In the past decade, with the rapid development of molecular medicine and the application of more sophisticated methods for disease diagnosis and treatment, a number of molecular markers have become available for liver diseases. Pathogenesis-related markers are likely to be effectively discovered and rigorously validated, due to the unique biological links to diseases. The present study reviews the predominant clinical and research articles in the previous decade to provide a pathogenic perspective of current and emerging biomarkers for liver diseases, including hepatocellular neoplasms (e.g. hepatocellular carcinoma), non-neoplastic hepatocellular diseases, intrahepatic biliary diseases, and other liver diseases. Although it remains challenging to cover all markers for the diagnosis and prognosis of liver diseases, current and emerging molecular markers in clinical practice and under investigation are reviewed in a wide spectrum of liver diseases, in order to help clinicians and researchers identify liver disease markers for reference.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is an important inflammation-related biomarker. The present study aimed to determine whether this affects the short-term prognosis of patients with acute-chronic liver failure (ACLF).

The serum sTREM-1 levels of 30 healthy subjects (HS), 40 chronic hepatitis patients without cirrhosis and liver failure (CH), 38 liver cirrhosis (LC) patients, and 59 ACLF patients were evaluated by enzyme-linked immunosorbent assay. The predictive accuracy of the logistic model for survival rate within 90 days in patients with ACLF was determined using the area under the receiver operating characteristic curve (AUC).Kaplan-Meier analysis and log-rank test were performed to revalidate the factors l for the 90-day survival rate of patients with ACLF.

Compared to the CH, LC and HS groups, the serum sTREM-1 levels of ACLF patients were significantly elevated (p < 0.001). In ACLF patients, the serum sTREM-1 levels further increased in non-survivors (661.51 [494.36–1,028.82] pg/mL), when compared to the survivors (440.92 [308.00–523.21] pg/mL) (p = 0.002). The multivariate logistic regression analysis indicated that serum sTREM-1, sodium, and the international normalized ratio (INR) were independent predictors for the 90-day mortality of patients with ACLF. The AUC value for logit (p) in predicting the 90-day prognosis of ACLF patients was 0.89 (0.78–1.00), with a sensitivity of 70%, a specificity of 89.74%.

Serum sTREM-1 is a valuable independent factor for determining the 90-day mortality of ACLF patients. Combining the INR and sodium in the logistic regression model may improve the accuracy in predicting the prognosis.

Although immune checkpoint inhibitors (ICIs) have been a revolutionary milestone in immuno-oncology, immune-related adverse events (irAEs) may occur due to enhanced T cell activation and immune dysregulation. The irAEs can occur as early as within days to reportedly as late as up to 26 weeks. They may affect any organ system in the body, most commonly the luminal gastrointestinal tract, liver, skin, endocrine system, and lungs. The mechanisms of irAEs are complex and have not been fully understood. A breach of self-tolerance, which leads to autoantigen reactivity due to the enhanced activation and infiltration of T cells or the production of autoantibodies, and a non-specific autoinflammatory mechanism have been proposed. Limited data is available on the clinical and pathologic features of ICI-induced liver injury. This review presents an overview of the clinical and common histopathologic features and patterns of ICI-induced liver injury, the differential diagnoses, and the clinical management. Available data suggest that the histopathologic findings of ICI-induced hepatic injury are often non-specific and overlap with other challenging differential diagnoses. Therefore, a good knowledge of the histopathologic spectrum of ICI-induced hepatic injury and their differential diagnoses combined with the serological test results, clinical correlation, and communication with the clinical team is necessary to make an accurate and timely diagnosis.

Autoimmune hepatitis (AIH) is a relatively rare liver disease with varying worldwide incidence of from 0.7 to 2 per 100,000 people. It is characterized by the presence of auto-antibodies. However, an average of 10% of AIH cases have AIH symptoms and pathology but lack autoimmune serology. For such seronegative AIH (snAIH) cases, there is currently no established diagnostic algorithm for diagnosis. and improper or delayed diagnosis of snAIH can lead to no or inappropriate treatment that results in progression to fulminant hepatitis or cirrhosis. This review aims to review the current literature and to present an update of seronegative autoimmune hepatitis, including its pathophysiology, clinical presentation, methods of diagnosis, and treatment in order to increase awareness and emphasize the necessity for timely management.

