Pharmacogenetic (PGx) testing could avoid adverse drug events and increase drug response. CYP2D6 and CYP2C19 actionable genotypes are the most important for antidepressants. The study was conducted to analyze the number of actionable genotypes in patients prior and post PGx testing in a naturalistic setting and also to examine the influence of a clinical pharmacist.

PGx testing was conducted in adult major depressive disorder inpatients (n = 108; 57% female). A retrospective analysis of the medication and actionable genotypes according to the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetic Working Group guidelines prior and post PGx testing was made with the t-test. The acceptance rate of the pharmacist´s recommendation was documented.

Forty-seven percent of all patients (n = 108) received antidepressants with dosing recommendations for the CYP2D6 and/or CYP2C19 genotypes. Of the 84 patients that were administered antidepressants prior to PGx testing, 49 patients (58%) received antidepressants and four patients (5%) received antipsychotics with guideline recommendations for the CYP2D6 and CYP2C19 genotypes. Twenty-eight actionable genotypes (55%) were found in 51 patients (53 prescriptions). The acceptance rate of the clinical pharmacist´s recommendation was 88%, and the reduction rate for the actionable genotypes was 93%. Patients had statistically significant lower number of actionable genotypes after PGx (p < 0.001).

A collaboration of psychiatrists and pharmacists seems advisable for the implementation of PGx testing into clinical practice. A pre-emptive testing approach should be applied in daily practice to ensure drug therapy safety.

Post-infantile giant cell hepatitis (PIGCH) is a rare disorder in adults with a multifactorial etiology and widely variable clinical courses and outcomes. The factors associated with the worse outcomes of this disease are still unclear. This study aimed to identify the factors that influence the prognosis of PIGCH.

We identified 68 PIGCH patients by conducting a systematic search on PubMed and performed a meta-analysis on the collected data. Various etiological factors and clinical parameters were analyzed to determine their association with patient outcomes.

Among the 68 patients, 32% of the cases were associated with autoimmune disorders, 21% with viral infections, 10% with medication, and 7% with malignancy. Additionally, 24% of the patients had more than one etiological factor, while 6% had other uncommon etiologies or unknown causes. At the time of reporting, 17 patients had died of the disease (poor outcome), and 51 patients remained alive with the disease (good outcome). Patients with a poor outcome were characterized by older age, lower levels of platelets and albumin, higher levels of total bilirubin, and a diffuse distribution pattern of giant cells in the liver. No differences were observed in gender distribution or levels of aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, nor in histological features such as interface hepatitis, necrosis, lobular inflammation, portal inflammation, cholestasis, or fibrosis.

Older age, lower platelet and albumin levels, higher total bilirubin levels, and a diffuse distribution of giant cells in the liver are associated with worse outcomes in PIGCH patients. Further studies are needed to better understand the disease mechanisms and uncover additional etiological factors and targeted therapies.

Hepatocellular carcinoma (HCC) is one of the most common and highly heterogeneous malignancies worldwide. Despite the rapid development of multidisciplinary treatment and personalized precision medicine strategies, the overall survival of HCC patients remains poor. The limited survival benefit may be attributed to difficulty in early diagnosis, the high recurrence rate and high tumor heterogeneity. Ferroptosis, a novel mode of cell death driven by iron-dependent lipid peroxidation, has been implicated in the development and therapeutic response of various tumors, including HCC. In this review, we discuss the regulatory network of ferroptosis, describe the crosstalk between ferroptosis and HCC-related signaling pathways, and elucidate the potential role of ferroptosis in various treatment modalities for HCC, such as systemic therapy, radiotherapy, immunotherapy, interventional therapy and nanotherapy, and applications in the diagnosis and prognosis of HCC, to provide a theoretical basis for the diagnosis and treatment of HCC to effectively improve the survival of HCC patients.

Esophageal verrucous squamous cell carcinoma and esophageal carcinoma cuniculatum are rare variants of extremely well-differentiated squamous cell carcinoma. These rare tumors share similar risk factors and clinical presentations with conventional esophageal squamous cell carcinoma. However, these tumors have distinct morphological features, molecular mutation profiles, and clinical outcomes. Diagnosis of esophageal verrucous squamous cell carcinoma and esophageal carcinoma cuniculatum can be challenging, requires high clinical suspicion, and often can only be diagnosed on a deep mucosal biopsy or resection specimen. Surgical treatment or endoscopic resection can be curative in early disease. This review presents the histomorphology and molecular profiling of the conventional type and the rare variants of the esophageal well-differentiated squamous cell carcinoma.

