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.

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.