Tenofovir versus entecavir on long-term prognosis in hepatocellular carcinoma patients with concurrent metabolic dysfunction-associated steatotic liver disease and hepatitis B.

BACKGROUND: Currently, there remains ongoing controversy about the selection of postoperative antiviral drugs for hepatocellular carcinoma (HCC) patients with concurrent metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatitis B virus (HBV) infection (HPMH) who underwent hepatectomy. METHOD: A multivariate Cox proportional hazards model and a propensity score matching (PSM) analysis were implemented to ensure equal baseline characteristics. The Kaplan‒Meier survival curves were employed for prognosis comparison between the two groups. RESULTS: This study included 225 HPMH who all received post-hepatectomy antiviral therapy; with 107 in the tenofovir disoproxil fumarate (TDF) group and 118 in the entecavir (ETV) group. In the entire cohort, according to the multivariate analysis, patients in the TDF group showed better recurrence-free survival (RFS) (HR = 0.78; 95% CI, 0.55-0.95; p = 0.030) and overall survival (OS) (HR = 0.52; 95% CI, 0.30-0.97; p = 0.021) than those in the ETV group. After executing a PSM analysis, Kaplan‒Meier survival curve analysis disclosed significant differences for both RFS and OS between the two groups (p = 0.03 and p = 0.01, respectively). CONCLUSIONS: In summary, our study suggests a more significant association of TDF in improving RFS and OS than ETV in HPMH who underwent hepatectomy through multivariate and PSM analysis. These findings indicate that the choice of antiviral drugs in HPHM holds crucial significance in guiding patient long-term prognosis.

Investigating causal links between gallstones, cholecystectomy, and 33 site-specific cancers: a Mendelian randomization post-meta-analysis study.

BACKGROUND AND AIM: The association between gallstones/cholecystectomy and cancer remains inconclusive in the current literature. This study aimed to explore the causal connections between gallstones/cholecystectomy and cancer risk by utilizing a bidirectional two-sample multivariable Mendelian randomization approach with Genome-Wide Association Studies data. METHODS: Utilizing Genome-Wide Association Studies data from the UK Biobank and FinnGen, this research employed multivariable Mendelian randomization analyses to explore the impact of gallstones and cholecystectomy on the risk of 33 distinct cancer types. Instrumental variables for gallstones and cholecystectomy were carefully selected to ensure robust analyses, and sensitivity and heterogeneity tests were conducted to verify the findings' validity. RESULTS: Multivariable Mendelian randomization analysis, incorporating data from more than 450,000 individuals for gallstones and cholecystectomy, revealed nuanced associations with cancer risk. Cholecystectomy was associated with a significantly increased risk of nonmelanoma skin cancer (OR = 1.59, 95% CI: 1.21 to 2.10, P = 0.001), while gallstones were linked to a decreased risk of the same cancer type (OR = 0.63, 95% CI: 0.47 to 0.84, P = 0.002). Interestingly, the analysis also suggested that cholecystectomy may lower the risk of small intestine tumors (OR = 0.18, 95% CI: 0.043 to 0.71, P = 0.015), with gallstones showing an inverse relationship, indicating an increased risk (OR = 6.41, 95% CI: 1.48 to 27.80, P = 0.013). CONCLUSIONS: The multivariable Mendelian randomization analysis highlights the differential impact of gallstones and cholecystectomy on cancer risk, specifically for nonmelanoma skin cancer and small intestine tumors. These results underscore the importance of nuanced clinical management strategies and further research to understand the underlying mechanisms and potential clinical implications of gallstone disease and cholecystectomy on cancer risk.

Genetically determined dietary habits and risk of Alzheimer's disease: a Mendelian randomization study.

