The liver has a vital role in many metabolic and regulatory processes in the body. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a chronic cholestatic autoimmune disease of the intrahepatic bile ducts associated with loss of tolerance to mitochondrial antigens. At this time there is no definitive cure for PBC; however, ursodeoxycholic acid (UDCA) has been shown to reduce injury when administered as the first line of treatment. Additional therapeutics can be given concurrently or as an alternative to UDCA to manage the symptoms and further curb disease progression. Currently, a liver transplant is the only potentially curative option when the patient has developed end-stage liver disease or intractable pruritus. This review aims to delineate the pathogenesis of primary biliary cholangitis and shed light on current therapeutic strategies in the treatment of PBC.

Lung cancer (LC), with its high incidence and less effective treatment strategies, is often not detected until it is in an advanced stage, which contributes to its high mortality rate. Hence, screening the DNA and RNA content in exosomes offers a promising method for its early diagnosis. New technologies for the early detection of LC are absolutely necessary to improve patient outcomes. Such an approach could be the exploitation of exosomes and their content. Exosomes contain DNA, different RNA species, proteins, ceramides, and cholesterol. They can transport their oncogenetic cargo derived from tumor cells to healthy cells over a range of distances to help propagate genetic information that could contribute to the initiation of cancer. This review provides an overview of the involvement of exosomes and their DNA/RNA together with cell-free DNA, summarizes potential biomarkers and describes the application of technologies for the characterization of exosomes with their possible tumor markers. Current radiological and scanning methods for the early detection of LC are also described and compared with nucleic acid analysis. The strengths and weaknesses of both approaches are considered.

We previously reported that carboxylesterase 1 (CES1) expression was suppressed following liver injury. The study aimed to explore the role of interleukin (IL)-33 in liver injury and examine the mechanism by which IL-33 regulates CES1.

IL-33 and CES1 levels were determined in the livers of patients and lipopolysaccharide (LPS)-, acetaminophen (APAP)-treated mice. We constructed IL-33 and ST2 knockout (KO) mice. ST2-enriched immune cells in livers were screened to identify the responsible cells. Macrophage-derived exosome (MDE) activity was tested by adding exosome inhibitors. Micro-RNAs (miRs) were extracted from control and IL-33-stimulated MDEs (IL-33-MDEs) and subjected miR sequencing (miR-Seq). Candidate miR was tested in vitro and in vivo and its binding of a target gene was assessed by luciferase reporter assays. Lentivirus-vector cellular transfection and transcript silencing were used to examine pathways mediating IL-33 suppression of miR-27b-3p.

Patient liver IL-33 and CES1 expression levels were inversely correlated. CES1 downregulation in liver injury was rescued in both IL-33–deficient and ST2 KO mice. Macrophages were shown to be responsible for IL-33 effects. IL-33-MDEs reduced CES1 levels in hepatocytes. Exosomal miR-Seq and qRT-PCR demonstrated increased miR-27b-3p levels in IL-33-MDEs; miR-27b-3p was implicated in Nrf2 targeting. IL-33 inhibition of miR-27b-3p was found to be GATA3-dependent.

IL-33–ST2–GATA3 pathway signaling increases miR-27b-3p content in MDEs, which upon being internalized by hepatocytes reduce CES1 expression by inhibiting Nrf2. The elucidation of this mechanism in this study contributes to a better understanding of CES1 dysregulation in liver injury.

A functional cure, or hepatitis B virus (HBV) surface antigen (HBsAg) loss, is difficult to achieve in patients with hepatitis B virus e antigen (HBeAg)-positive chronic hepatitis B. The HBV vaccine and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been reported to help reduce HBsAg levels and promote HBsAg loss. In this prospective randomized trial, we evaluated HBsAg loss in patients receiving pegylated interferon-α2b (PEGIFN-α2b) and tenofovir disoproxil fumarate (TDF), with and without GM-CSF and HBV vaccination.

A total of 287 patients with HBeAg positive chronic hepatitis B and seroconversion after nucleot(s)ide analog treatment were assigned randomly to three treatment groups for 48 weeks, TDF alone (control), PEGIFN-α2b + TDF, and PEGIFN-α2b + TDF + GM-CSF + HBV vaccine. The primary endpoints were the proportions of patients with HBsAg loss and seroconversion at 48 and 72 weeks.