In Tunisian folk medicine, several herbs are prescribed for reducing renal damage and to avoid kidney related complications. These can be of immense value in combating renal damage. In this review, we provide a description of the current literature on the use of indigenous herbs as alternative medicine for treating renal damage. The aim of this review was to collect information on promising active phytoconstituents such as organosulfur compounds, polyphenols, terpenes, alkaloids phenylpropanoids, and polysaccharides from Tunisian plants that have been scientifically examined for their nephroprotective capacities. Twenty-nine Tunisian medicinal plants have been reported for their significant nephroprotective activities against renal toxicities in animal models. Lamiaceae was the most commonly used Tunisian plant family used for renal protection. The leaves were maximally used for nephroprotection compared to the other plant parts. Nephrotoxicity is commonly the result of several nephrotoxins. Many studies have focussed on drug-caused renal failure which is one of the major problems in medical practice. Other studies focused on other important nephrotoxicity factors, including drugs and industrial chemicals. This literature review highlights the use of some medicinal plants as nephroprotective agents. To defend against this nephrotoxicity, some medicinal plants, known as nephroprotective agents, have been highlighted in this review.

Pancreatic adenocarcinoma (PAAD) is a common malignancy in the digestive tract. Emerging studies have reported that Bloom’s syndrome helicase (BLM) is closely associated with the tumor prognosis and immune microenvironment. Our study aimed to reveal BLM’s potential prognosis value in PAAD.

Potential oncogenic effects and prognostic influence of BLM were explored based on the TCGA and GETx databases. Gene mutation and methylation analyses were performed on the cBioPortal website and SMART database. The ARCHS4 and JASPAR2022 databases were used to predict the upstream transcription factor targets (TFs) of BLM. Starbase was used to explore the upstream ncRNAs. The relationship of BLM with the PAAD immune infiltration and immune checkpoints was analyzed using TIMER and GEPIA databases.

BLM was highly expressed and correlated with a poor prognosis in PAAD. The hypomethylation of BLM was observed in PAAD and correlated with a poor prognosis. The predicted TFs (E2F1 and ETS1) were also highly expressed and positively correlated with a poor prognosis in PAAD. LINC01133-miR-30b-5p axis was explored to be the most potential upstream ncRNAs of BLM in PAAD. Furthermore, the BLM expression was positively correlated with the PAAD immune infiltration cells. The BLM expression was also positively correlated with the expression of the immune checkpoints of PD1, PD-L1, CTLA-4, and CD47.

The high expression of BLM was associated with the poor prognosis of PAAD. In addition, a high BLM expression could facilitate the expression of the immune checkpoints in the immune infiltration cells, which would promote PAAD progression and affect its prognosis.

Managing chronic pediatric skin disorders is challenging due to a lack of approved medication and the relative weakness of research studies for this age group. Ustekinumab is a human monoclonal antibody that targets the p40 subunit shared by interleukin-12 and interleukin-23 and thereby modulates the inflammatory reaction triggered by the T-helper and T-helper 17 pathways, respectively. Currently, in dermatology, ustekinumab is the only interleukin-12/interleukin-23 inhibitor approved by regulatory authorities to treat moderate to severe psoriasis in adults, adolescents, and children aged six years and older. Although off-label and not supported by strong evidence, the therapeutic use of ustekinumab has been gradually extended to various other dermatoses. The reported adverse events of this biologic in pediatric patients were generally consistent with those in adults. However, its long-term safety remains to be confirmed. In this review, we discuss the existing evidence on the mechanisms of ustekinumab action, the current regulatory authority-approved indications, off-label use in pediatric cutaneous disorders, and the most reported adverse events related to this drug.

Chronic active Epstein-Barr virus hepatitis (CAEBVH) is a rare and highly lethal disease characterized by hepatitis and hepatomegaly. This study aimed to investigate the clinicopathological features and pathogenic mechanisms of CAEBVH.

Ten patients with confirmed Epstein-Barr virus hepatitis infection were enrolled. The clinicopathological characteristics of these patients were summarized and analyzed. Flow cytometry was utilized to detect peripheral blood immune cell phenotypes and whole exome sequencing was used to explore pathogenic genetic mechanisms. Lastly, immunohistochemical staining was employed to verify pathogenic mechanisms.

Clinical features observed in all Epstein-Barr virus hepatitis patients included fever (7/10), splenomegaly (10/10), hepatomegaly (9/10), abnormal liver function (8/10), and CD8+ T cell lymphopenia (6/7). Hematoxylin and eosin staining revealed lymphocytic infiltration in the liver. Positive Epstein-Barr virus-encoded small RNA in-situ hybridization (EBER-ISH) of lymphocytes of liver tissues was noted. Whole exome sequencing indicated that cytotoxic T lymphocytes and the complement system were involved. The expression of CD8, Fas, FasL, and Caspase-8 expression as well as apoptotic markers was enhanced in the Epstein-Barr virus hepatitis group relative to the controls (p<0.05). Lastly, Complement 1q and complement 3d expression, were higher in CAEBVH patients relative to controls (p<0.05).

CAEBVH patients developed fever, hepatosplenomegaly, and lymphadenopathy. Histopathological changes were a diffuse lymphocytic sinusoidal infiltrate with EBER-ISH positivity. Fas/FasL and complement activation were involved in CAEBVH patients.