Background: Emerging evidence have suggested that dietary habits have potential implication on the development of Alzheimer's disease (AD). However, elucidating the causal relationship between specific dietary factors and AD risk remains a challenge. Therefore, our study endeavors to investigate the causal association between dietary habits and the risk of AD. Materials and methods: We analyzed data on 231 dietary habits sourced from the UK Biobank and MRC-IEU, and AD data obtained from the FinnGen database. Employing a framework based on the classic two-sample Mendelian randomization (MR) study, we utilized the inverse-variance weighted (IVW) method as the primary analysis. Additionally, we conducted Steiger filtering and other methods to mitigate horizontal pleiotropy. The robustness of our overall findings was confirmed through multiple sensitivity analysis methods, and forward MR and reverse MR to address potential reverse causality bias. Results: Our study evaluated the causal effect between 231 dietary habits involving over 500,000 participants of European ancestry, and 10,520 AD cases. Only oily fish intake demonstrated a significant protective causal relationship with AD following FDR correction (raw p-value = 1.28e-4, FDR p-value = 0.011, OR = 0.60, 95%CI: 0.47-0.78). Additionally, six dietary habits potentially influenced AD risk, with protective causal effects observed for average monthly intake of other alcoholic drinks (raw p-value = 0.024, FDR p-value = 0.574, OR = 0.57, 95%CI: 0.35-0.93) and tea intake (raw p-value = 0.047, FDR p-value = 0.581, OR = 0.78, 95%CI: 0.603-1.00). Conversely, detrimental causal effects were observed for the average weekly champagne plus white wine intake (raw p-value = 0.006, FDR p-value = 0.243, OR = 2.96, 95%CI: 1.37-6.38), Danish pastry intake (raw p-value = 0.036, FDR p-value = 0.574, OR = 13.33, 95%CI: 1.19-149.69), and doughnut intake (raw p-value = 0.039, FDR p-value = 0.574, OR = 7.41, 95%CI: 1.11-49.57). Moreover, the protective effect of goat's cheese intake phenotype exhibited statistical significance only in the IVW method (raw p-value<0.05). Conclusion: Our results provide genetic support for a protective causal effect of oily fish intake on AD risk. Additionally, average monthly intake of other alcoholic drinks and tea consumption were also related with a lower risk of AD. Conversely, average weekly champagne plus white wine intake, Danish pastry intake, and doughnut intake were causally associated with increased risk of AD.

Adenosine 5'-Monophosphate-to-Threonine Ratio Promotes Abdominal Aortic Aneurysms via Up-Regulation of HLA-DR on Natural Killer Cells: A Bidirectional Mendelian Randomized Analysis.

Objective: Immune-metabolic interactions may have causal and therapeutic impacts on abdominal aortic aneurysms (AAAs). However, due to the lack of research on the relationship between immune-metabolic interactions and AAAs, further exploration of the mechanism faces challenges. Methods: A two-sample, two-step mediation analysis with Mendelian randomization (MR) based on genome-wide association studies (GWASs) was performed to determine the causal associations among blood immune cell signatures, metabolites, and AAAs. The stability, heterogeneity, and pleiotropy of the results were verified using a multivariate sensitivity analysis. Results: After multiple two-sample MRs using the AAA data from two large-scale GWAS databases, we determined that the human leukocyte antigen-DR (HLA-DR) levels on HLA-DR + natural killer (NK) cells (HLA-DR/NK) were associated with the causal effect of an AAA, with consistent results in the two databases (FinnGen: odds ratio (OR) = 1.054, 95% confidence interval (CI): 1.003-1.067, p-value = 0.036; UK Biobank: OR = 1.149, 95% CI: 1.046-1.261, p-value = 0.004). The metabolites associated with the risk of developing an AAA were enriched to find a specific metabolic model. We also found that the ratio of adenosine 5'-monophosphate (AMP) to threonine could act as a potential mediator between the HLA/NK and an AAA, with a direct effect (beta effect = 0.0496) and an indirect effect (beta effect = 0.0029). The mediation proportion was 5.56%. Conclusions: Our study found that an up-regulation of HLA-DR on HLA-DR/NK cells can increase the risk of an AAA via improvements in the AMP-to-threonine ratio, thus providing a potential new biomarker for the prediction and treatment of AAAs.

MG53 binding to CAV3 facilitates activation of eNOS/NO signaling pathway to enhance the therapeutic benefits of bone marrow-derived mesenchymal stem cells in diabetic wound healing.

