Translational pathology has not caught up with the quality and quantity of translational medicine. Thus, challenges and opportunities related to translational pathology are discussed here. Pathologists should actively participate in reverse translational research that seeks mechanistic insights to explain clinical findings and/or solve clinical problems. Challenges in translational pathology include ambiguity in defining translational pathology, pathologists’ mindsets about translational research, lack of sufficient workforce and immature publication outlets. However, with collective wisdom and support of various stakeholders, we can expand the pool of pathologist scientists, build a translational pathology community and drive innovations in medicine through computational, molecular genetic/genomic and digital pathology approaches. This review aimed to highlight the existing challenges in the field of translational pathology and emphasizes the importance of enhancing pathologists' involvement in translational research to foster medical innovations and improve clinical outcomes through advanced computational, molecular, genetic/genomic, and digital pathology approaches.

This study was designed to uncover the mechanism for extracellular polysaccharide (EPS1-1)-mediated effects on hepatocellular carcinoma (HCC) development.

HCC cells were treated with EPS1-1, miR-494-3p mimic, sh-TRIM36, and pcDNA3.1-TRIM36. The levels of miR-494-3p and TRIM36 were measured in normal hepatocytes, THLE-2, and HepG2 and HuH7HCC cell lines, along with the protein expression of cyclin D/E and p21. The proliferation, cell cycle, and apoptosis of HCC cells were assayed. The interactions between miR-494-3p and TRIM36, and between TRIM36 and cyclin E were assessed. Finally, the expression and localization of TRIM36 and cyclin E were monitored, and tumor apoptosis was detected, in tumor xenograft model.

EPS1-1 suppressed HCC cell proliferation and cyclin D/E expression and promoted apoptosis and p21 expression. miR-494-3p was upregulated and TRIM36 was downregulated in HCC cells. Transfection with miR-494-3p mimic or sh-TRIM36 facilitated HCC cell proliferation and the expression of cyclin D/E protein but they inhibited apoptosis and p21 expression in the presence of EPS1-1. Overexpression of TRIM36 further consolidated EPS1-1-mediated inhibition of HCC proliferation, cyclin D/E, and the promotion of apoptosis and p21 expression. Those effects were reversed by miR-494-3p overexpression. TRIM36 was a target gene of miR-494-3p, and TRIM36 induced cyclin E ubiquitination. EPS1-1 suppressed cyclin E expression, promoted TRIM36 expression and tumor apoptosis, all of which were abrogated by increasing the expression of miR-494-3p in vivo.

EPS1-1 protected against HCC by limiting its proliferation and survival through the miR-494-3p/TRIM36 axis and by inducing cyclin E ubiquitination.

Nonalcoholic fatty liver disease (NAFLD), including advanced-stage nonalcoholic steatohepatitis (NASH), is currently the most common chronic liver disease worldwide and is projected to become the leading indication for liver transplantation (LT). However, there are no effective pharmacological therapies for NAFLD. Endoscopic bariatric and metabolic therapies (EBMTs) are less invasive procedures for the treatment of obesity and its metabolic comorbidities. Several recent studies have demonstrated the beneficial effects of EBMTs on NAFLD/NASH. In this review, we summarize the major EBMTs and their mechanisms of action. We further discuss the current evidence on the efficacy and safety of EBMTs in people with NAFLD/NASH and obese cirrhotic LT candidates. The potential utility of EBMTs in reducing liver volume and perioperative complications in bariatric surgery candidates is also discussed. Moreover, we review the development of liver abscesses as a common serious adverse event in duodenal-jejunal bypass liner implantation.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the incidence and mortality rates are increasing. Given the limited treatments of HCC and promising application of immunotherapy for cancer, we aimed to identify an immune-related prognostic signature that can predict overall survival (OS) rates and immunotherapy response in HCC.

The initial signature development was conducted using a training dataset from the Cancer Genome Atlas followed by independent internal and external validations from that resource and the Gene Expression Omnibus. A signature based nomogram was generated using multivariate Cox regression analysis. The associations of signature score with tumor immune phenotype and response to immunotherapy were analyzed using single-sample gene set enrichment analysis and tumor immune dysfunction and exclusion algorithm. A cohort from Zhongshan Hospital was employed to verify the predictive robustness of the signature regarding prognostic risk and immunotherapy response.

The prognostic signature, IGSHCC, consisting of 22 immune-related genes, had independent prognostic ability, with training and validation cohorts. Also, IGSHCC stratified HCC patients with different outcomes in subgroups. The prognostic accuracy of IGSHCC was better than three reported prognostic signatures. The IGSHCC-based nomogram had high accuracy and significant clinical benefits in predicting 3- and 5-year OS. IGSHCC reflected distinct immunosuppressive phenotypes in low- and high-score groups. Patients with low IGSHCC scores were more likely than those with high scores to benefit from immunotherapy.

