A CYP78As-small grain4-coat protein complex â ¡ pathway promotes grain size in rice.

CYP78A, a cytochrome P450 subfamily that includes rice (Oryza sativa L.) BIG GRAIN2 (BG2, CYP78A13) and Arabidopsis thaliana KLUH (KLU, CYP78A5), generate an unknown mobile growth signal (referred to as a CYP78A-derived signal) that increases grain (seed) size. However, the mechanism by which the CYP78A pathway increases grain size remains elusive. Here, we characterized a rice small grain mutant, small grain4 (smg4), with smaller grains than its wild type due to restricted cell expansion and cell proliferation in spikelet hulls. SMG4 encodes a multidrug and toxic compound extrusion (MATE) transporter. Loss of function of SMG4 causes smaller grains while overexpressing SMG4 results in larger grains. SMG4 is mainly localized to endoplasmic reticulum (ER) exit sites (ERESs) and partially localized to the ER and Golgi. Biochemically, SMG4 interacts with coat protein complex Ⅱ (COPⅡ) components (Sar1, Sec23, and Sec24) and CYP78As (BG2, GRAIN LENGTH 3.2 [GL3.2], and BG2-LIKE 1 [BG2L1]). Genetically, SMG4 acts, at least in part, in a common pathway with Sar1 and CYP78As to regulate grain size. In summary, our findings reveal a CYP78As-SMG4-COPⅡ regulatory pathway for grain size in rice, thus providing new insights into the molecular and genetic regulatory mechanism of grain size.

Prognostic and therapeutic significance of microbial cell-free DNA in plasma of people with acute decompensation of cirrhosis.

BACKGROUND & AIMS: Although the effect of bacterial infection on cirrhosis has been well-described, the effect of non-hepatotropic virus (NHV) infection is unknown. This study evaluated the genome fragments of circulating microorganisms using metagenomic next-generation sequencing (mNGS) in individuals with acute decompensation (AD) of cirrhosis, focusing on NHVs, and related the findings to clinical outcomes. METHODS: Plasma mNGS was performed in 129 individuals with AD of cirrhosis in the study cohort. Ten healthy volunteers and 20, 39, and 81 individuals with stable cirrhosis, severe sepsis and hematological malignancies, respectively, were enrolled as controls. Validation assays for human cytomegalovirus (CMV) reactivation were performed in a validation cohort (n = 58) and exploratory treatment was instituted. RESULTS: In the study cohort, 188 microorganisms were detected in 74.4% (96/129) of patients, including viruses (58.0%), bacteria (34.1%), fungi (7.4%) and chlamydia (0.5%). A NHV signature was identified in individuals with AD, and CMV was the most frequent NHV, which correlated with the clinical effect of empirical antibiotic treatment, progression to acute-on-chronic liver failure, and 90-day mortality. The NHV signature in individuals with acute-on-chronic liver failure was similar to that in those with sepsis and hematological malignancies. CMV was detected in 24.1% (14/58) of patients in the validation cohort. Of the 14 cases with detectable CMV by mNGS, nine were further validated by real-time PCR or pp65 antigenemia testing. Three patients with CMV reactivation received ganciclovir therapy in an exploratory manner and experienced clinical resolutions. CONCLUSIONS: The results of this study suggest that NHVs may play a pathogenic role in complicating the course of AD. Further validation is needed to define whether this should be incorporated into the routine management of individuals with AD of cirrhosis. IMPACT AND IMPLICATIONS: A non-hepatotropic virus (NHV) signature, which was similar to that in individuals with sepsis and hematological malignancies, was identified in individuals with acute decompensation of cirrhosis. The detected viral signature had clinical correlates, including clinical efficacy of empirical antibiotic treatment, progression to acute-on-chronic liver failure and short-term mortality. Cytomegalovirus reactivation, which is treatable, may adversely affect clinical outcomes in some individuals with decompensated cirrhosis. Routine screening for NHVs, especially cytomegalovirus, may be useful for the management of individuals with acute decompensation of cirrhosis.

