Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer for which effective therapeutic agents are lacking. Fibroblast growth factor receptor 2 (FGFR2) has become a promising therapeutic target in ICC; however, its incidence and optimum testing method have not been fully assessed. This study investigated the rearrangement of FGFR2 in intrahepatic cholangiocarcinoma using multiple molecular detection methods.

The samples and clinical data of 167 patients who underwent surgical resection of intrahepatic cholangiocarcinoma in Zhongshan hospital, Fudan university were collected. The presence of FGFR2 gene rearrangement was confirmed using fluorescence in situ hybridization (FISH) and targeted next-generation sequencing (NGS). FGFR2 protein expression was determined using immunohistochemistry (IHC). The concordance between the methods was statistically compared. PD-L1 expression was also assessed in this cohort. The clinicopathological characteristics and genomic profile related to FGFR2 rearrangements were also analyzed to assist candidate-screening for targeted therapies.

FGFR2 rearrangement was detected in 21 of the 167 ICC cases (12.5%) using FISH. NGS analysis revealed that FGFR2 rearrangement was present in 16 of the 20 FISH-positive cases, which was consistent with the FISH results (kappa value=0.696, p<0.01). IHC showed that 80 of the 167 cases (48%) were positive for FGFR2 expression, which was discordant with both FISH and NGS results. By comparison, FGFR2-positivity tended to correlate with unique clinicopathological subgroups, featuring early clinical stage, histologically small duct subtype, and reduced mucus production (P<0.05), with improved overall survival (p<0.05). FGFR2-positivity was not associated with PD-L1 expression in ICCs. In genome research, we identified eight partner genes fused with FGFR2, among which FGFR2-BICC1 was the most common fusion type. BAP1, CDKN2A, and CDKN2B were the most common concomitant genetic alterations of FGFR2, whereas KRAS and IDH1 mutations were mutually exclusive to FGFR2 rearrangements.

FISH achieved satisfactory concordance with NGS, has potential value for FGFR2 screening for targeted therapies. FGFR2 detection should be prioritized for unique clinical subgroups in ICC, which features a histological small duct subtype, early clinical stage, and reduced mucus production.

Major depressive disorder (MDD) is a prevalent and highly debilitating illness that causes significant functional impairment in many patients. Conventional pharmacotherapy, such as monoaminergic antidepressant agents, usually takes several weeks to improve symptomatology and has some adverse side effects, and in many cases, patients show clinical non-response. This has resulted in a quest to identify novel means of targeting the illness. Ketamine, a glutamate N-methyl-D-aspartate receptor antagonist, has been widely researched as an alternative intervention. Originally developed as an anesthetic, ketamine has been shown to exert an antidepressant effect at subanesthetic doses. A single dose of ketamine has been shown to have a rapid effect in resolving serious depressive symptoms including suicidal ideation with antidepressant effects. However, further research is needed as, in longer-term use, ketamine has the potential to be abused and certain psychological side effects, including psychotomimetic or dissociative effects, must be considered. This review highlights some of the benefits and risks of the use of ketamine in the treatment of MDD.

Stress granules (SGs) as membrane-less cytoplasmic foci formed in response to unfavorable external stimuli could promote cancer cells to adapt to hostile environments. Hepatocellular carcinoma (HCC) is prone to be highly aggressive once diagnosed, which markedly reduces patient survival time. Therefore, it is crucial to develop valid diagnostic markers to prognosticate HCC patient prognosis, which promotes individualized precision therapeutics in HCC. Considering the pro-tumorigenic activity of SGs, it is of great potential value to construct a prognostic tool for HCC based on the expression profiles of SG-related genes (SGGs).

Bioinformatic analysis was employed to establish an SGG-based prognostic signature. Western blotting and real-time polymerase chain reaction assays were used to assess the expression patterns of the related SGGs. Loss-of-function experiments were performed to analyze the effect of the SGGs on SG formation and cell survival.

A four-SGG signature (KPNA2, MEX3A, WDR62, and SFN) targeting HCC was established and validated to exhibit a robust performance in predicting HCC prognosis. Consistently, all four genes were further found to be highly expressed in human HCC tissues. More important, we demonstrated that individually knocking down the four SGGs significantly reduced HCC cell proliferation and metastasis by compromising the SG formation process.