IGSHCC predicted HCC prognosis and response to immunotherapy, and contributed to individualized clinical management.

The prevalence of chronic diseases, which is a worldwide public health problem, is increasing with prolonged life expectancy worldwide. Cardiovascular diseases (CVDs), diabetes, respiratory system diseases, and cancers are among the most important chronic diseases. Chronic diseases, which affect individuals physically, psychologically, and sociologically, negatively affect daily self-care activities, treatment costs, length of hospital stay, and quality of life. Therefore, a multimodal approach is required to protect or regain the health of individuals with bio-psycho-socio-cultural and spiritual dimensions. A multimodal approach to chronic diseases deals with risk assessment, classification, diagnosis, pharmacological treatment, lifestyle changes, management of psychosocial factors, and surgical intervention with a multidisciplinary approach. It is known that this approach, which expresses patient-centered and holistic care, increases patient satisfaction, reduces health costs and inequalities, and improves the quality of care and health outcomes by addressing the biological, physiological, social, cultural, and spiritual needs of patients. In this review, the multimodal approach to CVD, diabetes, and chronic obstructive pulmonary disease is included in line with current guidelines.

Hepatitis B vaccine is the most effective preventive measure against hepatitis B virus (HBV) infection. However, the risk of HBV breakthrough infection in fully immunized children (neonatal hepatitis B immunization) who receive immunosuppressive therapy and transfusion of blood components is not well characterized. In this real-world study, we aimed to investigate the immune protection conferred by neonatal hepatitis B vaccine in children with acute lymphoblastic leukemia (ALL) who were treated with immunosuppressive therapy and blood component transfusions.

Children with ALL who had received all three doses of neonatal hepatitis B vaccine were included in this study. HBV seromarkers were detected before and after the initiation of immunosuppressive therapy.

A total of 1,011 children with ALL who were fully vaccinated against hepatitis B in infancy before the initiation of immunosuppressive therapy were eligible for inclusion. HBV infection was detected in four of 410 children (0.98%) with an HBsAg test after the initiation of immunosuppressive therapy. The median interval from treatment initiation was 19 months.

Three doses of neonatal hepatitis B vaccine conferred adequate protection. In endemic regions, there is a low risk of HBV breakthrough infection in fully immunized children with immunosuppressive therapy.

In recent years, miRNAs have been shown to play an important role in many diseases, most notably cancers. Traditional experiments for cancer diagnostics are time-consuming and expensive, thus more attention is being diverted towards discovering computational methods for predicting miRNA–disease association and using them in cancer diagnostics.

miRNA numerical sequence information and genes targeted by miRNA were used for the construction of descriptors for machine-learning models. Next, we generated a table of miRNA descriptors using all of the miRNAs in a specific cancer dataset for disease classification. To show the effectiveness of the system, we constructed miRNA descriptor systems for pancreatic cancer, lung cancer, and breast cancer.

With the Random Forest classifier, we obtained classification accuracies of 86.9%, 86.3%, and 85.1% for the above-mentioned cancers, respectively. Next, different disease datasets were tested on each model, including new miRNA sets for each cancer type from other studies. The models were able to classify the corresponding cancer miRNAs with >90% accuracy and other disease and cancer datasets with <60% accuracy.

With this information, we constructed a hard-voting scheme using the three cancer classification models that is able to perform cancer diagnostics. The results suggest that our method is effective in miRNA–disease association prediction and performing cancer diagnostics.

Sepsis is a systemic inflammatory response syndrome that is caused by infection. It is one of the most common critical diseases clinically. Although more anti-inflammatory drugs are available, the treatment options for sepsis remain limited. The nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome is a multiprotein complex that has been implicated in the development and evolution of sepsis and other autoimmune inflammatory diseases. Although the activation pathway and biological function of NLRP3 in sepsis are becoming clear, the treatment of sepsis by regulating NLRP3 is being explored. This article will review the status of various NLRP3 modulators that might improve the symptoms of sepsis to provide a basis for further research into the treatment of sepsis.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a newly proposed term based on modified criteria. Although nonalcoholic fatty liver disease (NAFLD) has been well-documented as a multisystem disease, research on the correlation of MAFLD and extra-hepatic diseases is limited. This study aimed to clarify the association of MAFLD, as well as NAFLD status with cognitive function.

A total of 5,662 participants 20–59 years of age who underwent cognitive tests and liver ultrasonography in the Third National Health and Nutrition Examination Survey were included in the analysis. Cognitive function was evaluated using three computer-administered tests, the serial digit learning test (SDLT), the simple reaction time test (SRTT) and the symbol digit substitution test (SDST).