The cumulative HBsAg loss rates in the control, PEGIFN-α2b + TDF, and PEGIFN-α2b + TDF + GM-CSF + HBV vaccine groups at week 48 were 0.0%, 28.3%, and 41.1%, respectively. The cumulative HBsAg seroconversion rates in these groups at week 48 were 0.0%, 21.7%, and 33.9%, respectively. Multivariate regression analysis showed that GM-CSF use plus HBV vaccination was significantly associated with HBsAg loss (p=0.017) and seroconversion (p=0.030).

In patients with HBeAg-positive chronic hepatitis B and seroconversion after nucleot(s)ide analog treatment, immunomodulatory/antiviral treatment regimens effectively improved HBsAg loss, and the regimen including GM-CSF and HBV vaccination was most effective.

Mother-to-child transmission (MTCT) of hepatitis B virus (HBV) is the primary cause of chronic HBV infection worldwide. MTCT prevention and antiviral treatment of infected individuals could eliminate this public health burden. Antiviral treatment of hepatitis B surface antigen (HBsAg)-positive pregnant women and immunoprophylaxis with HBV vaccine and hepatitis B immune globulin are the most effective strategies to interfere with MTCT of HBV. However, for worldwide application of those strategies, feasibility, availability, cost, safety, and effectiveness should be considered. Cesarean section and breastfeeding avoidance in hepatitis B e antigen-positive mothers with a high viral load and without antiviral therapy during pregnancy could be an option, but more supporting evidence is needed. HBsAg screening of all pregnant women is recommended when initiating antiviral therapy and immunoprophylaxis for MTCT prevention, except in areas with limited resources. Timely HBV vaccination series administered soon after birth might be the mainstay of prevention. This review aimed to provide a concise update on the effectiveness of available strategies to prevent MTCT of HBV.

Chinese government lifted its “Zero COVID-19” policy in December 2022. The estimated COVDI-19 new cases and deaths after the policy change are 167–279 million (about 12.0% to 20.1% of the Chinese population) and 0.68–2.1 million, respectively. Recent data also revealed continuous drops in fertility rate and historically lowest growth in gross domestic production in China. Thus, balancing COVID-19 control and economic recovery in China is of paramount importance yet very difficult. Supply chain disruption, essential service reduction and shortage of intensive care units have been discussed as the challenges associated with lifting “Zero COVID-19” policy. The additional challenges may include triple epidemic of COVID-19, respiratory syncytial virus and influenza, mental health issues of healthcare providers, care givers and patients, impact on human mobility, lack of robust genomic and epidemiological data and long COVID-19. However, the policy-associated opportunities and other challenges are largely untouched, but warrant attention of and prompt reactions by the policy makers, healthcare providers, public health officials and other stakeholders. The associated benefits are quick reach of herd immunity, boost of economy and business activities and increase in social activities. At this moment, we must embrace the policy change, effectively mitigate its associated problems and timely and effectively maximize its associated benefits.

Previous trials comparing cyclosporine and tacrolimus after liver transplantation (LT) showed conflicting results. Most used trough monitoring for cyclosporine (C0), leading to less accurate dosing than with 2-h monitoring (C2). Only one larger trial compared C2 with tacrolimus based on trough level (T0) after LT, with similar treated biopsy-proven acute rejection (tBPAR) and graft loss, while a smaller trial had less tBPAR with C2 compared to T0. Therefore, it is still unclear which calcineurin inhibitor is preferred after LT. We aimed to demonstrate superior efficacy (tBPAR), tolerability, and safety of C2 or T0 after first LT.

Patients after first LT were randomized to C2 or T0. tBPAR, patient- and graft survival, safety and tolerability were the main endpoints, with analysis by Fisher test, Kaplan–Meier survival analysis and log-rank test.

