexual communication between these isolated populations and compromise the efficiency of sex pheromone tools. Investigations into these speculations were conducted, and results indicate that local adaptation and other selection forces in contrasting environments are important in sexual communication and selection in T. leucotreta but do not necessarily prevent recognition of sexual signals and attraction between geographically isolated populations.


Abstract

Thaumatotibia leucotreta (Meyrick) (Lepidoptera: Tortricidae) is a quarantine pest for certain export markets due to its phytosanitary status in affected crops in sub-Saharan Africa, including citrus. Consequently, there is a zero-tolerance policy for T. leucotreta in export markets. In South Africa, an integrated pest management strategy, incorporating a systems approach is used to achieve complete control of T. leucotreta. Preharvest management is multi-faceted, including reliance on sex pheromone tools such as monitoring, attract-and-kill, mating disruptions, and sterile insect technique (SIT). Geographically isolated populations of T. leucotreta occur in South Africa, and there is speculation concerning the possible loss of sexual communication between these isolated populations, thereby compromising the efficiency of sex pheromone tools. To investigate this possibility, we collected samples from five geographically isolated populations of T. leucotreta and a population used for SIT in South Africa. These were subjected to sexual attraction trials under choice and no-choice scenarios in a semi-natural environment. Results of the choice tests revealed that males of each population preferred their corresponding population females, except irradiated males. However, when we deprived males of their preferred females, these preferences dissipated, and they were equally attracted to females from all populations. These results indicate that local adaptation and other selection forces in contrasting environments are important in sexual communication and selection in T. leucotreta but do not necessarily prevent recognition of sexual signals and attraction between geographically isolated populations. These findings are crucial for area-wide IPM and precision control of T. leucotreta.

Generation of novel anti‐apoE monoclonal antibodies that selectively recognize apoE isoforms

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Generation of novel anti-apoE monoclonal antibodies that selectively recognize apoE isoforms

Apolipoprotein E (apoE) is a regulator of lipid metabolism, cholesterol transport, and the clearance and aggregation of amyloid β in the brain. Human apoE4 isoform is a risk factor for apoE-related diseases, although only one or two residues are different in other isoforms. Here, we generated novel anti-apoE monoclonal antibodies and constructed a sandwich ELISA system to selectively detect the apoE4 isoform.


Apolipoprotein E (apoE) is a regulator of lipid metabolism, cholesterol transport, and the clearance and aggregation of amyloid β in the brain. The three human apoE isoforms apoE2, apoE3, and apoE4 only differ in one or two residues. Nevertheless, the functions highly depend on the isoform types and lipidated states. Here, we generated novel anti-apoE monoclonal antibodies (mAbs) and obtained an apoE4-selective mAb whose epitope is within residues 110–117. ELISA and bio-layer interferometry measurements demonstrated that the dissociation constants of mAbs are within the nanomolar range. Using the generated antibodies, we successfully constructed sandwich ELISA systems, which can detect all apoE isoforms or selectively detect apoE4. These results suggest the usability of the generated anti-apoE mAbs for selective detection of apoE isoforms.

Comparative structural and functional analysis of the glycine‐rich regions of Class A and B J‐domain protein cochaperones of Hsp70

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Comparative structural and functional analysis of the glycine-rich regions of Class A and B J-domain protein cochaperones of Hsp70

This study provides new perspectives on the functions of the glycine-rich region adjacent to the J-domain of Classes A and B J-domain proteins. Within the glycine-rich region of both Classes A and B, a role for helical segments that are similar in chemical character and conserved across phylogeny in mediating functionally important interactions is indicated—in addition to that already established for Class B.


J-domain proteins are critical Hsp70 co-chaperones. A and B types have a poorly understood glycine-rich region (Grich) adjacent to their N-terminal J-domain (Jdom). We analyzed the ability of Jdom/Grich segments of yeast Class B Sis1 and a suppressor variant of Class A, Ydj1, to rescue the inviability of sis1-∆. In each, we identified a cluster of Grich residues required for rescue. Both contain conserved hydrophobic and acidic residues and are predicted to form helices. While, as expected, the Sis1 segment docks on its J-domain, that of Ydj1 does not. However, data suggest both interact with Hsp70. We speculate that the Grich–Hsp70 interaction of Classes A and B J-domain proteins can fine tune the activity of Hsp70, thus being particularly important for the function of Class B.