Baveno VII algorithm outperformed other models in ruling out high-risk varices in individuals with HBV-related cirrhosis.

BACKGROUND & AIMS: The Baveno VII consensus recommends that spleen stiffness measurement (SSM) ≤40 kPa is safe for ruling out high-risk varices (HRVs) and avoiding endoscopic screening in patients who do not meet the Baveno VI criteria. This study aimed to validate the performance of the Baveno VII algorithm in individuals with HBV-related cirrhosis. METHODS: Consecutive individuals with HBV-related cirrhosis who underwent liver stiffness measurement (LSM) and SSM - using a 50 Hz shear wave frequency, spleen diameter measurement, and esophagogastroduodenoscopy (EGD) were prospectively enrolled from June 2020. A 100 Hz probe has been adopted for additional SSM assessment since July 2021. RESULTS: From June 2020 to January 2022, 996 patients were screened and 504 were enrolled for analysis. Among the 504 patients in whom SSM was assessed using a 50 Hz probe, the Baveno VII algorithm avoided more EGDs (56.7% vs. 39.1%, p <0.001) than Baveno VI criteria, with a comparable missed HRV rate (3.8% vs. 2.5%). Missed HRV rates were >5% for all other measures: 11.3% for LSM-longitudinal spleen diameter to platelet ratio score, 20.0% for platelet count/longitudinal spleen diameter ratio, and 8.8% for Rete Sicilia Selezione Terapia-hepatitis. SSM@100 Hz was assessed in 232 patients, and the Baveno VII algorithm with SSM@100 Hz spared more EGDs (75.4% vs. 59.5%, p <0.001) than that with SSM@50 Hz, both with a missed HRV rate of 3.0% (1/33). CONCLUSIONS: We validated the Baveno VII algorithm, demonstrating the excellent performance of SSM@50 Hz and SSM@100 Hz in ruling out HRV in individuals with HBV-related cirrhosis. Furthermore, the Baveno VII algorithm with SSM@100 Hz could safely rule out more EGDs than that with SSM@50 Hz. CLINICAL TRIAL NUMBER: NCT04890730. IMPACT AND IMPLICATIONS: The Baveno VII guideline proposed that for patients who do not meet the Baveno VI criteria, SSM ≤40 kPa could avoid further unnecessary endoscopic screening. The current study validated the Baveno VII algorithm using 50 Hz and 100 Hz probes, which both exhibited excellent performance in ruling out HRVs in individuals with HBV-related cirrhosis. Compared with the Baveno VII algorithm with SSM@50 Hz, SSM@100 Hz had a better capability to safely rule out unnecessary EGDs. Baveno VII algorithm will be a practical tool to triage individuals with cirrhosis in future clinical practice.

HBsAg quantification predicts off-treatment response to interferon in chronic hepatitis B patients: a retrospective study of 250 cases.