Impaired wound healing in diabetes results from a complex interplay of factors that disrupt epithelialization and wound closure. MG53, a tripartite motif (TRIM) family protein, plays a key role in repairing cell membrane damage and facilitating tissue regeneration. In this study, bone marrow-derived mesenchymal stem cells (BMSCs) were transduced with lentiviral vectors overexpressing MG53 to investigate their efficacy in diabetic wound healing. Using a db/db mouse wound model, we observed that BMSCs-MG53 significantly enhanced diabetic wound healing. This improvement was associated with marked increase in re-epithelialization and vascularization. BMSCs-MG53 promoted recruitment and survival of BMSCs, as evidenced by an increase in MG53/Ki67-positive BMSCs and their improved response to scratch wounding. The combination therapy also promoted angiogenesis in diabetic wound tissues by upregulating the expression of angiogenic growth factors. MG53 overexpression accelerated the differentiation of BMSCs into endothelial cells, manifested as the formation of mature vascular network structure and a remarkable increase in DiI-Ac-LDL uptake. Our mechanistic investigation revealed that MG53 binds to caveolin-3 (CAV3) and subsequently increases phosphorylation of eNOS, thereby activating eNOS/NO signaling. Notably, CAV3 knockdown reversed the promoting effects of MG53 on BMSCs endothelial differentiation. Overall, our findings support the notion that MG53 binds to CAV3, activates eNOS/NO signaling pathway, and accelerates the therapeutic effect of BMSCs in the context of diabetic wound healing. These insights hold promise for the development of innovative strategies for treating diabetic-related impairments in wound healing.

Radical resection benefits patients suffering pancreatic ductal adenocarcinoma with liver oligometastases.

Purpose: Whether patients suffering liver oligometastases from pancreatic ductal adenocarcinoma (LOPDA) should undergo surgical treatment remains controversial. Methods: PubMed and Embase databases were systematically reviewed until 2023 June. Survival data were collected from the Kaplan-Meier curves. Safety and survival were evaluated using primary outcomes such as 1-year, 3-year, and 5-year survival rates, and 30-day mortality and morbidity. A subgroup meta-analysis was conducted to compare survival rates post-synchronous resection and resection post-neoadjuvant chemotherapy in LOPDA. Results: Our analysis of 15 studies involving 1,818 patients (surgical group, 648 and nonsurgical group, 1,170) indicates that radical hepatectomy for LOPDA notably improved 1-year (odds ratio [OR], 3.24; 95% confidence interval [CI], 2.45-4.28; P < 0.001), 3-year (OR, 5.74; 95% CI, 3.36-8.90; P < 0.001), and 5-year (OR, 4.89; 95% CI, 2.56-9.35; P < 0.001) overall survival (OS) rates. A separate analysis of 6 studies with 750 patients demonstrated the safety of LOPDA surgery, with no increase in postoperative complications (P = 0.26 for overall morbidity and P = 0.99 for mortality) compared to the patients with no metastatic disease from the pancreatic ductal adenocarcinoma (NMPDA) group. The NMPDA group showed superior 1-year and 3-year OS rates, but not 5-year OS rates compared to the LOPDA group. Conclusion: Surgical treatment apparently offers a survival advantage to LOPDA by comparing with nonsurgical groups in 1-, 3-, and 5-year OS rates. Radical resection for LOPDA is a safe treatment without more postoperative complications than NMPDA.

Rediscovery and systematics of the enigmatic genus Helicostoa reveals a new species of sessile freshwater snail with remarkable sexual dimorphism.

Helicostoa sinensis E. Lamy, 1926 is a unique freshwater gastropod species with a sessile habit. This enigmatic species was first found cemented on river limestones from China about 120 years ago and described together with the genus. It was never collected again and has been considered monotypic. Here, we report the rediscovery of Helicostoa from several rivers in China, and describe a second species of this genus based on a comprehensive study. In addition to the unique sessile habit of both species, the new Helicostoa species presents one of the most remarkable cases of sexual dimorphism within molluscs. Only the adult female is sessile and the original aperture of the female is sealed by shell matter or rock, while an opening on the body whorl takes the function of the original aperture. The male is vagile, with a normal aperture. Our results confirm the recently suggested placement of Helicostoa within the family Bithyniidae. The sessility of Helicostoa species is considered as an adaption to the limestone habitat in large rivers. The extreme sexual dimorphism and secondary aperture of females are considered as adaptations to overcome the obstacles for mating and feeding that come with a sessile life style.

