Evolutionary, structural and functional insights in nuclear organisation and nucleocytoplasmic transport in trypanosomes

Evolutionary, structural and functional insights in nuclear organisation and nucleocytoplasmic transport in trypanosomes

We consider the features of the nuclear lamina and NPC comparing humans, yeasts and trypanosomes. We discuss how those nuclear elements are structured in trypanosomes and how they differ from, or are conserved with other eukaryotic lineages. We also discuss the functional and evolutionary aspects of those fundamental elements of nuclear structure.


One of the remarkable features of eukaryotes is the nucleus, delimited by the nuclear envelope, a complex structure and home to the nuclear lamina and nuclear pore complex (NPC). For decades these structures were believed to be mainly architectural elements and, in the case of the NPC, simply facilitating nucleocytoplasmic trafficking. More recently the critical roles of the lamina, NPC and other nuclear envelope constituents in genome organisation, maintaining chromosomal domains and regulating gene expression have been recognised. Importantly, mutations in genes encoding lamina and NPC components lead to pathogenesis in humans, while in pathogenic protozoa disrupt the progression of normal development and expression of pathogenesis-related genes. Here we review features of the lamina and NPC across eukaryotes and discuss how these elements are structured in trypanosomes, protozoa of high medical and veterinary importance, highlighting lineage-specific and conserved aspects of nuclear organisation.

Inhibiting SETD7 methyl‐transferase activity impairs differentiation, lipid metabolism and lactogenesis in mammary epithelial cells

Inhibiting SETD7 methyl-transferase activity impairs differentiation, lipid metabolism and lactogenesis in mammary epithelial cells

SETD7 (SET7/9, KMT7) is a lysine methyltransferase that regulates several pathways. In mammary epithelial cells (HC11 and EpH4), inhibiting SETD7 catalytic activity with the compound (R)-PFI2 increased cell proliferation, altered expression of E-cadherin, beta-catenin, lactoferrin, insulin-like growth factor binding protein 5, and beta-casein, and disrupted the lipid profile. These findings indicate that inhibiting SETD7 activity impairs mammary epithelial and lactogenic differentiation.


SETD7 (SET7/9, KMT7) is a lysine methyltransferase that targets master regulators of cell proliferation and differentiation. Here, the impact of inhibiting SETD7 catalytic activity on mammary epithelial cell differentiation was studied by focusing on genes associated with epithelial differentiation, lactogenesis, and lipid metabolism in HC11 and EpH4 cell lines. Setd7 mRNA and protein levels were induced upon lactogenic differentiation in both cell lines. Inhibition of SETD7 activity by the compound (R)-PFI-2 increased cell proliferation and downregulated E-cadherin, beta-catenin, lactoferrin, insulin-like growth factor binding protein 5, and beta-casein levels. In addition, inhibition of SETD7 activity affected the lipid profile and altered the mRNA expression of the phospholipid biosynthesis-related genes choline phosphotransferase 1, and ethanolamine-phosphate cytidylyltransferase. Altogether, the results suggest that inhibiting SETD7 catalytic activity impairs mammary epithelial and lactogenic differentiation.

Genetic associations between stayability to consecutive calvings and traits of economic interest in taurine and zebu breeds

Abstract

Stayability (STAY) is a way to evaluate the productive longevity of females. Measuring the STAY at each cow calving allows earlier indicators of longevity to be obtained. Our objective with this study was to verify the association between STAY and consecutive calvings and traits potentially used as selection criteria in beef cattle, such as age at first calving (AFC), days to calving (DC), weaning weight (WW), and yearling weight (YW). Data from the Nelore, Angus/Brangus, and Hereford/Braford breeds were used. The estimation of variance components and subsequent prediction of breeding values were performed for all traits. The estimated breeding values (EBV) were used to analyse the association between STAY and the other traits. The Pearson's correlation estimated between the EBV for the intercept coefficient for STAY to consecutive calvings and those of AFC, DC, WW (direct and maternal effects), and YW was favourable and of low magnitude (<0.25) depending on the breed studied. The influence of the genetic merit of AFC on the chance of selection for STAY was favourable and relevant regardless of the intensity of selection and breed. DC and WW (maternal effect) traits were favourably influenced by the chance of selection for STAY, irrespective of breed. The WW (direct effect) did not affect the chance of selection for STAY for the Nelore and Hereford/Braford breeds and negatively influenced, but to a small extent, the Angus/Brangus breed. For YW, an increase in genetic merit affected the chances of selection for STAY, depending on the breed and selection intensity evaluated. The influence of the genetic merit for AFC, DC, and WW (maternal effect) on the chance of selection for STAY to consecutive calvings was favourable and relevant regardless of the selection intensity scenario evaluated. The WW (direct effect) did not influence the chance of selection for STAY. For the scenario with high selection intensity, the selection for YW favourably influenced the chance of selection for STAY in Angus/Brangus and Hereford/Braford breeds but not in Nelore.