Estimation of heritability with genomic information by method R

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Abstract

Estimating heritabilities with large genomic models by established methods such as restricted maximum likelihood (REML) or Bayesian via Gibbs sampling is computationally expensive. Alternatively, heritability can be estimated indirectly by method R and by maximum predictivity, referred to as MaxPred here, at a much lower computing cost. By method R, the heritability used for predictions with whole and partial data is considered the best estimate when the predictions based on partial data are unbiased relative to those with the complete data. By MaxPred, the heritability estimate is the one that maximizes predictivity. This study compared heritability estimation with genomic information using average information REML (AI–REML), method R and MaxPred. A simulated population was generated with ten generations of 5000 animals each and an effective population size of 80. Each animal had one record for a trait with a heritability of 0.3, a phenotypic variance of 10.0 and was genotyped at 50 k SNP. In method R, the heritability estimate is found when the expectation of a regression coefficient is equal to one. The regression is the EBV of selection candidates calculated with the whole dataset regressed on the EBV of candidates calculated from a partial dataset. In this study, we used the GBLUP framework and therefore, GEBV was calculated. The partial dataset was created by removing the last generation of phenotypes. Predictivity was defined as the correlation between the adjusted phenotypes of the selection candidates and their GEBV calculated from the partial data. We estimated the heritability for populations that included between three and 10 generations. In every scenario, predictivity increased as more data was used and was the highest at the simulated heritability. However, the predictivity for all data subsets and all heritabilities compared did not differ more than 0.01, suggesting MaxPred is not the best indication for heritability estimation. For the whole dataset, the heritability was estimated as 0.30 ± 0.01, 0.26 ± 0.01 and 0.30 ± 0.04 for AI–REML without genomics, AI–REML with genomics and method R with genomics, respectively. Heritability estimation with genomics by method R reduced timing by 83%, implying a reduction in computing time from 9.5 to 1.6 h, on average, compared to AI–REML with genomics. Method R has the potential to estimate heritabilities with large genomic information at a low cost when many generations of animals are present; however, the standard error can be high when only a few iterations are used.

Epidemiology of Fontan‐associated liver disease in Japan: Results from a nationwide survey in 2021

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Epidemiology of Fontan-associated liver disease in Japan: Results from a nationwide survey in 2021

In Japan, the number of post-Fontan procedure patients was estimated to be 7810 in 2020, and 3120 (40%) of these patients were diagnosed with Fontan-associated liver disease (FALD) during the median follow-up of 13.8 years after the procedure. The most common sign leading to the diagnosis of FALD other than liver fibrosis was an elevated γ-glutamyl transpeptidase level. More than half of the patients without a diagnosis of FALD had increased liver enzymes, suggesting that the number of patients with FALD was underestimated.


Abstract

Aim

Although the Fontan procedure has improved the survival of patients with single-ventricle heart disease, the long-term consequences of the procedure have been a concern. This study aimed to explore the patients' postoperative clinical characteristics, including a diagnosis of Fontan-associated liver disease (FALD).

Methods

A nationwide Japanese epidemiological survey of post-Fontan patients was undertaken in 2021. The survey targets were selected from all departments of pediatrics, pediatric surgery, cardiology, cardiovascular surgery, and gastroenterology using stratified random sampling by the number of beds. Each department was asked to complete a mail-back questionnaire on the numbers of patients and their clinical characteristics. The diagnosis of FALD was made by each attending physician.

Results

The estimated number of post-Fontan patients was 7810 (95% confidence interval, 5430−10 200) in 2020, with a period prevalence of 61.9 per million. During the follow-up of 13.8 years after the Fontan procedure, 40% of patients were diagnosed with FALD. An elevated γ-glutamyl transpeptidase level was the most common finding leading to the FALD diagnosis (41%), and 45% of the patients also showed liver fibrosis. Compared with non-FALD patients, FALD patients were older, had longer duration since the Fontan procedure, and had more severe cardiac or liver conditions. However, more than half of the non-FALD patients had elevated liver enzyme levels, suggesting underestimation of the number of FALD patients.

Conclusions

In 2020, approximately 40% of post-Fontan patients underwent follow-up with a diagnosis of FALD, although the lack of established diagnostic criteria for FALD could affect the reported prevalence of FALD.

Changes in the prevalence of fungal species causing post‐harvest diseases of carrot in Finland

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Changes in the prevalence of fungal species causing post-harvest diseases of carrot in Finland

Carrot post-harvest diseases were analysed in samples from 52 different field plots in Finland, during 3 years. After 5 months at 0–1°C, the average loss due to diseases was 20%–21% every year. Decay of the root tip was the most common disease symptom, followed by pits on the side and black rot in the crown, detected in 69.2%, 15.0% and 9.0% of the symptomatic samples, respectively. The frequency of different fungal pathogens varied between the years and the time points during storage. At first Fusarium spp. were prevalent, whereas Mycocentrospora acerina and Botrytis cinerea peaked later.


Abstract

Post-harvest diseases cause significant economic losses in the carrot production chain. In this study, storage losses and fungal pathogens causing them were analysed in the carrot yield from 52 different field plots in four areas in Finland in 3 years (2016–2018). Over 30,000 carrots were sampled and analysed at three time points during cold storage at 0–1°C. In March, after 5–6 months' storage, the average loss due to diseases was 20%–21% every year. Decay of the root tip was the most common disease symptom, followed by pits on the side and black rot in the crown, detected in 69.2%, 15.0% and 9.0% of the symptomatic samples, respectively. Both intensive carrot cultivation practice and early timing of harvest increased storage losses. Pathogens in 3057 symptomatic carrot tissue samples were isolated by culturing, and fungal species were identified. The most common fungal species detected were Mycocentrospora acerina, Botrytis cinerea and Fusarium spp., especially F. avenaceum. However, the frequency of different pathogens varied between the different years and time points during storage. Species-specific PCR tests revealed that M. acerina and F. avenaceum were present in many early time-point samples where they could not yet be detected by the culturing method. In Finland, this study on carrot post-harvest diseases is the first large-scale survey in which the fungal pathogens were isolated and identified by laboratory tests. In comparison with the previous studies, Fusarium spp. were detected more frequently in this study, while grey mould and Sclerotinia rot were less frequent.