Enhanced prognosis of HCC patients undergoing radical treatments with tenofovir versus entecavir: A meta-analysis based on propensity score matching studies.

The selection of postoperative antiviral therapy for hepatocellular carcinoma (HCC) patients with HBV infection undergoing radical treatments (HPHR) is a topic of ongoing debate and controversy. The primary aim of this study was to compare the prognostic impact of selecting entecavir (ETV) or tenofovir disoproxil fumarate (TDF) as antiviral therapy options in HPHR. All the studies included in this analysis were implemented propensity score matching (PSM) methodology. Meta-analysis was performed using R statistical software (version 4.3.0). The primary outcome measures, overall survival (OS) and recurrence-free survival (RFS), were quantified using hazard ratios (HR) and 95% confidence intervals (CI). This study analyzed 13 studies involving 6961 patients (2394 in the TDF group and 4567 in the ETV group). We conducted a meta-analysis of 8 studies that included a total of 5289 patients using the PSM analysis method. In comparison to the ETV group, the TDF group demonstrated significantly better RFS (HR = 0.81; 95% CI, 0.70-0.93; p = 0.0034) and OS (HR = 0.61; 95% CI, 0.42-0.88; p = 0.0085). Furthermore, the disparity between the two drugs was particularly evident in the prognosis of patients undergoing hepatectomy. Regional disparities were observed, with mainland China studies favoring RFS benefits and Taiwan or Korea studies favoring OS benefits. In conclusion, TDF has demonstrated significant superiority over ETV in terms of RFS and OS outcomes for HPHR. The findings hold significant implications for informing clinical decision-making and guiding the selection of postoperative antiviral therapy drugs in HCC patients.

The Impact of Imaging-Diagnosed Sarcopenia on Long-term Prognosis After Curative Resection for Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

BACKGROUND: Recent research suggests that sarcopenia potentially influences the long-term postoperative prognosis of malignant tumors. Thus, the primary objective of this study was to investigate the impact of imaging-diagnosed sarcopenia on the long-term prognosis of hepatocellular carcinoma (HCC) patients after curative resection. METHODS: In our approach, all studies incorporated in this study employed Cox proportional hazards models with multivariable adjusted hazard ratios. The meta-analysis was performed using R statistical software. The primary outcomes were quantified using hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: This study analyzed 30 studies, involving 7352 HCC patients after curative resection (2695 in the sarcopenia group and 4657 in the non-sarcopenia group). The meta-analysis of 28 studies indicated that patients in the sarcopenia group demonstrated notably inferior overall survival (OS) compared with the non-sarcopenia group (HR=2.20; 95% CI, 1.88-2.58; p < 0.01). Similarly, sarcopenia exhibits a significant association with poor recurrence-free survival (RFS) and disease-free survival (DFS) based on 16 and 6 studies (HR=1.50; 95% CI, 1.39-1.63; p < 0.01 and HR=1.96; 95% CI, 1.83-2.10; p < 0.01, respectively). CONCLUSION: In conclusion, imaging-diagnosed sarcopenia adversely affects the long-term prognosis, including OS, RFS, and DFS, in HCC patients after curative resection. The findings hold considerable importance in guiding comprehensive healthcare procedures for HCC patients after surgery.

Identification of lignans as ATP citrate lyase (ACLY) inhibitors from the roots of Pouzolzia zeylanica.

A new lignan, named pouzolignan P (1), together with 14 known ones (2 - 15) were isolated from the roots of Pouzolzia zeylanica (L.) Benn. Their structures were deduced based on the detailed spectroscopic analysis. All the isolates were evaluated for their inhibitory activities toward the ATP citrate lyase (ACLY). Among them, four lignans, isopouzolignan K (3), gnemontanins E (5), gnetuhainin I (6), and styraxlignolide D (15) showed excellent ACLY inhibitory effect with IC50 values of 9.06, 0.59, 2.63, and 7.62 µM, respectively. These compounds were further evaluated for their cholesterol-lowing effects on ox-LDL-induced high-cholesterol HepG2 cells. Compound 15 emerges as the most potent ACLY inhibitor, which significantly decreased the TC level in a dose-dependent manner. In addition, molecular docking simulations elucidated that 15 formed a strong hydrogen-bond interaction with Glu599 of ACLY, which was an important site responsible for the enzyme catalytic activity.