Cancer research has made a magnificent progress in past decades with an advancement of molecular biology. However, the mechanisms of cancer transformation are still not fully revealed. Thus, we must think about if there are some unknown factors playing a causative role in the cancer formation. Mitochondrial complex I oxidizes NADH to NAD+ and reduces ubiquinone to ubiquinol, regenerated NAD+ keeping pyruvate dehydrogenase and Krebs cycle function. Hydrogenases are widespread in nature, they occur in bacteria, archaea, and some eukarya. It is unknown whether hydrogenase activity exists in human mitochondria. The complex I shares a last common ancestor with hydrogenases, and is closely related with hydrogenase in sequence and modular structure. The hydrogenase activity has been observed recently in complex I of higher plants. Based on these observations, I propose a hypothesis that mitochondrial complex I in human may also retain the hydrogenase activity. The hypothetical hydrogenase activity could release excessive reducing equivalents of NADH from electron transport chain when a cell is in hypoxia, decreased oxidative phosphorylation or a low ATP demand. Loss of the hydrogenase activity may result in aerobic glycolysis, activation of pentose phosphate pathway, elevated lipid synthesis, and activations of oncoproteins via acetylation, all of these alterations lead to cell proliferations and cancer transformation. Reducing mitochondrial NADH/NAD+ ratio or recovering the hydrogenase activity would reverse the cell transformation.

We report a case of a patient with c-MET amplified hepatocellular carcinoma (HCC) who had a dramatic response to cabozantinib despite being refractory to four previous lines of systemic therapy. The patient had previously received regorafenib plus nivolumab as first-line treatment, lenvatinib as second-line, sorafenib as third-line, and ipilimumab plus nivolumab as fourth-line treatment in sequence. However, all regimens showed early progression within 2 months. The patient’s HCC was well-controlled, with a partial response (PR) of over 9 months after beginning cabozantinib treatment. Although there were mild adverse events such as diarrhea and elevated liver enzymes, they were tolerable. Next-generation sequencing (NGS) of the patient’s previous surgical specimen indicated amplification of c-MET genes. Although it is well known that cabozantinib has excellent effectiveness for inhibiting c-MET at the preclinical level, to the best of our knowledge this is the first case of dramatic response to cabozantinib in a patient with advanced HCC with c-MET amplification.

Hepatectomy is an effective treatment for selected patients with large hepatocellular carcinoma (HCC). This study aimed to develop a nomogram incorporating non-tumoral liver volume (non-TLV) and liver function markers to predict the patients’ overall survival (OS) and disease-free survival (DFS).

Data of 198 consecutive large HCC patients who underwent hepatectomy at the Zhongshan Hospital Xiamen University were collected. Another 68 patients from the Mengchao Hepatobiliary Surgery Hospital served as an external validation cohort. The nomograms were developed based on the independent prognostic factors screened by multivariate Cox regression analyses. Concordance index (C-index), calibration curves, and time-dependent receiver operating characteristic (ROC) curves were used to measure the discrimination and predictive accuracy of the models.

High HBV DNA level, low non-TLV/ICG, vascular invasion, and a poorly differentiated tumor were confirmed as independent risk factors for both OS and DFS. The model established in this study predicted 5-year post-operative survival and DFS in good agreement with the actual observation confirmed by the calibration curves. The C-indexes of the nomograms in predicting OS and DFS were 0.812 and 0.823 in the training cohort, 0.821 and 0.846 in the internal validation cohort, and 0.724 and 0.755 in the external validation cohort. The areas under the ROC curves (AUCs) of nomograms for predicted OS and DFS at 1, 3, and 5 year were 0.85, 0.86, 0.83 and 0.76, 0.76, 0.63, respectively.

Nomograms with non-TLV/ICG predicted the prognosis of single large HCC patients accurately and effectively.

Natural products featured by an abundant molecule skeleton and structural complexity exhibit extensive pharmacological or biological activities. Thus, natural active ingredients are an important source of drug research and development. However, the inherent defects, including low solubility, low bioavailability, and unacceptable off-target toxicity, affect their development into clinical drugs. Recently, carrier-free supermolecule nanodrugs have attracted considerable attention. These nanodrugs are self-assembled by pure drugs mainly through hydrophobicity, hydrogen bond, π-π stacking, and electrostatic interaction, which possess a high drug loading capability, enhanced water solubility of the drugs, and synergistic therapeutic efficacy. In this review, natural product-based carrier-free nanoplatforms with self-assembly for efficient bioactivity were examined. These self-assembled natural products included triterpenoids, alkaloids, flavonoids, and anthraquinones. Moreover, the morphology of the formed nanoplatforms could be a nanosphere, nanofiber, nanorod, or fibrillar network, and they could exhibit several bioactivities, such as antitumor, anti-inflammatory, immunoregulation, and liver protection. Briefly, we analyzed the types and sources, formation mechanism, biological activity, and mode of action of the nanomedicine, and discussed the future of this field. We believe this review would provide a landscape of natural product-based carrier-free nanoplatforms.