In intention-to-treat analysis 84 patients on C2 and 85 on T0 were included. Cumulative incidence of tBPAR C2 vs. T0 was 17.7% vs. 8.4% at 3 months (p=0.104), and 21.9% vs. 9.7% at 6 and 12 months (p=0.049). One-year cumulative mortality C2 vs. T0 was 15.5% vs. 5.9% (p=0.049) and graft loss 23.8% vs. 9.4% (p=0.015). Serum triglyceride and LDL-cholesterol was lower with T0 than with C2. Incidence of diarrhea in T0 vs, C2 was 64% vs. 31% (p≤0.001), with no other differences in safety and tolerability.

In the first year after LT immunosuppression with T0 leads to less tBPAR and better patient-/re-transplant-free survival as compared to C2.

We report a patient with refractory ascites because of portal hypertension caused by hemochromatosis secondary to osteopetrosis. To our knowledge, this is the first well-documented case of this association. A 46-year-old male patient who was repeatedly infused with red blood cells for anemia secondary to osteopetrosis suffered from refractory ascites. The serum-ascites albumin gradient was 29.9 g/L. Abdominal computed tomography (CT) showed a large amount of ascites, hepatomegaly, and splenomegaly. Bone marrow biopsy showed a small bone marrow cavity with no hematopoietic tissue. A peripheral blood smear showed tear drop red blood cells and metarubricytes. Serum ferritin was 8,855.0 ng/mL. Therefore, we considered that the ascites resulted from portal hypertension caused by hemochromatosis secondary to osteopetrosis. We simultaneously performed the transjungular intrahepatic portal-systemic shunt (TIPS) and obtained a transjungular liver biopsy. The portal pressure gradient before TIPS was 28 mmHg, and iron staining was strongly positive on liver biopsy, which confirmed our diagnosis. After TIPS, both abdominal distention and ascites gradually resolved, and no recurrence as observed after the 12-month postoperative follow-up was observed. This case indicated that regular monitoring of iron load is important for patients with osteopetrosis. TIPS is safe and effective for portal hypertension complications due to osteopetrosis.

This work aimed to evaluate the phenolic profile and antioxidant capacity of water extracts of three different date seed varieties i.e., Aseel, Karbalaen and Khupro. Date (Phoenix dactylifera L.) seeds are available in bulk quantities after manufacturing of pitted dates or syrup and are considered as waste stream.

Total phenolic content in date seeds was determined with Folin-Ciocalteu’s phenol reagent. The phenolic compounds profile was determined by high performance liquid chromatography. Antioxidant capacity of each variety was investigated by 2,2′-Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid), oxygen radical absorbance capacity, ferric reducing antioxidant power assay and 2,2-diphenyl-1-picryl-hydrazyl-hydrate assays.

Eight phenolics including gallic acid, caffeic acid, p-coumaric acid, vanillic acid, catechin, epicatechin, chlorogenic acid and sinapic acid were detected in date seeds. The highest content of phenolics was found in Aseel, followed by Karbalaen and Khupro date seeds respectively. Furthermore, the phenolic profile also correlated with the antioxidant capacity of these samples.

Date seeds contain significant level of phenolics and possess high antioxidant activity. Therefore, date seeds could be promising candidates for biomedical applications, functional foods and fortification to increase the shelf life of food products.

This study aimed to analyze the influence of alloferon on the Epstein-Barr virus (EBV) DNA copy number in saliva samples and the changes of natural killer (NK) cell content, cytotoxic activity of killer cells, and production of interferon alpha and gamma in patients suffering chronic EBV infection (CEBVI) at 6 weeks after therapy completion.

One hundred CEBVI patients (69 females and 31 males were divided into two groups: alloferon (n = 70; nine injections s/c, 1.0 mg every alternate day) and valacyclovir (n = 30; 500 mg two times/day, orally). The EBV DNA quantity in the saliva samples, the number of killer cells in the blood, and the cytotoxic activity of killer cells via spontaneous and induced expression of CD107a, a marker of degranulation, were determined after treatment with alloferon. The dynamics of interferon alpha and gamma production before and after alloferon therapy were also assessed.

