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.

Non-alcoholic fatty liver disease (NAFLD) is closely associated with gut microbiota and has become the most common chronic liver disease worldwide, but the relationship between specific strains and NAFLD has not been fully elucidated. We aimed to investigate whether Akkermansia muciniphila and Bifidobacterium bifidum could prevent NAFLD, the effects of their action alone or in combination, possible mechanisms, and modulation of the gut microbiota.

Mice were fed with high-fat diets (HFD) for 20 weeks, in which experimental groups were pretreated with quadruple antibiotics and then given the corresponding bacterial solution or PBS. The expression of the glycolipid metabolism indicators, liver, and intestinal farnesol X receptors (FXR), and intestinal mucosal tight junction proteins were detected. We also analyzed the alterations of inflammatory and immune status and the gut microbiota of mice.

Both strains were able to attenuate mass gain (p<0.001), insulin resistance (p<0.001), and liver lipid deposition (p<0.001). They also reduced the levels of the pro-inflammatory factors (p<0.05) and the proportion of Th17 (p<0.001), while elevating the proportion of Treg (p<0.01). Both strains activated hepatic FXR while suppressing intestinal FXR (p<0.05), and elevating tight junction protein expression (p<0.05). We also perceived changes in the gut microbiota and found both strains were able to synergize beneficial microbiota to function.

Administration of A. muciniphila or B. bifidum alone or in combination was protective against HFD-induced NAFLD formation and could be used as alternative treatment strategy for NAFLD after further exploration.

Hepatocellular carcinoma (HCC) is one of the most lethal and widespread cancers in the human race. Despite its fatal attributes, there is only a limited understanding of the factors contributing to its pathogenesis at the cellular and molecular levels. Consequently, unraveling new facets involved in HCC progression is elemental for establishing novel targets and biomarkers for this disease. Over the last few years, emerging evidence signifies the role of RNA-induced silencing complex in mediating gene silencing and contributing to HCC. Recent studies also highlight the importance of human telomerase holoenzyme and its complex accessory proteins in the development of HCC. The current review encompasses the multifaceted roles of RNA-induced silencing complex and telomerase activity as well as their synergistic function in HCC.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the leading causes of hepatic fibrosis and liver-related mortality worldwide, despite efficient hepatitis B and C antiviral therapies that have dramatically lowered the disease load. Although significant efforts have been exerted to understand the molecular basis of disease pathogenesis, there are currently few therapeutic alternatives available for NAFLD-associated fibrosis. Thus, NAFLD prevention is critical before the development of disease-related complications. In this context, there is a tremendous substantial global burden on public health systems to actively search for effective preventive and therapeutic targets for NAFLD. In this review, we highlight the current strategies to prevent progression and poor outcomes of NAFLD and to avoid complications associated with disease fibrosis, notably cirrhosis, portal hypertension, and liver cancer. We discuss different nonpharmacological measures, such as lifestyle modifications (weight loss, exercise, healthy diet) and other pharmacological interventions that could prevent NAFLD.

In 2015, the Chinese Society of Hepatology and the Chinese Society of Gastroenterology published a consensus on primary biliary cholangitis (PBC). In the past years, numerous clinical studies have been published in the field of PBC. To guide the clinical diagnosis and management of PBC patients, the Chinese Society of Hepatology invited a panel of experts to assess the new clinical evidence and formulate the current guidelines.

Both combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and cholangiolocarcinoma are rare primary liver cancers. cHCC-CCA is believed to originate from transformed hepatocellular carcinoma or liver stem/progenitor cells. Cholangiolocarcinoma is characterized by ductular reaction-like anastomosing cords and glands resembling cholangioles or canals containing hepatocellular carcinoma components and adenocarcinoma cells. According to the 2019 revision of the World Health Organization criteria, a subtype with stem cell features as a subclassification of cHCC-CCA was abolished for lack of conclusive evidence of the stem cell origin theory. That led to the classification of cholangiolocarcinoma with hepatocytic differentiation as cHCC-CCA. Consequently, cholangiolocarcinoma without hepatocytic differentiation is classified as a subtype of small-duct cholangiocarcinoma and is assumed to originate from the bile duct. Herein, we report the first case of double primary cHCC-CCA and cholangiolocarcinoma without hepatocytic differentiation in different hepatic segments of a cirrhotic liver. We believe this case supports the validity of the new World Health Organization criteria because the pathological finding of cHCC-CCA in this case shows the transformation of hepatocellular carcinoma to cholangiocarcinoma. Furthermore, this case may demonstrate that immature ductular cell stemness and mature hepatocyte cell stemness in hepatocarcinogenesis can coexist in the same environment. The results provide valuable insights into the mechanisms of growth, differentiation, and regulation of liver cancers.