We developed an SGG-based predictive signature that can be used as an independent prognostic tool for HCC. The strong predictive power of this signature was further elucidated by the carcinogenic activity of KPNA2, MEX3A, WDR62, and SFN in HCC cells by regulating SG formation.

Cell death is associated with a variety of liver diseases, and hepatocyte death is a core factor in the occurrence and progression of liver diseases. In recent years, new cell death modes have been identified, and certain biomarkers have been detected in the circulation during various cell death modes that mediate liver injury. In this review, cell death modes associated with liver diseases are summarized, including some cell death modes that have emerged in recent years. We described the mechanisms associated with liver diseases and summarized recent applications of targeting cell death in liver diseases. It provides new ideas for the diagnosis and treatment of liver diseases. In addition, multiple cell death modes can contribute to the same liver disease. Different cell death modes are not isolated, and they interact with each other in liver diseases. Future studies may focus on exploring the regulation between various cell death response pathways in liver diseases.

Intrahepatic cholangiocarcinoma (iCCA) can originate from the large bile duct group (segment bile ducts and area bile ducts), small bile duct group (septal bile ducts and interlobular bile ducts), and terminal bile duct group (bile ductules and canals of Hering) of the intrahepatic biliary tree, which can be histopathological corresponding to large duct type iCCA, small duct type iCCA and iCCA with ductal plate malformation pattern, and cholangiolocarcinoma, respectively. The challenge in pathological diagnosis of above subtypes of iCCA falls in the distinction of cellular morphologies, tissue structures, growth patterns, invasive behaviors, immunophenotypes, molecular mutations, and surgical prognoses. For these reasons, this expert consensus provides nine recommendations as a reference for standardizing and refining the diagnosis of pathological subtypes of iCCA, mainly based on the 5th edition of the World Health Organization Classification of Tumours of the Digestive System.

The gastrointestinal microbiome remains an explosively increasing topic of study, assessing the potentially pivotal roles of the microbiome in maintaining health or causality in disease pathogenesis. Gastroesophageal reflux disease (GERD) has long been understood to be a result of direct acidic injury. However, emerging evidence suggests that GERD could also be caused by alterations in the esophageal microbiome, causing an induction of a submucosal inflammatory cytokine cascade, that has a retrograde effect on the luminal mucosa. This concept of a microbial shift/dysbiosis in the causality of GERD is clearly a paradigm shift and has led to possible treatment strategies beyond the traditional approach of acid-suppressive therapies. This review focuses on the current evidence surrounding GERD and the rationale for possible esophageal microbiome-directed treatment strategies.

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and represents a global health challenge. Liver cancer ranks third in cancer-related mortality with 830,000 deaths and sixth in incidence with 906,000 new cases annually worldwide. HCC most commonly occurs in patients with underlying liver disease, especially chronic hepatitis B virus (HBV) infection in highly endemic areas. Predicting HCC risk based on scoring models for patients with chronic liver disease is a simple, effective strategy for identifying and stratifying patients to improve the early diagnosis rate and prognosis of HCC. We examined 23 HCC risk scores published worldwide in CHB patients with (n=10) or without (n=13) antiviral treatment. We also described the characteristics of the risk score’s predictive performance and application status. In the future, higher predictive accuracy could be achieved by combining novel technologies and machine learning algorithms to develop and update HCC risk score models and integrated early warning and diagnosis systems for HCC in hospitals and communities.

Transient receptor potential vanilloid 1 (TRPV1) channel is a non-selective cation channel that plays a pivotal role in pain transduction. However, more than a pain sensor, it is involved in an array of vital processes in different body systems. The findings of several studies illustrated that many disorders are associated with alterations in the function and/or expression of the TRPV1 channel. Accordingly, the TRPV1 channel has become an important target in numerous therapeutic interventions. Several TRPV1 antagonists are already in the market, however, there is a need for new drugs with fewer or no side effects. This review highlights the involvement of the TRPV1 channel in a plethora of physiological and pathological conditions and points to its importance as a therapeutic target.