Recent prevalence and characteristics of patients with hepatitis delta virus in Hokkaido, Japan

Recent prevalence and characteristics of patients with hepatitis delta virus in Hokkaido, Japan

Although hepatitis delta virus (HDV) co-infection with hepatitis B virus (HBV) is a global health concern, the global prevalence of HDV infections remains unknown due to insufficient data in many countries. In Japan, HDV prevalence has not been updated for over 20 years. The objective of our study was to investigate the recent prevalence of HDV infections in Hokkaido, Japan. We found that the current prevalence of HDV infections in Japanese patients with HBV was 1.7% (10/601). These patients experienced rapid liver fibrosis progression, highlighting the importance of routine HDV testing.


Abstract

Aim

Although hepatitis delta virus (HDV) coinfection with hepatitis B virus (HBV) is a global health concern, the global prevalence of HDV infections remains unknown due to insufficient data in many countries. In Japan, HDV prevalence has not been updated for over 20 years. We aimed to investigate the recent prevalence of HDV infections in Japan.

Methods

We screened 1264 consecutive patients with HBV infection at Hokkaido University Hospital between 2006 and 2022. Patients' serums were preserved and subsequently tested for HDV antibody (immunoglobulin-G). Available clinical information was collected and analyzed. We compared the changes in liver fibrosis using the Fibrosis-4 (FIB-4) index between propensity-matched patients with and without the evidence of anti-HDV antibodies and corrected for baseline FIB-4 index, nucleoside/nucleotide analog treatment, alcohol intake, sex, HIV coinfection, liver cirrhosis, and age.

Results

After excluding patients without properly stored serums and those lacking appropriate clinical information, 601 patients with HBV were included. Of these, 1.7% of patients had detectable anti-HDV antibodies. Patients with anti-HDV antibody serum positivity had a significantly higher prevalence of liver cirrhosis, significantly lower prothrombin time, and a higher prevalence of HIV coinfection than those who demonstrated serum anti-HDV antibody negativity. A propensity-matched longitudinal analysis revealed that liver fibrosis (FIB-4 index) progressed more rapidly in patients with positive results for anti-HDV antibody tests.

Conclusions

The recent prevalence of HDV infections in Japanese patients with HBV was 1.7% (10/601). These patients experienced rapid liver fibrosis progression, highlighting the importance of routine HDV testing.

Determinants of the effectiveness of bezafibrate combined with ursodeoxycholic acid in patients with primary biliary cholangitis

Determinants of the effectiveness of bezafibrate combined with ursodeoxycholic acid in patients with primary biliary cholangitis

This study focused on patients with primary biliary cholangitis (PBC) who did not respond well to the usual treatment with ursodeoxycholic acid (UDCA), and received a combination therapy with UDCA and bezafibrate (BZF). The study explored factors that could predict the outcomes of patients who received a combination therapy of two drugs. The results showed that certain indicators, such as high bilirubin levels and advanced histological stage, were associated with the patients' survival without requiring liver transplantation. The study emphasizes the need for early diagnosis of PBC to improve the effectiveness of the combination treatment.


Abstract

Background and Aims

For patients with primary biliary cholangitis (PBC) exhibiting suboptimal responses to ursodeoxycholic acid (UDCA), obeticholic acid (OCA), and bezafibrate (BZF) are currently used and shown to improve long-term outcomes. Nevertheless, we encounter patients who die or undergo liver transplantation (LT) even with combination treatment. In this study, we explored prognostic indicators in patients receiving combination treatment of UDCA and BZF.

Methods

We took advantage of the Japanese PBC registry and enrolled patients who received both UDCA and BZF therapy in 2000 or later. The covariates investigated included baseline covariates as well as treatment covariates. Two main outcomes (all-cause death or LT and liver-related death or LT) were assessed using multivariable-adjusted Cox proportional hazards models.