In the era of antiviral therapy, the main goal of treatment has shifted from the persistent inhibition of hepatitis B virus (HBV) replication to the pursuit of serological clearance of HBs surface antigen (HBsAg). Based on the life cycle of HBV, HBsAg originates from covalently closed circular DNA (cccDNA) and integrated HBV DNA, thus reflecting their transcriptional activity. Complete HBsAg loss may mean elimination or persistent inactivity of the HBV genome including cccDNA and integrated HBV DNA. HBsAg loss improves the recovery of abnormal immune function, which in turn, may further promote the clearance of residual viruses. Combined with functional cure and the great improvement of clinical outcomes, the continuous seroclearance of high-sensitivity quantitative HBsAg may represent the complete cure of chronic hepatitis B (CHB). For many other risk factors besides HBV itself, patients with HBsAg loss still need regular monitoring. In this review, we summarized the evolution of CHB treatment, the origin of serum HBsAg, the pattern of HBsAg seroclearance, and the effect of HBsAg loss on immune function and disease outcomes. In addition, we discuss the significance of high-sensitivity HBsAg detection and its possibility as a surrogate of complete cure.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. The mechanisms involved in NAFLD onset are complicated and multifactorial. Recent literature has indicated that altered intestinal barrier function is related to the occurrence and progression of liver disease. The intestinal barrier is important for absorbing nutrients and electrolytes and for defending against toxins and antigens in the enteric environment. Major mechanisms by which the intestinal barrier influences the development of NAFLD involve the altered epithelial layer, decreased intracellular junction integrity, and increased intestinal barrier permeability. Increased intestinal permeability leads to luminal dysbiosis and allows the translocation of pathogenic bacteria and metabolites into the liver, inducing inflammation, immune response, and hepatocyte injury in NAFLD. Although research has been directed to NAFLD in recent decades, the pathophysiological changes in NAFLD initiation and progression are still not completely understood, and the therapeutic targets remain limited. A deeper understanding on the correlation between NAFLD pathogenesis and intestinal barrier regulation must be attained. Therefore, in this review, the components of the intestinal barrier and their respective functions and disruptions during the progression of NAFLD are discussed.

The COVID-19 pandemic has impacted the care of patients with liver disease. We examined impact of COVID-19 on liver transplant (LT) activity in the USA.

LT listings in the United Network for Organ Sharing (UNOS) database (April 2018–May 2021) were analyzed to examine the impact of COVID-19 pandemic on the LT activity based on etiology: hepatitis C virus (HCV), alcohol-associated liver disease (ALD), alcoholic hepatitis (AH), and nonalcoholic steatohepatitis (NASH) complications: hepatocellular carcinoma (HCC) and acute-on-chronic liver failure (ACLF) grade 2 or 3) and Model for End-Stage Liver Disease (MELD) score. Joinpoint regression models assessed time trend changes on a log scale.

Of 23,871 recipients (8,995 in the COVID era, April 2018–February 2020), mean age 52 years, 62% men, 61% Caucasian, 32% ALD, 15% HCC, 30% ACLF grades 2–3, and mean MELD score 20.5), monthly LT changes were a decrease of 3.4% for overall LTs and 22% for HCC after September 2020, and increase of 4.5% for ALD since 11/2020 and 17% since 03/2021 for ACLF grade 2–3. Monthly MELD scores increased by 0.7 and 0.36 after June 2020 for HCV and HCC respectively.

The COVID-19 pandemic has impacted LT activity, with a decrease of LTs especially for HCC, and an increase of LTs for ALD and severe ACLF. Strategies are needed to reorganize cirrhosis patients to overcome the aftereffects of COVID-19 pandemic.