At 6 weeks after therapy completion, EBV DNA was not found in 38 (54.28%) patients in the alloferon group and in 9 (30.0%) patients in the valacyclovir group (p = 0.001). In addition, a reliable increase of the NK cell content and stimulation of cytotoxic activity of NK cells were detected in the CEBVI patients. Moreover, alloferon treatment did not lead to a reliable increase of interferon alpha or gamma production at 6 weeks after therapy completion.

Alloferon significantly reduces the EBV DNA copy number in saliva samples and induces the expansion of NK cells and cytotoxic activity of NK cells in CEBV patients. Alloferon also significantly affects the clinical complaints of CEBVI patients.

Natural vaginal delivery and breastfeeding favor the development of a strong immune system in infants, and the immune response of infants to vaccines is closely related to their immune system. This large prospective cohort study aimed to explore the effects of delivery and feeding mode on infant’s immune response to hepatitis B vaccine (HepB).

A total of 1,254 infants who completed the whole course of HepB immunization and whose parents were both HBsAg negative were enrolled from infants born in Jinchang City during 2018–2019 by cluster sampling method.

Twenty (1.59%) of the 1,254 infants were nonresponders to HepB. Among the other 1,234 infants, 10.05% (124/1,234), 81.69% (1,008/1,234) and 8.27% (102/1,234) of infants had low, medium, and high responses to HepB, respectively. Logistic regression analysis showed that cesarean section (OR: 8.58, 95% CI: 3.11–23.65, p<0.001) and birth weight <3.18 kg (OR: 5.58, 95% CI: 1.89–16.51, p=0.002) were independent risk factors for infant nonresponse to HepB, and cesarean section (OR: 7.63, 95% CI: 4.64–12.56, p<0.001), formula feeding (OR: 4.91, 95% CI: 1.47–16.45, p=0.001), maternal anti-HBs negativity (OR: 27.2, 95% CI: 10.67–69.35, p<0.001), paternal non-response history of HepB (OR: 7.86, 95% CI: 2.22–27.82, p=0.014) and birth weight <3.22 kg (OR: 4.00, 95% CI: 2.43–6.59, p<0.001) were independent risk factors for infant low response to HepB. In cases where birth weight and genetic factors are unmodifiable and maternal anti-HBs effects are controversial, it makes sense to enhance infant response by changing delivery and feeding patterns.

Natural vaginal delivery and breastfeeding are beneficial to the infant’s immune response to HepB.

Mitochondria, which are one of the main organelles of the cell, have vital importance for the body. Mitochondrial mechanisms, which have critical roles in many physiological processes, are active in drug-induced toxic tissue damage as well as in diseases related to mitochondrial dysfunction. Mitochondrial dysfunction is a major mechanism by which various drugs can cause adverse effects in various tissues such as the liver, kidney and heart. Inhibiting respiratory complexes of the electron chain; disrupting cell bioenergetic mechanisms; inducing mitochondrial oxidative stress; inhibiting DNA replication, transcription, or translation; and reduction of protein synthesis are the most common ways drugs harm mitochondria. Mitochondrial transplantation has emerged as a promising area that has been studied more frequently in recent years. The importance of mitochondrial transplantation in a variety of mitochondrial dysfunction-related diseases such as cardiovascular diseases, neurodegenerative diseases, and ischemia has been emphasized. The purpose of this review article is to present current information on the role of mitochondria in toxic drug damage and the possible effects of mitochondrial transplantation on toxic damage.

Primary biliary cholangitis (PBC) is a complex cholestatic liver disease with an unresolved etiology. The gut microbiota is composed of a dynamic community of bacteria, archaea, fungi, and viruses that have a key role in physiological processes related to nutrition, immunity, and host defense responses. A number of recent studies found that the composition of the gut microbiota of PBC patients was significantly altered, and reported that gut dysbiosis might arise during PBC development because of the close interactions of the liver and the gut. In light of the growing interest in this topic, the focus of this review is to characterize PBC gut microbiota alterations, the correlation between PBC pathology and the gut microbiota, and prospective therapies that target the altered gut microbiota, such as probiotics and fecal microbiota transplantation.