Results

In total, 772 patients were included. The median follow-up was 7.1 years. Using the Cox regression model, bilirubin (hazard ratio [HR] 6.85, 95% confidence interval [CI] 1.73–27.1, p = 0.006), alkaline phosphatase (HR 5.46, 95% CI 1.32–22.6, p = 0.019), and histological stage (HR 4.87, 95% CI 1.16–20.5, p = 0.031) were found associated with LT-free survival. For survival free from liver disease-related death or LT, albumin (HR 7.72, 95% CI 1.48–40.4, p = 0.016) and bilirubin (HR 14.5, 95% CI 2.37–88.5, p = 0.004) were found significantly associated.

Conclusion

In patients with PBC receiving combination therapy, prognostic variables were similar to those in patients receiving UDCA monotherapy. These results indicate the importance of diagnosing patients with PBC at an earlier stage because of the reduced effectiveness of BZF at advanced stages.

Impact of liver fibrosis on the relative abundance of a urease‐positive Streptococcus salivarius group from saliva in patients with chronic liver disease

Abstract

Aim

We performed genomic analysis to study the relative abundance of a urease-positive Streptococcus salivarius group isolated from the saliva of patients with chronic liver disease.

Methods

Male and female patients with chronic liver disease aged over 20 years were included. First, we assessed the frequency and type of the S. salivarius group isolated from oral saliva using molecular biology techniques based on 16S rRNA and dephospho-coenzyme A kinase gene sequencing. Next, we assessed the correlation between the urease positivity rate in the S. salivarius group isolated from oral saliva and liver fibrosis based on chronic liver disease. Urease-positive strains were identified by the urease test using urea broth (Difco, Franklin Lakes, NJ, USA). Liver fibrosis was evaluated by the liver stiffness measurement value based on magnetic resonance elastography.

Results

A total of 45 patients identified using the multiplex polymerase chain reaction for the 16S rRNA gene were tested using the multiplex polymerase chain reaction for the dephospho-coenzyme A kinase gene. Confirming the strains detected in each of the 45 patients, urease-positive S. salivarius was detected in 28 patients (62%), urease-negative S. salivarius in 25 patients (56%), and urease-positive Streptococcus vestibularis in 12 patients (27%). There was no patient with urease-negative S. vestibularis. The urease-positive rate of the S. salivarius group in the cirrhosis and non-cirrhosis groups were 82.2% and 39.2%, respectively. The liver cirrhosis group had a higher urease positivity rate than the non-cirrhotic group (p < 0.001).

Conclusions

Liver fibrosis influences the frequency of a urease-positive S. salivarius group isolated from oral saliva.

Serial increase and high alpha‐fetoprotein levels predict the development of hepatocellular carcinoma in 6 months

Serial increase and high alpha-fetoprotein levels predict the development of hepatocellular carcinoma in 6 months

A combination of a serial AFP-increase of ≥10% every 3–6 months with an AFP level of ≥20 ng/ml may predict the risk of HCC in 6 months. Regular AFP surveillance helps to detect HCC at early stage and should be included in the surveillance test for HCC.


Abstract

Aim

Alpha-fetoprotein (AFP) checkup with abdominal ultrasonography for hepatocellular carcinoma (HCC) surveillance remains controversial. We evaluated a serial AFP-increase and high AFP levels in the prediction of HCC.

Methods

At-risk patients with chronic liver disease underwent HCC surveillance with trimonthly AFP measurement were included and categorized into HCC and non-HCC groups. Their AFP levels at 12, 9, and 6 months (−6M) before the outcome date were evaluated. Group-based trajectory analysis and multivariable regression analysis were performed to identify AFP trajectories as risk predictors for HCC.

Results

Overall, 2776 patients were included in the HCC (n = 326) and non-HCC (n = 2450) groups. Serial AFP levels were significantly higher in the HCC than the non-HCC groups. Trajectory analysis identified AFP-increase group (11%) increased 24-fold risks of HCC compared with the AFP-stable (89%) group. Compared with patients without the AFP-increase, a serial 3-month AFP-increase ≥10% elevated HCC risk by 12.1-fold (95% CI: 6.5–22.4) in 6 months, and the HCC risks increased 13–60 fold in patients with cirrhosis, hepatitis B, or C receiving antiviral therapy, or AFP levels <20 ng/ml. Combining serial AFP-increase ≥10% and AFP ≥20 ng/ml at −6M significantly increased 41.7-fold (95% CI: 13.8–126.2) HCC risks. In patients who underwent biannual AFP checkups, those with both 6-month AFP-increase ≥10% and AFP ≥20 ng/ml increased 22.1-fold (95% CI: 12.52–39.16) HCC risks in 6 months. Most HCCs were detected at an early stage.