Hepatic ischemia-reperfusion injury (IRI) is a common pathophysiological phenomenon in clinical practice, which usually occurs in liver transplantation, liver resection, severe trauma, and hemorrhagic shock. Proanthocyanidin (PC), exerted from various plants with antioxidant, antitumor, and antiaging activity, were administrated in our study to investigate the underlying mechanism of its protective function on IRI.

Two doses of PC (50 mg/kg, 100 mg/kg) were given to BALB/c mice by intragastric administration for 7 days before partial (70%) warm IR surgery. Serum and liver tissues were collected 2, 8, and 24 h after reperfusion for relevant experiments.

The results of transaminase and hematoxylin and eosin staining indicated that PC pretreatment significantly alleviated IRI in mice. Serum total superoxide dismutase increased and malondialdehyde decreased in PC pretreatment groups. Enzyme-linked immunosorbent assays, western blotting, quantitative real-time polymerase chain reaction, and immunohistochemistry showed that inflammation, apoptosis, and autophagy in PC preprocessing groups were significantly inhibited and were dose-dependent. The protein, mRNA expression, and immunohistochemical staining results of peroxisome proliferator-activated receptor alpha (PPARα) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) in the PC pretreatment groups were significantly upregulated compared with the IR group in a dose-dependent manner.

PC pretreatment suppressed inflammation, apoptosis, and autophagy via the PPAR-α signaling pathway to protect against IRI of the liver in mice.

Identification of prognostic factors for hepatocellular carcinoma (HCC) opens new perspectives for therapy. Circulating and cellular onco-miRNAs are noncoding RNAs which can control the expression of genes involved in oncogenesis through post-transcriptional mechanisms. These microRNAs (miRNAs) are considered novel prognostic and predictive factors in HCC. The apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) contributes to the quality control and processing of specific onco-miRNAs and is a negative prognostic factor in several tumors. The present work aims to: a) define APE1 prognostic value in HCC; b) identify miRNAs regulated by APE1 and their relative target genes and c) study their prognostic value.

We used The Cancer Genome Atlas (commonly known as TCGA) data analysis to evaluate the expression of APE1 in HCC. To identify differentially-expressed miRNAs (DEmiRNAs) upon APE1 depletion through specific small interfering RNA, we used NGS and nanostring approaches in the JHH-6 HCC tumor cell line. Bioinformatics analyses were performed to identify signaling pathways involving APE1-regulated miRNAs. Microarray analysis was performed to identify miRNAs correlating with serum APE1 expression.

APE1 is considerably overexpressed in HCC tissues compared to normal liver, according to the TCGA-liver HCC (known as LIHC) dataset. Enrichment analyses showed that APE1-regulated miRNAs are implicated in signaling and metabolic pathways linked to cell proliferation, transformation, and angiogenesis, identifying Cyclin Dependent Kinase 6 and Lysosomal Associated Membrane Protein 2 as targets. miR-33a-5p, miR-769, and miR-877 are related to lower overall survival in HCC patients. Through array profiling, we identified eight circulating DE-miRNAs associated with APE1 overexpression. A training phase identified positive association between sAPE1 and miR-3180-3p and miR-769.

APE1 regulates specific miRNAs having prognostic value in HCC.

Alzheimer’s disease (AD) is characterized by the progressive degeneration of neurons and pathological activation of glial cells. The present study aimed to investigate the potential protective effects of Nosustrophine, a nootropic supplement derived from young porcine (Sus scrofa domesticus) brains on the progression of neurodegeneration.

Different concentrations of the lyophilized Nosustrophine extract were added into the SH-SY5Y neuroblastoma cell line, hepatocarcinoma heppG2 cell line and rat neuronal and glial cells with or without different treatments. The viability of cells and the response of neurons, astrocytes and microglia to oxidative stress were measured and compared.