Participants with MAFLD had significantly poorer performance on the SRTT [odds ratio (OR) 1.47, 95% confidence interval (CI): 1.14–1.89)]. MAFLD with moderate-severe liver steatosis was associated with higher risks of scoring low in the SDLT (OR 1.37, 95% CI: 1.04–1.82) and SRTT (OR 1.55, 95% CI: 1.19–2.02). NAFLD combined with metabolic dysfunction, instead of NAFLD without metabolic disorders, was associated an increased risk of a low SRTT score (OR 1.44, 95% CI: 1.10–1.82). MAFLD patients had a high probability of fibrosis, prediabetes, and diabetes and were also significantly associated with increased risks based on the SDST or SRTT score.

MAFLD was significantly associated with increased risk of cognitive impairment, especially among MAFLD patients with a high degree of liver fibrosis, moderate-severe steatosis, or hyperglycemia.

Myocardial ischemia/reperfusion (I/R) exacerbates ischemic cell death, in which endoplasmic reticulum (ER) stress and pyroptosis have major implications. Previous evidence has shown that the stimulator of interferon genes/interferon regulatory factor (STING/IRF3) pathway regulates numerous immune and inflammatory responses and is implicated in a range of autoimmune diseases, pathogenic infections, cancer, and cardiovascular diseases. Our most recent study linked STING activation to ER stress and the unfolded protein response (UPR). In addition, STING has a potential role in activating the NOD-like receptor protein 3 (NLRP3)/caspase-1 inflammasome cascade and inducing cell pyroptosis. Therefore, the STING/IRF3 pathway could be a bridge between the upstream ER and oxidative stress and downstream NLRP3/Caspase-1 pathway and pyroptosis and the expression and release of the inflammatory cytokines interleukin-1 (IL-1β) and interleukin-18 (IL-18) triggers, and therefore, myocardial I/R injury. The targeting of STING/IRF3 is of increasing interest in therapeutic agents to reduce I/R injury.

Rifaximin is effective in preventing and treating hepatic encephalopathy (HE). This study aimed to investigate the efficacy and safety of different dosages of rifaximin in the treatment of cirrhotic patients with covert HE (CHE).

In this single-center, randomized, controlled, open-label study, CHE was diagnosed using a combination of the psychometric HE score and the EncephalApp Stroop test. Cirrhotic patients with CHE were recruited and randomly assigned to low-dose rifaximin 800 mg/day, high-dose rifaximin (1,200 mg/day), and control groups, and were treated for 8 weeks. The sickness impact profile (SIP) scale was used to evaluate the health-related quality of life (HRQOL) of patients. Forty patients were included in the study, 12 were assigned to the low-dose group, 14 to the high-dose group, and 14 patients to the control group.

The percentage of patients with CHE reversal was significantly higher in both the low-dose (41.67%, 5/12) and high-dose (57.14%, 8/14) groups than in the control group (7.14%, 1/14) at 8 weeks (p=0.037 and p=0.005, respectively). In addition, both doses of rifaximin resulted in significant improvement of the total SIP score compared with the control group. There were no significant differences in the CHE reversal rate, total SIP score improvement, and incidence of adverse event between the low-dose and high-dose groups (p>0.05).

Low-dose rifaximin reverses CHE and improves HRQOL in cirrhotic patients with comparable effects and safety to high-dose rifaximin.

Transient elastography (TE) has been widely used in nonalcoholic fatty liver disease (NAFLD). The focus of the present study was to provide a reference for researchers and further clarify the research topics, in addition to the frontiers for TE in NAFLD.

Based on previous studies on NAFLD and TE found in the Web of Science (WoS) database, author, institution, country, journal, and keyword co-occurrence analyses were conducted using CiteSpace 5.8 software.

Through data retrieval and review, 1,685 publications were obtained, and the high-yield countries included the US, China, Italy, Japan, and others. The Chinese University of Hong Kong, the University of California, and Yonsei University were all major research institutions. Wong VWS, Rohit Loomba, and Grace Lai-Hung Wong were among the most prolific authors. The clustering directions of the keywords were divided into NAFLD, nonalcoholic steatohepatitis, hepatocyte steatosis, fibrosis, and noninvasive diagnosis. Biological diagnostic markers, epidemiology, management, and fibrosis degree measurement were all high-intensity burst keywords. The research period in the present field could be split into three stages: the exploration period; the experience summary period; and the promotion and application period.

Applying the quantitative advantages of TE to fat content and fibrosis degree in large-scale epidemiological investigations or disease management could become a trending topic in future research into NAFLD. CiteSpace literature analysis could intuitively display the overall research status of TE in NAFLD and provide references for relevant scholars for the topic and research direction.