Conclusions

Serial 3–6-month AFP-increase of ≥10% previously and AFP level of ≥20 ng/ml significantly increased HCC risks in 6 months.

Tumor steatosis and glutamine synthetase expression in patients with advanced hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy

Abstract

Aim

The anti-programmed death-ligand 1 antibody atezolizumab and vascular endothelial growth factor-neutralizing antibody bevacizumab in combination (Atezo + Bev) have become the first-line therapy in advanced hepatocellular carcinoma (HCC). Distinct types of tumor immune microenvironment (TIME) and their associations with specific molecular subclasses and driver gene mutations have been identified in HCC; however, these insights are mainly based on surgically resected early-stage tumors. The current study aimed to reveal the biology and TIME of advanced HCC and their significance in predicting clinical outcomes of Atezo + Bev therapy.

Methods

Thirty-three patients with advanced HCC who were scheduled for treatment with Atezo + Bev therapy were included in this study. Pretreatment tumor biopsy, pre- and posttreatment diffusion-weighted magnetic resonance imaging (MRI) with nine b values (0–1500 s/mm2), and other clinicopathologic factors were analyzed.

Results

Compared with resectable HCC, advanced HCC was characterized by higher proliferative activity, a higher frequency of Wnt/β-catenin-activated HCC, and lower lymphocytic infiltration. Prognostically, two metabolism-related factors, histopathologically determined tumor steatosis and/or glutamine synthetase (GS) expression, and MRI-determined tumor steatosis, were the most significant prognostic indicators for progression-free survival (PFS) and overall survival after Atezo + Bev therapy. Furthermore, changes in the pre- and posttreatment true diffusion coefficients on MRI, which might reflect changes in TIME after treatment, were significantly associated with better PFS.

Conclusions

The biology and TIME of HCC were strikingly different in advanced HCC compared with those of surgically resected HCC. Two metabolism-related factors, pathologically determined tumor steatosis and/or GS expression, and MRI-determined tumor steatosis, were found to be the most significant prognostic indicators for Atezo + Bev therapy in advanced HCC.

Geriatric nutritional risk index as an easy‐to‐use assessment tool for nutritional status in hepatocellular carcinoma treated with atezolizumab plus bevacizumab

Abstract

Aim

The present study focused on Geriatric Nutritional Risk Index (GNRI), which is based on bodyweight and serum albumin, and known as an easy-to-use nutritional assessment tool in clinical settings, to elucidate the prognostic predictive ability of GNRI in patients treated with atezolizumab plus bevacizumab (Atez/Bev) for hepatocellular carcinoma (HCC).

Methods

A total of 525 HCC patients treated with Atez/Bev, based on their classification of unsuitable status for curative treatments and/or transarterial catheter chemoembolization, were enrolled (Child–Pugh A:B:C = 484:40:1, Barcelona Clinic Liver Cancer stage 0:A:B:C:D = 7:25:192:283:18). Prognosis was evaluated retrospectively using GNRI.

Results

Atez/Bev was used in 338 of the present cohort as first-line systemic chemotherapy (64.4%). Median progression-free survival based on GNRI indicating normal, mild decline, moderate decline, and severe decline was 8.3, 6.7, 5.3, and 2.4 months, respectively, whereas median overall survival was 21.4, 17.0, 11.5. and 7.3 months, respectively (both p < 0.001). The concordance index (c-index) values of GNRI for predicting prognosis (progression-free survival/overall survival) were superior to those of Child–Pugh class and albumin-bilirubin grade (0.574/0.632 vs. 0.527/0.570 vs. 0.565/0.629). As a subanalysis, muscle volume loss was observed in 37.5% of 256 patients with computed tomography data available. Along with GNRI decline, frequency of muscle volume loss became progressively larger (normal vs. mild vs. moderate vs. severe = 17.6% vs. 29.2% vs. 41.2% vs. 57.9%, p < 0.001), and a GNRI value of 97.8 was predictive of its occurrence (AUC 0.715, 95% CI 0.649–0.781; specificity/sensitivity = 0.644/0.688).

Conclusion

These findings indicate that GNRI is an effective nutritional prognostic tool for predicting prognosis and muscle volume loss complication in HCC patients treated with Atez/Bev.