The cell viability of SH-SY5Y cells treated with low concentrations of Nosustrophine was notably improved, when compared to control cells. In the HepG2 hepatocarcinoma cell line, Nosustrophine had a moderate, concentration-dependent impact on cell viability, with the most significant effects observed at concentrations greater than 1 mg/mL. However, Nosustrophine did not confer any toxic effects on human cell lines, sustain neuronal survivability rates, or significantly enhance the astroglial cell survival in mouse primary neuronal and glial cells. The protective effect of Nosustrophine on microglia was inversely correlated to the drug concentration in the culture medium. It was found that Nosustrophine was protective against Aβ1-42-induced neurodegeneration in mouse organotypic hippocampal slice cultures.

Nosustrophine has potent neuroprotective properties, enhances neural plasticity, and may be a potential therapeutic option for degenerative diseases.

Biophysiologic monitoring exists as a method of collecting objective information about the neurosurgical patient throughout their treatment and recovery process. Such data is crucial for an improved understanding of the disease processes while providing the surgeon additional clarity as they decipher the next best steps in decision-making and medical recommendations. In the current review article, the authors discuss the commonly used wearable and placeable monitoring devices and the biophysiological data that can be collected to monitor, as well as, assess the neurosurgical patient. Special focus is placed on invasive and non-invasive neurologic monitoring devices, but important and commonly used monitors for the rest of the body are also discussed as they relate to the neurosurgical patient. Last, the authors review new, as well as, upcoming devices and measurements to better analyze the neurosurgical patient’s bodily function and physiologic status as needed. The synthesis of methods contained herein may provide meaningful guidance for neurosurgeons in effectively monitoring and treating their patients while also helping to guide their future efforts in patient biophysiologic monitoring developments within neurosurgery.

Ustekinumab is a human antibody that interacts with the p40 chain shared by both interleukin (IL)-12 and IL-23. Treatment with ustekinumab can effectively inactivate the biological functions of IL-12 and IL-23 to control aberrant Th1 and Th17 immunological responses. Ustekinumab is the first unique IL-12/IL-23 blocker approved by the Food and Drug Administration for the treatment of patients with moderate or severe psoriasis. Subsequently, its application has extended as a therapeutic option for psoriatic arthritis and inflammatory bowel diseases. Given its therapeutic mechanism, usterkinumab may be used as a potential alternative for treatment of a variety of inflammatory skin conditions. More importantly, usterkinumab is relatively safe, as the associated adverse reactions are generally non-serious and rare; although continuous monitoring of its adverse events is warranted. Here, we discuss the therapeutic effects of ustekinumab and its clinical applications specifically in dermatology.

Amino acid neurotransmitters are closely correlated to the neurological function of the brain, and the imbalance of amino acid neurotransmitters can lead to a variety of neurological diseases. Therefore, the development of a simple method to detect five neurotransmitters (aspartate, glutamate, glycine, taurine, γ-aminobutyric) in the brain is urgently needed.

The sample was initially treated and derived, and analyzed using liquid chromatography. In the range of 0.300–100.000 mol/L, the linear relationship was good, and the correlation coefficient was ≥0.999. Furthermore, the intra-day accuracy of this method was 1.48–13.85%, and the inter-day accuracy was 2.13–12.61%. Moreover, the limit of detection (LOD, signal-to-noise ratio 3 [S/N = 3]) was 0.15–0.20 mol/L, and the limit of quantitation (LOQ, S/N = 10) was 0.30–0.55 mol/L. This approach was used to compare the content of amino acids in the brain of pigs and rats.

The data revealed that most of the amino acid neurotransmitters were higher in the five brain tissues obtained from pigs, when compared to those obtained from rats. Aspartate and taurine had the greatest concentrations in brain tissues obtained from pigs and rats, respectively (except the cerebellum).

It can be concluded that there are differences in the content of neurotransmitters in brain regions among animals. The development of this method would support the detection of neurotransmitters in the brain.

Alcohol-related liver disease is a major public health problem, with a varying clinical course and often devastating consequences. Its spectrum can vary from alcohol-related fatty liver, alcoholic hepatitis, cirrhosis, and hepatocellular carcinoma. Multiple environmental, genetic, socio-economic and epigenetic factors are intrinsically involved, affecting disease behavior and progression. Recent advances in genome-wide association studies have identified multiple genetic polymorphisms that may affect the pathophysiological process, and in turn, affect disease progression. Although the present understanding of this complex process remains nascent at best, there is an ardent need to incorporate available genetic markers into diagnostic and prognostic algorithms. This may pave the way for future research into targeted therapies.