Sarcopenia Imperils Postoperative Long-Term Survival in HCC Patients with Metabolic Dysfunction-Associated Fatty Liver Disease: A Propensity Score Matching Analysis.

Background: Recent research has suggested that sarcopenia may have an impact on postoperative outcomes. The number of hepatocellular carcinoma (HCC) patients with metabolic dysfunction-associated fatty liver disease (MAFLD) has increased significantly over time. The main objective of this study was to investigate the impact of sarcopenia on the prognosis of HCC patients with MAFLD after hepatectomy. Methods: A multivariate Cox proportional hazards model and a propensity score matching (PSM) analysis were conducted to ensure that the baseline characteristics were similar. Kaplan‒Meier survival curves were used to compare the prognosis of the two groups. Results: This study involved 112 HCC patients with MAFLD undergoing hepatectomy. Sarcopenia was indicated as a risk factor for both recurrence-free survival (RFS) and overall survival (OS) in HCC patients with MAFLD after multivariate analysis (p=0.002 and 0.022, respectively). After conducting PSM analysis, Kaplan‒Meier survival curve analysis revealed significant differences in both the RFS and OS between the two groups (p=0.0002 and p=0.0047, respectively). All results showed that sarcopenia had a poor prognosis for HCC patients with MAFLD undergoing hepatectomy. Conclusion: In summary, our study suggests that sarcopenia might be a risk factor for OS and RFS in HCC patients with MAFLD who underwent hepatectomy through multivariate analysis and PSM analysis. Sarcopenia imperils postoperative survival rates and this finding can guide clinical decision-making. For postoperative patients, preventing or treating sarcopenia can potentially improve survival outcomes for patients with HCC and MAFLD.

Altered fear engram encoding underlying conditioned versus unconditioned stimulus-initiated memory updating.

It is known that post-retrieval extinction but not extinction alone could erase fear memory. However, whether the coding pattern of original fear engrams is remodeled or inhibited remains largely unclear. We found increased reactivation of engram cells in the prelimbic cortex and basolateral amygdala during memory updating. Moreover, conditioned stimulus- and unconditioned stimulus-initiated memory updating depends on the engram cell reactivation in the prelimbic cortex and basolateral amygdala, respectively. Last, we found that memory updating causes increased overlapping between fear and extinction cells, and the original fear engram encoding was altered during memory updating. Our data provide the first evidence to show the overlapping ensembles between fear and extinction cells and the functional reorganization of original engrams underlying conditioned stimulus- and unconditioned stimulus-initiated memory updating.

Integrative taxonomy revealing a troglobitic new genus of Diplommatinidae from Jiangxi, China (Gastropoda: Caenogastropoda: Cyclophoroidea).

A new subterranean diplommatinid snail is described and illustrated from Jiangxi, China. The species is diagnosed by its cylindrical-fusiform shell and absence of internal columellar lamellae and parietal folds. The morphological and molecular phylogenetic characterization of the new species supports the erection of a new genus, Sohtsuia Z.-Y. Chen, gen. nov. A molecular phylogeny of representative East Asian continental species of Diplommatina Benson, 1949 is provided and the relationships of the new genus are discussed. Sohtsuia diting sp. nov. is described as new species.

Electroacupuncture alleviates depression-like behaviours via a neural mechanism involving activation of Nucleus Accumbens Shell.