Liver transplantation (LT) is the final treatment option for patients with end-stage liver disease. The increasing donor shortage results in the wide usage of grafts from extended criteria donors across the world. Using such grafts is associated with the elevated incidences of post-transplant complications including initial nonfunction and ischemic biliary tract diseases, which significantly reduce recipient survival. Although several clinical factors have been demonstrated to impact donor liver quality, accurate, comprehensive, and effective assessment systems to guide decision-making for organ usage, restoration or discard are lacking. In addition, the development of biochemical technologies and bioinformatic analysis in recent years helps us better understand graft injury during the perioperative period and find potential ways to restore graft function. Moreover, such advances reveal the molecular profiles of grafts or perfusate that are susceptible to poor graft function and provide insight into finding novel biomarkers for graft quality assessment. Focusing on donors and grafts, we updated potential biomarkers in donor blood, liver tissue, or perfusates that predict graft quality following LT, and summarized strategies for restoring graft function in the era of extended criteria donors. In this review, we also discuss the advantages and drawbacks of these potential biomarkers and offer suggestions for future research.

Plants usually produce a large number of secondary metabolites, including antimicrobial peptides rich in cysteine. Phytopeptides, categorized into five to eight groups, exhibit varied lengths, secondary structures, and disulphide bridge patterns. Cyclotides, a specific group, possess an end-to-end cyclic structure with a knot-like disulphide bridge, which are known for their anti-nematode, anti-mollusk, and anti-trematode activities. This review provides comprehensive insights into cyclotides, covering their origin, structural and functional characteristics, therapeutic potential, biotechnological applications, and future prospects. Studies indicate that modifications in cyclotide loop regions do not alter their conformation significantly, a crucial aspect for biotechnological applications. Cyclotides, identified as peptides with a cysteine-knot motif, offer a versatile scaffold for drug delivery and combinatorial libraries due to their high tolerance for sequence variability. Molecular characterization reveals the selective targeting of G-coupled oxytocin and vasopressin receptors by the first identified cyclotide, facilitating endometrial movement during labor onset.

Hydrazone ligands along with their metal complexes exhibit important biological potential. Our objective was to synthesize new Schiff base ligands and their metal complexes which can act as vital drugs.

Metal complexes of Zn(II), Ni(II), Cu(II), Mn(II), Co(II), Hg(II), Cd(II), Sn(II), Zr(II), and Fe(II) were synthesized from a novel Schiff base (1-((3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)methylene) hydrazine) ligand using the condensation method. The ligand and metal complexes were characterized using analytical techniques. Their antimicrobial, antimalarial, and anti-tubercular activities were investigated.

The synthesized ligand was found to be bidentate in nature. The stoichiometry of the metal ions to ligand was 1:2. Complexes of Co(II), Cu(II), Mn(II), and Cd(II) displayed excellent antimicrobial activity. The Mn(II) complex was active against M. TuberculosisThe Cu(II) and Cd(II) complexes displayed excellent activity against malaria, moderate to good antimicrobial and anti-tubercular activity while Zn(II), Co(II), Sn(II), Ni(II), Hg(II), and Fe(II) were active against malaria.

We report the synthesis and characterization of a new (1-((3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)methylene) hydrazine) Schiff base bidentate ligand and metal complexes. The antitubercular, antimicrobial, and antimalarial activity of the synthesized metal complexes revealed good antimicrobial potential of Cu(II), Co(II), Mn(II), and Cd(II) complexes. The Mn(II) was remarkably active against Mycobacterium Tuberculosis.

Traumatic brain injury (TBI) can contribute to extensive dysbiosis of the gastrointestinal system, leading to worsened outcomes. The importance of nutrition in recovery is underappreciated but highly important. In this focused review, we discuss the timing of nutritional interventions with supporting data. We highlight routes of administration that are important given the extent of injury often seen in TBI. The increased energy demands can be met through these approaches. Furthermore, patients need increased vitamins, minerals, and supplements. These interventions are constantly being refined. The current standards are reviewed with an emphasis on evidence-based practices.

Interleukin (IL) 1 superfamily members are a cornerstone of a variety of inflammatory processes occurring in various organs including the liver. Progression of acute and chronic liver diseases regardless of etiology depends on the stage of hepatocyte damage, the release of inflammatory cytokines and disturbances in gut microbiota. IL1 cytokines and receptors can have pro- or anti-inflammatory roles, even dual functionalities conditioned by the microenvironment. Developing novel therapeutic strategies to block the IL1/IL1R signaling pathways seems like a reasonable option. This mode of action is now exploited by anakinra and canakinumab, which are used to treat different inflammatory illnesses, and studies in liver diseases are on the way. In this mini review, we have focused on the IL1 superfamily members, given their crucial role in liver inflammation diseases, specifically discussing their potential role in developing new treatment strategies.