Cannabis sativa contains phytocannabinoids that are psychoactive and neurotoxic (delta-9-tetrahydrocannabinol: Δ9THC) or nonpsychoactive and presumptively neuroprotective (cannabidiol: CBD). Along with rising legalization, availability, and demand, the Δ9THC:CBD ratio also has increased. Cannabis legalization means that use will likely increase in pregnant or breastfeeding women, affecting all stages of brain and neurodevelopment of their offspring. Δ9THC exposure in utero or during development leads to lasting detrimental effects on behavior, cognition, locomotor activity, as well as epigenetic changes. Caution is urged with cannabis use. CBD is one of the most actively studied therapies for a broad spectrum of neurological, inflammatory, and mental diseases (e.g., Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, schizophrenia) because of its efficacy, low toxicity, and availability. While data indicate that the benefits of CBD may outweigh its risks, there are indications that it poses a risk for adverse effects on neurodevelopment from in-utero exposure as well as detrimental effects on male reproduction. Therefore, there is a clear need to continue researching the effects of Δ9THC exposure as well as the optimal CBD treatment related to disease management while stressing the need to further characterize possible adverse effects.

Traditional Chinese medicine (TCM) prescriptions are complex compositions according to certain compatibility rules to treat different diseases. Therefore, understanding the superposition, inhibition, and interaction between the effective components is essential. This study aimed to use modern information technology and the established TCM databases to analyze and explore the effectiveness of TCM compositions in terms of prescription and regulation.

We adopted data mining technology to analyze the composition rules and active components among the spleen and stomach prescriptions that mainly includes the core algorithms of the apriori method and the frequent pattern (FP)-growth method.

In the present work, a new algorithm was developed that uses the modified FP-tree and the head table structure, producing only the FP-tree once and the head table structure at each recursion.

The new algorithm can be used to obtain the same results as the original algorithm of frequent item set mining, but it is at least two times faster than the FP-growth method. Thereafter, it can be used to screen and preprocess other agent data as well as to create a database by using the improved algorithm, thus establishing a simulation system for effective component and computer-composing principles of TCM that is characterized by frequent item sets, association rules, and the clustering analysis algorithm and consequently undergoes analysis for the frequency of medicinal herbal ingredients, frequency of symptoms with certain compounds, medicine-sickness connection, and pharmaceutical composition clustering to determine the related effective ingredients to treat disorders of the spleen and stomach.

Immune-mediated liver injury is a fatal side effect of sintilimab. This study aimed to shed light on the associated risk factors and characteristics of this adverse event.

The clinical records of 772 patients treated with sintilimab were retrospectively reviewed to investigate risk factors associated with sintilimab immune-related hepatotoxicity, as well as its incidence and outcome. The Roussel Uclaf Causality Assessment Method was used to identify cases of sintilimab-induced hepatotoxicity. Furthermore, logistic regressions were performed to compare the clinical and bloodwork characteristics of patients with and without immune-mediated liver injury caused by checkpoint inhibitors.

Of the 585 patients included in the study, 71 (12.1%) developed liver injury during sintilimab use. The median RUCAM score with interquartile range was 7 (6, 8). Hypoproteinemia, dyslipidemia, and the presence of thyroid peroxidase antibodies were risk factors for sintilimab-related hepatotoxicity. A nomogram model was constructed for sintilimab-induced immune-mediated liver injury based on these risk factors, which had a C-index value of 0.713 and a good calibration curve. When applied to patients with grade ≥3 and ≥4 sintilimab-induced immune-mediated liver injury, it achieved C-index values of 0.752 and 0.811, respectively. The nomogram model also showed a good prediction potential in patients ≥65 years and males. Six of the patients with sintilimab-related hepatotoxicity showed improved liver function upon treatment with steroids.

This study demonstrated that hypoproteinemia, dyslipidemia, and the presence of thyroid peroxidase antibodies were clinically feasible prognostic biomarkers to predict liver injury in patients treated with sintilimab.