Genotyping is crucial for studying gene functions in animals and detecting genetic variants in humans. Traditional methods using agarose or polyacrylamide gel electrophoresis focus on detecting large-size differences (20–2,000 bp) between wild-type and mutant genes. While endonuclease digestion can identify heterozygous mutations, it fails to distinguish wild-type genes from homozygous mutants of similar size. This study aimed to develop a novel, simple, and reliable genotyping method for animals or cells following genetic modifications.

We introduced an improved genotyping method utilizing 2% agarose gel electrophoresis after T7E1 or Surveyor endonuclease digestion to initially separate heterozygous mutations from wild-type and homozygous mutations. By adding a wild-type PCR product to potentially homozygous samples, forming heteroduplexes, we differentiated wild-type from homozygous mutations with nearly identical sizes or single base pair substitutions without relying on Sanger sequencing.

This method was validated in genotyping zebrafish mutants with 2-8 bp deletions or insertions and mouse mutants with 1- or 8-bp substitutions. Agarose gel clearly distinguished wild-type, heterozygous, and homozygous mutations ranging from 1–8 bp. Sanger sequencing confirmed the accuracy of our genotyping results.

Our novel and improved genotyping method offers a rapid, economical approach for genotyping small deletions or single base pair substitutions. This technique has broad applications in clinical and research laboratories, especially in the era of gene editing and for detecting naturally occurring mutations.

Liver transplantation is the most effective treatment of advanced liver disease, and the use of extended criteria donor organs has broadened the source of available livers. Although normothermic machine perfusion (NMP) has become a useful tool in liver transplantation, there are no consistent criteria that can be used to evaluate the viability of livers during NMP. This review summarizes the criteria, indicators, and methods used to evaluate liver viability during NMP. The shape, appearance, and hemodynamics of the liver can be analyzed at a macroscopic level, while markers of liver injury, indicators of liver and bile duct function, and other relevant indicators can be evaluated by biochemical analysis. The liver can also be assessed by tissue biopsy at the microscopic level. Novel methods for assessment of liver viability are introduced. The limitations of evaluating liver viability during NMP are discussed and suggestions for future clinical practice are provided.

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related mortality worldwide, but its pathogenesis remains largely unknown. Nevertheless, genomic instability has been recognized as one of the facilitating characteristics of cancer hallmarks that expedites the acquisition of genetic diversity. Genomic instability is associated with a greater tendency to accumulate DNA damage and tumor-specific DNA repair defects, which gives rise to gene mutations and chromosomal damage and causes oncogenic transformation and tumor progression. Histone deacetylases (HDACs) have been shown to impair a variety of cellular processes of genome stability, including the regulation of DNA damage and repair, reactive oxygen species generation and elimination, and progression to mitosis. In this review, we provide an overview of the role of HDAC in the different aspects of DNA repair and genome instability in HCC as well as the current progress on the development of HDAC-specific inhibitors as new cancer therapies.

This study aimed to summarize the clinical pharmacokinetics and bioequivalence of generic and branded linagliptin tablets during fasting and fed conditions, and the influence of food on the pharmacokinetics (PK) of linagliptin tablets was also explored in healthy Chinese subjects.

An open-label, randomized, single-center, two-period, and single-dose crossover bioequivalence study was performed in this research. Healthy subjects in fasting (n = 32) and fed (n = 32) conditions received 5 mg of generic (test) linagliptin or a commercial (reference) capsule, respectively. Blood sample collection was conducted at the baseline and post-dose. Plasma concentrations of linagliptin were detected by a a high-performance liquid chromatography with tandem mass spectrometry method. A non-compartmental method was performed to analyze pharmacokinetic parameters, and safety was monitored.

A total of 64 subjects completed the study, 32 for the fasting and 32 for the fed study. The major PK parameters of linagliptin, including Cmax and area under the concentration-time curve from time 0 to 72 hours (AUC0–72), were similar between the preparations under fasting and fed conditions. Under fasting conditions, the 90% confidence intervals (CI) of the test/reference ratios (T/R) of Cmax and AUC0–72 were 95.9∼110.9% and 96.8∼101.9%, respectively. Under fed conditions, the 90% CI of T/R of Cmax and AUC0–72 were 98.2∼103.4% and 97.7∼103.5%, respectively. None of the volunteers had a severe adverse event.