Hepatitis B is a vaccine-preventable liver infection caused by the hepatitis B virus (HBV), and is seen as a serious global health problem. HBV infection induces the expression of type I interferon (IFN), including IFN-α and IFN-β, which have anti-HBV activities, and have been used for HBV treatment. IL2-inducible T-cell kinase (ITK) is a tyrosine kinase, which regulates T-cell differentiation and activation, while its precise effects on type I IFN production during HBV infection remain unknown.

We monitored the ITK expression in peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with acute and chronic HBV infection. We used ITK inhibitor ibrutinib to treat hepatocytes and evaluated the type I IFN expression after HBV infection. We also administrated ibrutinib to mice and evaluated its effect on HBV infection in vivo. We generated ITK, suppressor of cytokine signaling 1 (SOCS1) knockout and ITK/SOCS1 double knockout cells using CRISPR, and monitored the HBV-induced type I IFN production.

ITK and type I IFN were upregulated in patients with acute HBV infection. Inhibition of ITK by ibrutinib suppressed HBV-induced expression of type I IFN mRNA in mice. ITK knockout cells had decreased IRF3 activation but promoted the expression of SOCS1. ITK negatively regulated SOSC1 expression. The down regulation of type I IFN in ITK knockout cells after HBV stimulation was abolished in the absence of SOCS1.

ITK regulated HBV-induced expression of type I IFN mRNA by modulating SOCS1.

Personalized medicine is a relatively new approach that addresses differences between patients based on unique features such as genetic make-up, environment, and physiology. Aptamers are synthetic sequences of single-stranded DNA or RNA with a particular three-dimensional conformation that binds to a target. Aptamer-based biosensors are promising tools to detect disease markers, especially in cancer. Gastric cancer is the third most common cause of cancer-related deaths worldwide and has very high prevalence in Asia. Currently, there is a lack of effective screening tools for the early detection of gastric cancer. Thus, identifying new methods to detect markers of gastric cancer is crucial. In this study, the role of aptamer-based biomarkers in early diagnosis of gastric cancer is reviewed.

Iron homeostasis is a complex process in which iron uptake and use are tightly balanced. Primary Type 1 or HFE hemochromatosis results from homozygous mutations in the gene that encodes human homeostatic iron regulator (known as human factors engineering, HFE) protein, a regulator of hepcidin, and makes up approximately 90% of all hemochromatosis cases. However, four types of hemochromatosis do not involve the HFE gene. They are non-HFE hemochromatosis type 2A (HFE2, encoding HJV), type 2B (HAMP, encoding hepcidin), type 3 (TFR2, encoding transferring receptor-2), and types 4A and B (SLC40A1, encoding ferroportin. Non-HFE hemochromatosis is extremely rare. Pathogenic allele frequencies have been estimated to be 74/100,000 for type 2A, 20/100,000 for type 2B, 30/100,000 for type 3, and 90/100,000 for type 4 hemochromatosis. Current guidelines recommend that the diagnosis be made by ruling out HFE mutations, history, physical examination, laboratory values (ferritin and transferrin saturation), magnetic resonance or other imaging, and liver biopsy if needed. While less common, non-HFE hemochromatosis can cause iron overload as severe as the HFE type. In most cases, treatment involves phlebotomy and is successful if started before irreversible damage occurs. Early diagnosis and treatment are important because it prevents chronic liver disease. This review updates the mutations and their pathogenetic consequences, the clinical picture, diagnostic guidelines, and treatment of hemochromatosis.