BACKGROUND: For chronic hepatitis B (CHB) patients without willingness to extend the routine duration of interferon (IFN) therapy, it is important to identify patients who will benefit from treatment cessation. Hepatitis B surface antigen (HBsAg) quantification is recommended for management of IFN therapy. At present, the understanding on end-of-treatment (EOT) HBsAg level predicting post-treatment response to IFN is still finite. METHODS: A total of 2451 non-cirrhosis, HBsAg-postive patients treated with IFN-based therapy during the period from December 2010 to December 2017 at Nanfang Hospital were enrolled in this study. Serum HBsAg levels at EOT were measured to evaluate the associations between EOT HBsAg levels (Group 1, HBsAg > 0.05 and ≤ 10 IU/mL; Group 2, HBsAg > 10 and ≤ 200 IU/mL; Group 3, HBsAg > 200 IU/mL) with post-treatment HBsAg loss. Chi-squared, t-test,,Kaplan-Meier analysis, Cox regression analysis, and Multivariate Logistic regression analysis were used to analyse and evaluate differences between the there groups. RESULTS: The cumulative HBsAg loss rates 5 years after treatment in Group 1-3 were 30.4% (17/56), 9.8%(4/41) and 0%(0/153) (p < 0.001). An EOT HBsAg level of > 10 IU/mL showed relatively high negative predictive value (NPV) of up to 97.9% for HBsAg loss. Low baseline HBsAg level < 25,000 IU/mL, on-treatment HBsAg decline > 1 log10IU/mL at week 24 and EOT HBsAg level ≤ 10 IU/mL were found significantly associated with HBsAg loss. A total of 6 patients have achieved HBsAg loss at EOT and 17 patients with EOT HBsAg level ≤ 10 IU/mL have achieved post-treatment HBsAg loss. Baseline characteristics, dynamic changes of on-treatment HBsAg and duration of IFN therapy were balanced across patients with EOT or post-treatment HBsAg loss. CONCLUSION: EOT HBsAg level can serve as a monitoring indicator for IFN therapy. EOT HBsAg level ≤ 10 IU/mL was found to lead to high rate of post-treatment HBsAg loss. For patients without willingness to extend IFN treatment, off-treatment follow-up could be considered when HBsAg level decreased to ≤10 IU/mL.

Spleen-dedicated stiffness measurement performed well to rule out high-risk varices in HBV-related hepatocellular carcinoma: Screening for high-risk varices in HCC.

BACKGROUND: Esophagogastroduodenoscopy (EGD) is required to screen for high-risk varices (HRV) in patients with hepatocellular carcinoma (HCC), especially since overall survival rates have dramatically improved with new systemic therapies. AIM: To assess the Baveno VI and Baveno VII algorithms' ability to rule out HRV in hepatitis B virus (HBV)-related HCC METHODS: We prospectively enrolled consecutive patients with HBV related, compensated cirrhosis and newly diagnosed HCC who underwent liver stiffness measurement, spleen stiffness measurement (SSM) using a 100-Hz shear wave frequency, and EGD. RESULTS: From September 2021 to August 2023, we enrolled 219 patients with HCC, with 107 (48.9%) Barcelona Clinic Liver Cancer (BCLC) A, 28 (12.8%) BCLC B and 84 (38.3%) BCLC C, respectively. HRV prevalence was 28.8% (63/219). Baveno VI criteria safely (HRV missing rate, 3.2%) avoided 27.4% unnecessary EGDs, while the Baveno VII algorithm avoided 49.3% with HRV missing rate at 7.9% (5/63). The SSM ≤40 kPa avoided 47.5% of EGDs safely (HRV missing rate, 4.8%), significantly better than the Baveno VI criteria (p < 0.001) and comparable to the Baveno VII algorithm (p = 0.390). The SSM ≤40 kPa safely avoided EGDs in patient subgroups within Milan criteria, with portal vein tumour thrombosis or BCLC B/C or candidates for systemic therapy. CONCLUSIONS: We validated that the SSM ≤40 kPa using a 100-Hz probe could safely eliminate more unnecessary EGDs than the Baveno VI criteria in patients with HBV-related HCC. However, the efficacy of the Baveno VII algorithm in patients with HCC requires further investigation.

Combined model with acoustic radiation force impulse to rule out high-risk varices in HBV-related cirrhosis with viral suppression.