Generic linagliptin tablet is bioequivalent to the reference drug under both fasting and feeding conditions. Food delays the absorption of linagliptin. Chinese subjects taking a single dose of linagliptin of 5 mg have good tolerance to the drug.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. According to the Barcelona Clinic Liver Cancer (BCLC) staging system, transarterial chemoembolization (TACE) is the first-line recommendation for intermediate-stage HCC. In real-world clinical practice, TACE also plays an important role in early- and advanced-stage HCC. This review article by the experts from Chinese Liver Cancer Clinical Study Alliance (CHANCE) summarizes the available clinical evidence pertaining to the current application of TACE in patients with early-, intermediate-, and advanced-stage HCC. In addition, combination of TACE with other treatment modalities, especially immunotherapy, is reviewed.

Percutaneous ablation under imaging guidance is a curative treatment that can induce complete tumor necrosis with advantages of minimal invasiveness and a low risk of complications. Thermal ablation, which includes radiofrequency ablation and microwave ablation, is a representative technique that has sufficient antitumor effects in cases of hepatocellular carcinoma with ≤3 lesions measuring ≤3 cm and preserved liver function. The short- and long-term outcomes of patients are comparable with those achieved with surgical resection. Despite their nonmalignant nature, some benign liver tumors require treatment for symptoms caused by the presence of the tumor and/or continuous enlargement. Ablation may be the treatment of choice because it has lower burden on patients than surgical treatment. This review describes the recent concepts, progress, and limitations of ablation-based treatment for benign liver tumors.

Goblet cell adenocarcinoma (GCA) is a new name for goblet cell carcinoid used by the fifth edition of the World Health Organization Classification of Tumors of the Digestive System published in 2019. This name change put an end to the years’ name confusion and led to the simplification and standardization of the diagnostic criteria and grading system for this unique epithelial neoplasm almost exclusively occurring in the appendix. This is extremely important because accurate diagnosis and grading are essential to patient management and prognostication. Under this new name, GCA is recognized to have low-grade and high-grade components with variable proportions. As such, the presence of the low-grade components is required for the diagnosis, but the proportion of the high-grade components dictates the prognosis. With regard to the nomenclature, GCA does not seem to be an ideal name for this tumor because goblet cells are apparently not the cell origin nor the unique cell population of the tumor. While the histogenesis remains ambiguous, the name “crypt cell carcinoma” would appear more appropriate for this tumor, as it would at least emphasize the crypt-like architecture and cellular composition of the tumor nests. This review aimed to clarify the diagnostic criteria and grading system for goblet cell adenocarcinoma (GCA) as outlined in the latest World Health Organization Classification.

Biliary tract cancers (BTCs) are a group of malignant neoplasms that have recently increased in incidence and have a poor prognosis. Surgery is the only curative therapy. However, most patients are only indicated for palliative therapy because of advanced-stage disease at diagnosis and rapid progression. The current first-line treatment for advanced BTC is gemcitabine and cisplatin chemotherapy. Nonetheless, many patients develop resistance to this regimen. Over the years, few chemotherapy regimens have managed to improve the overall survival of patients. Accordingly, novel therapies such as targeted therapy have been introduced to treat this patient population. Extensive research on tumorigenesis and the genetic profiling of BTC have revealed the heterogenicity and potential target pathways, such as EGFR, VEGF, MEK/ERK, PI3K and mTOR. Moreover, mutational analysis has documented the presence of IDH1, FGFR2, HER2, PRKACA, PRKACB, BRAF, and KRAS gene aberrations. The emergence of immunotherapy in recent years has expanded the treatment landscape for this group of malignancies. Cancer vaccines, adoptive cell transfer, and immune checkpoint inhibitors have been extensively investigated in trials of BTC. Therefore, patient stratification and a combination of various therapies have become a reasonable and important clinical strategy to improve patient outcomes. This review elaborates the literature on combined treatment strategies for advanced BTC from the past few years and ongoing clinical trials to provide new inspiration for the treatment of advanced BTC.

The tumor microenvironment (TME) is an integral part of cancer that serves as a harbor where tumor cells communicate with neighboring cells and non-cancerous components to determine the progression of the tumor. Researchers are increasingly turning their focus away from tumor cells alone and toward the dynamic and intricate tumor microenvironment to acquire a stronger insight into malignancies. The active crosstalk on TME and its heterogeneity make it challenging to reveal its characteristics, while details of the regulatory mechanisms remain unknown. A deep understanding of TME remodeling may provide potential biomarkers and treatment targets to enhance tumor therapy. Circular RNAs (circRNAs) are subpopulations of noncoding RNAs with unique characteristics and a wide range of biological properties involved in tumorigenesis and metastasis. Accumulating evidence has shown that circRNAs have abnormal expression and mediate signaling pathways. They play various roles in human malignancy events, such as angiogenesis, immune escape, and others. The role of circRNAs in the TME cannot be ignored, which may provide a novel path to elucidate the underlying regulatory mechanisms of TME remodeling. This review summarizes the history of TME and circRNAs and their roles and activities in the TME.