OBJECTIVES: This study investigated the effects of electroacupuncture (EA) on the depression-like behaviours in a mouse model of chronic restraint stress (CRS) and explored the underlying neural mechanisms. METHODS: Depression-like behaviours including sucrose preference test (SPT), open field test (OFT) and tail suspension test (TST) were carried out to evaluate the effects of CRS and EA treatment. Using immunohistochemistry to measure the expression of c-Fos. The Nucleus Accumbens Shell (NAc Shell) in C57BL/6J mice were activated or inhibited using Chemogenetics. RESULTS: All the CRS stimulated groups showed lower sucrose preference in the SPT and decreased centre times in the OFT, and increased immobility time in the TST when compared to the normal control. Interestingly, EA at LR3 or HT7 exerted anti-depressant effects, and LR3 EA exhibited a more significant restoration than HT7. Furthermore, EA at LR3 increased expression of c-Fos in the NAc Shell. Chemogenetic inhibition of NAc Shell blocked the effects of EA, whereas enhancement of NAc Shell activity profoundly reversed depressive phenotypes. CONCLUSIONS: LR3 EA was effective in alleviating the depressive-like behaviours, and this therapeutic effect was associated with the activation of NAc Shell. Collectively, these findings revealed that EA may represent a promising therapeutic strategy for depression.

The role of noninvasive scoring systems for predicting cardiovascular disease risk in patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.

BACKGROUNDS: Cardiovascular disease (CVD) is suggested as a leading cause of death among patients with nonalcoholic fatty liver disease (NAFLD). The aim of this work was to clarify the role of noninvasive scoring systems (NSSs) in predicting CVD risk among this population. METHODS: The PubMed, Web of Science, and Cochrane databases were searched until 23 March 2022. Meta-analysis was performed for three most commonly used NSS separately, that is, fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), and AST/platelet ratio index (APRI). RESULTS: Totally, nine studies including 155 382 patients with NAFLD were enrolled. Patients with NAFLD had a higher risk of CVD with increasing FIB-4 score (1.94, 1.52-2.46), the association remained significant after adjustment for age, sex, body mass index, hypertension, and diabetes (2.44, 1.85-3.22). Similarly, a higher risk of CVD was also observed in patients with increasing NFS (2.17, 1.58-2.98) and APRI scores (1.36, 1.04-1.79) in the unadjusted model. However, in the adjusted model, the association was significant only for NFS (3.83, 1.40-10.43), but not for APRI (1.41, 0.79-2.51). Additionally, the increment in CVD risk was most noticeable in subgroup of FIB > 2.67 vs. FIB ≤ 1.3 (6.52, 3.07-13.86) and subgroup of NFS > 0.676 vs. NFS ≤ -1.455 (16.88, 5.68-50.23). All subgroup analyses showed significant associations between FIB-4, NFS, and risk of CVD. Sensitivity analyses did not modify these results. CONCLUSIONS: FIB-4 and NFS might be useful in identifying those who are at higher risk of CVD among patients with NAFLD. However, APRI was not recommended for this use.

Extrahepatic morbidities and mortality of NAFLD: an umbrella review of meta-analyses.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has reached pandemic proportions currently and may contribute to multiple extrahepatic outcomes. AIM: To comprehensively summarise evidence of associations between NAFLD and risk of extrahepatic outcomes. METHODS: We conducted an umbrella review. We searched PubMed, Web of Science and Cochrane database from inception to 27 November 2021. RESULTS: We included 22 meta-analyses with 374 original studies in our analysis. Subjects with NAFLD had an increased risk of mortality, multiple cardiovascular complications, extrahepatic cancers, diabetes and chronic kidney disease (CKD) than those without NAFLD. Excess risks of several other extrahepatic outcomes including hypothyroidism, urolithiasis, gastro-oesophageal reflux disease, gallstones, depression and worse maternal and foetal outcomes were also observed in this population. However, associations were not significant for prostate cancer, female organ genital cancer, haematological cancer, diabetic retinopathy or osteoporotic fracture. The risks of CVD, diabetes and CKD were similar in obese and non-obese patients. Most associations were heterogeneous across regions; significantly, Europeans with NAFLD were more prone to all-cause mortality than North Americans. The certainty of evidence was graded from only very low to moderate as all included studies were observational. CONCLUSIONS: Patients with NAFLD are at heightened risk of extrahepatic outcomes. However, the certainty of evidence is only from very low to moderate. Further studies at low risk of bias are required to support the evidence and elucidate any causal associations.