AIMS: To prospectively evaluate the performance of spleen stiffness measurement (SSM) and liver stiffness measurement (LSM) via acoustic radiation force impulse (ARFI) imaging combined with platelet counts (PLT) in ruling out HRV in HBV-related cirrhotic patients with viral suppression. METHODS: Patients with cirrhosis enrolled between June 2020-March 2022 were divided into a derivation cohort and validation cohort. LSM and SSM ARFI-based, and esophagogastroduodenoscopy (EGD) were performed at enrollment. RESULTS: In the derivation cohort, overall, 236 HBV-related cirrhotic patients with maintained viral suppression were enrolled, and the prevalence of HRV was 19.5% (46/236). With the aim of identifying HRV, the most accurate LSM and SSM cut-offs were chosen of 1.46 m/s and 2.28 m/s, respectively. The combined model (LSM<1.46 m/s and PLT>150 × 109/L strategy combined with SSM ≤ 2.28 m/s) can spare 38.6% of EGDs and 4.3% of HRV cases were misclassified. In the validation cohort, we analysed 323 HBV-related cirrhotic patients with maintained viral suppression and validated the combined model can spare 33.4% (108/323) of EGD, and the HRV missed rate was 3.4%. CONCLUSIONS: A non-invasive prediction model combining LSM<1.46 m/s and PLT>150 × 109/L strategy with SSM ≤ 2.28 m/s exhibited excellent performance in ruling out HRV and avoided a significantly large number (38.6% vs 33.4%) of unnecessary EGDs in HBV-related cirrhotic patients with viral suppression.

Thyroid dysfunction is associated with the loss of hepatitis B surface antigen in patients with chronic hepatitis B undergoing treatment with α-interferon.

OBJECTIVE: To investigate the influence of thyroid dysfunction on the antiviral efficacy of α-interferon in adult patients with chronic hepatitis B (CHB). METHODS: We performed a retrospective study of 342 patients with CHB who underwent interferon treatment for >12 weeks. Patients with thyroid dysfunction before or during treatment were defined as the thyroid dysfunction group (n = 141) and those with normal thyroid function were defined as the normal thyroid function group (n = 201). The prevalences of hepatitis B virus (HBV) DNA undetectability, low hepatitis B surface antigen (HBsAg) titre (<250 IU/mL), HBsAg loss, and hepatitis B envelope antigen loss were compared. RESULTS: During interferon treatment, 69 of 270 (25.6%) participants with normal thyroid function at baseline developed thyroid dysfunction, whereas 11 of 72 (15.3%) with thyroid dysfunction at baseline regained normal thyroid function. The thyroid dysfunction group had significantly higher prevalences of low HBsAg titre (29.8% vs. 18.9%) and HBV DNA undetectability (66.0% vs. 40.3%). Multivariate logistic regression analysis showed that thyroid dysfunction was associated with HBsAg loss (odds ratio 4.945, 95% confidence interval 1.325-18.462). CONCLUSIONS: These results suggest that thyroid dysfunction is not an absolute contraindication, but is associated with HBsAg loss, in patients with CHB undergoing α-interferon treatment.

[Clinical characteristics of patients with acute-on-chronic liver failure and splenomegaly].

OBJECTIVE: To observe the clinical characteristics and short-term survival of patients with splenomegaly and acute-on-chronic liver failure related to chronic HBV infection. METHODS: Electronic medical records of patients with acute-on-chronic liver failure were collected to analyze the clinical parameters and 4-week survival of patients with or without splenomegaly. RESULTS: Of the 149 patients enrolled, the overall 28-day mortality rate was 48.3%, which was lower in patients with enlarged spleen than those without (34.2% vs 54.1%, P=0.034). Compared with patients without splenomegaly, patients with splenomegaly had lower platelet counts (P=0.001), lower ALT levels (P=0.005) and lower PT-INR (P=0.010). Although the occurrence of hepatic encephalopathy was comparable between patients with or without splenomegaly, severe conditions were more frequent in those without splenomegaly. Hepatic encephalopathy grades, serum creatinine levels, neutrophil percentages over 70%, PT-INR and splenomegaly were independent factors associated with the 28-day survival, and this novel model was superior to model of end-stage of liver disease in predicting the 4-week survival (P=0.017). CONCLUSION: Patients with splenomegaly that evolves into acute-on-chronic liver failure have unique clinical characteristics and further clinical observations are warranted.