Liver fibrosis is a key risk factor for cirrhosis, hepatocellular carcinoma and end stage liver failure. The National Institute for Health and Care Excellence guidelines for assessment for advanced (≥F3) liver fibrosis in people with nonalcoholic fatty liver disease recommend the use of enhanced liver fibrosis (ELF) test, followed by vibration-controlled transient elastography (VCTE). Performance of ELF at predicting significant (≥F2) fibrosis in real-world practice is uncertain. To assess the accuracy of ELF using VCTE; investigate the optimum ELF cutoff value to identify ≥F2 and ≥F3; and develop a simple algorithm, with and without ELF score, for detecting ≥F2.

Retrospective evaluation of patients referred to a Community Liver Service for VCTE, Jan-Dec 2020. Assessment included: body mass index (BMI), diabetes status, alanine aminotransferase (ALT) levels, ELF score and biopsy-validated fibrosis stages according to VCTE.

Data from 273 patients were available. n=110 patients had diabetes. ELF showed fair performance for ≥F2 and ≥F3, area under the curve (AUC) = 0.70, 95% confidence interval (CI) 0.64–0.76 and AUC=0.72, 95% CI: 0.65–0.79 respectively. For ≥F2 Youden’s index for ELF=9.85 and for ≥F3, ELF=9.95. Combining ALT, BMI, and HbA1c (ALBA algorithm) to predict ≥F2 showed good performance (AUC=0.80, 95% CI: 0.69–0.92), adding ALBA to ELF improved performance (AUC=0.82, 95% CI: 0.77–0.88). Results were independently validated.

Optimal ELF cutoff for ≥F2 is 9.85 and 9.95 for ≥F3. ALT, BMI, and HbA1c (ALBA algorithm) can stratify patients at risk of ≥F2. ELF performance is improved by adding ALBA.

Testicular cancer accounts for ∼1% of all cancers in men worldwide, with over 90% of testicular cancers being germ cell tumors (GCTs). Since the introduction of multimodal therapy, testicular GCTs have been among the most curable solid tumors. However, some patients may develop late relapse, which is defined as recurrence at least two years after the initial complete remission. Late recurrence is particularly common in patients with teratomatous GCTs and is associated with somatic-type malignancy (SM) development. Approximately 2.5–8.0% of testicular GCT patients may develop SM, a distinct secondary component that resembles cancers seen in other organs and tissues. The histological subtypes of SM are diverse and may show morphological features of sarcomas, carcinomas, embryonic-type neuroectodermal tumors, nephroblastomas, hematologic malignancies, or a combination of different forms. Several studies have demonstrated that the development of SM in testicular GCTs, particularly at metastatic sites, is associated with a poor prognosis. In the current review, we discuss the concept of GCTs with SM, the diagnostic criteria, the common histological subtypes, the pathogenesis, and the clinical outcomes of GCT patients with SM.

Multiple myeloma (MM) is the second most common hematologic malignancy with high morbidity and mortality indices. The emerging risk factors and complex pathogenic mechanisms surrounding the disease evolution are challenging. Thus, understanding these risk factors and the pathogenic basis of the disease will lead to better interventions and targeted therapies. We conduct an integrated review of the literature on MM, risk assessment, pathogenic mechanisms, and the evolution of anti-myeloma target therapies using PubMed, Medline, CINAHL, Google Scholar, African Journal Online, and Cochrane databases. The review analyze the prevalence, risk factors, and pathogenesis of MM, as well as highlights antimyeloma therapies. The literature indicates that eight risk factors are linked with MM, and two major pathogenic pathways are paramount in its evolution. We identify nine antimyeloma targeted pathways including immunomodulatory agents, proteasome inhibitors, monoclonal antibodies, fibrin growth factor receptor inhibitors, histone deacetylase inhibitors, BCL inhibitors, immune checkpoint inhibitors, chimeric antigen receptor T-cell and B-cell maturation antigen-targeted monoclonal antibody. To holistically address the burden of MM, there is a need for in-depth knowledge of the environmental risk factors and disease pathogenic mechanisms. The cytogenetic, immunologic, and skeletal mechanisms that lead to disease evolution play significant roles in risk stratification, prognostication, and emergence of new antimyeloma therapies. A policy on MM risk assessment is therefore strongly recommended for exposed target population.