Cholangiopancreatoscopy with the SpyGlass system is a direct and minimally invasive examination method in which the lesions in the pancreatic bile tract can be observed directly by inserting an ultra-fine endoscope through the biopsy channel of a duodenoscope. Compared with endoscopic retrograde cholangiopancreatography (ERCP), enhanced computed tomography, magnetic resonance imaging, and endoscopic ultrasonography, cholangiopancreatoscopy with the SpyGlass system has unique advantages for observing and identifying lesions originating in the pancreatic bile duct. In recent years, with the upgrading of endoscopic equipment and the improvement of operating technology, the application of cholangiopancreatoscopy is becoming more and more widespread. This article reviews the use of cholangiopancreatoscopy with the SpyGlass system for the diagnosis and treatment of pancreaticobiliary disease.

Immunomodulation is a diverse process by which immunomodulators enhance or suppress immune responses to control disease progression. Immunomodulators are a broad class of drugs that include immunosuppressants and immunostimulants. These agents have been used to fight against the dysregulated immune responses observed during tissue/organ transplantation and disorders, such as rheumatoid arthritis, ulcerative colitis, and cancers. Immunomodulators obtained from a myriad of plant sources are a major class of compounds that are known to have medicinal properties and are used for the treatment of various diseases. However, the mechanisms underlying the action of plant-derived compounds are poorly understood. Here, we discuss the major classes of plant-based immunomodulators with examples and their effects on the major signaling pathways, such as the nuclear factor kappa light chain enhancer of activated B cells (NF-κB), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin pathways. Importantly, we discuss the preclinical and clinical research to date to understand the importance of these immunomodulators. Overall, this review highlights the significance of plant-based immunomodulators as an alternative therapeutic strategy for combating various diseases.

Approximately 10% of patients with acute decompensated (AD) cirrhosis develop acute-on-chronic liver failure (ACLF) within 28 days. Such cases have high mortality and are difficult to predict. Therefore, we aimed to establish and validate an algorithm to identify these patients on hospitalization.

Hospitalized patients with AD who developed ACLF within 28 days were considered pre-ACLF. Organ dysfunction was defined according to the chronic liver failure-sequential organ failure assessment (CLIF-SOFA) criteria, and proven bacterial infection was taken to indicate immune system dysfunction. A retrospective multicenter cohort and prospective one were used to derive and to validate the potential algorithm, respectively. A miss rate of <5% was acceptable for the calculating algorithm to rule out pre-ACLF.

In the derivation cohort (n=673), 46 patients developed ACLF within 28 days. Serum total bilirubin, creatinine, international normalized ratio, and present proven bacterial infection at admission were associated with the development of ACLF. AD patients with ≥2 organ dysfunctions had a higher risk for pre-ACLF patients [odds ratio=16.581 95% confidence interval: (4.271–64.363), p<0.001]. In the derivation cohort, 67.5% of patients (454/673) had ≤1 organ dysfunction and two patients (0.4%) were pre-ACLF, with a miss rate of 4.3% (missed/total, 2/46). In the validation cohort, 65.9% of patients (914/1388) had ≤1 organ dysfunction, and four (0.3%) of them were pre-ACLF, with a miss rate of 3.4% (missed/total, 4/117).

AD patients with ≤1 organ dysfunction had a significantly lower risk of developing ACLF within 28 days of admission and could be safely ruled out with a pre-ACLF miss rate of <5%.

Sarcopenia, a condition of low muscle mass, quality, and strength, is commonly found in patients with chronic liver disease (CLD) and is associated with adverse clinical outcomes including reduction in quality of life, increased mortality, and complications. A major contributor to sarcopenia in CLD is the imbalance in muscle protein turnover wherein changes in various metabolic factors such as hyperammonemia, amino acid deprivation, hormonal imbalance, gut dysbiosis, insulin resistance, chronic inflammation, etc. have important roles. In particular, hyperammonemia is a key mediator of the liver-gut axis and is known to contribute to sarcopenia by various mechanisms including increased expression of myostatin, increased phosphorylation of eukaryotic initiation factor 2a, cataplerosis of α-ketoglutarate, mitochondrial dysfunction, increased reactive oxygen species that decrease protein synthesis and increased autophagy-mediated proteolysis. Skeletal muscle is a major organ of insulin-induced glucose metabolism, and sarcopenia is closely linked to insulin resistance and metabolic syndrome. Patients with liver cirrhosis are in a hypermetabolic state that is associated with catabolism and depletion of amino acids, particularly branched-chain amino acids. Sarcopenia can have significant implications for nonalcoholic fatty liver disease, the most common form of CLD worldwide, because of the close link between metabolic syndrome and sarcopenia. This review discusses the potential metabolic derangement as a cause or effect of sarcopenia in CLD, as well as interorgan crosstalk, which that might help identifying a novel therapeutic strategies.