Cholangiocarcinoma (CCA) is a highly aggressive biliary tree malignancy with intrahepatic and extra-hepatic subtypes that differ in molecular pathogeneses, epidemiology, clinical manifestations, treatment, and prognosis. The overall prognosis and patient survival remains poor because of lack of early diagnosis and effective treatments. Preclinical in vivo studies have become increasingly paramount as they are helpful not only for the study of the fundamental molecular mechanisms of CCA but also for developing novel and effective therapeutic approaches of this fatal cancer. Recent advancements in cell and molecular biology have made it possible to mimic the pathogenicity of human CCA in chemical-mechanical, infection-induced inflammatory, implantation, and genetically engineered animal models. This review is intended to help investigators understand the particular strengths and weaknesses of the currently used in vivo animal models of human CCA and their related modeling techniques to aid in the selection of the one that is the best for their research needs.

The recent pandemic was caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which enters cells through a known enzyme angiotensin-converting enzyme 2 (ACE2) and a protease transmembrane protease serine-2 (TMPRSS2). ACE2 and its expression at the cellular level play a vital role in dilating arteries and preventing hypertension, protecting against lung lesions, and exerting anti-inflammatory and antifibrotic effects. However, TMPRSS2 is an enzyme that in humans is encoded by TMPRSS2. Increased expression of this protease further activates the Coronavirus 2019 (COVID-19) virus and increases its presence in virus-infected cells. The regulation and expression of these cell surface receptors are effective in COVID-19 infection. According to the literature, various factors, such as exercise, can affect the expression of these receptors. The positive effect of regular exercise on ACE2 and TMPRSS2 levels in other diseases has been investigated. At the start of this study, no data were found to indicate that exercise would protect against COVID-19; however, based on previous studies into other diseases, regular exercise before COVID-19 might increase the expression of ACE2, decrease TMPRSS2 expression, and reduce the complications of the disease.

The rapid clearance of hepatitis C virus induced by direct-acting antivirals (DAAs) affects natural killer (NK) cells, but the reported results are not consistent, and the relative mechanism was unclear. This study focused on the dynamic changes of NK cells during and after DAA treatment and analyzed the reasons.

Peripheral blood from 35 chronic hepatitis C patients who were treated with DAAs were collected at baseline and weeks 1, 2, 4, 12, and post-treatment week-12. The frequency, subset, and phenotype of NK cells were assayed by flow cytometry. Lactate dehydrogenase assays were used to evaluate the cytotoxicity of NK cells. Cytokine concentrations were measured with Luminex kits.

All patients achieved a sustained viral response (SVR), and the NK cell frequencies were not changed significantly during DAA therapy. However, the cytotoxicity of NK cells recovered significantly early in week 1, and then continuously decreased below normal levels. The changes of genotypes including NKp30+, NKp46+, and NKG2A+ NK cells were parallel to NK function. The subset of CD56dim NK cells continuously increased and did not return to normal even at 12 weeks after treatment. Interleukin (IL)-2, IL10, IL15, interferon-gamma, and tumor necrosis factor-alpha all increased after week 4, peaked at the end of therapy, and then exhibited varying degrees of reduction with time.

DAA treatment led to transient functional recovery of NK cells in the early stage of treatment, and then continuously decreased to below normal levels. Alterations of NK subsets, phenotypes, and the microenvironment may be involved in the changes.

Ferroptosis is a form of programmed cell necrosis with unique mechanisms. However, the ferroptosis-related genes (FRGs) in the prognosis of hepatocellular carcinoma (HCC) have not been clarified.

In this research, the corresponding clinical data and original mRNA transcripts for HCC patients were acquired from The Cancer Genome Atlas. A new survival model of 10 FRGs was established using the least absolute shrinkage and selection operator regression analysis. The risk scores of these genes and HCC stages were analyzed for independent risk factors for the worst survival. The enrichment scores of different immune cells and immune-related pathways were analyzed by single-sample gene set enrichment analysis (ssGSEA). The prognostic risk characteristics associated with clinical characteristics were analyzed for independent prognostic indicators for the survival of HCC patients.

The 10 gene signatures (ACACA, SLC7A11, SQSTM1, SRXN1, SLC2A1, SLC38A1, MYB, ZFP69B, G6PD, STMN1) were used for a prognostic model for HCC. Compared with the low-risk group, the high-risk group had a worse prognosis and lower survival rate. The validation results revealed that the risk model was a better measure for the prognosis of HCC patients. Combined with the clinical characteristics, a nomogram with good prognostic prediction was established. Functional enrichment analysis revealed that immune-related pathways were highly enriched, including the highly enriched T cell-related pathway.

The risk model for ferroptosis-related risk signatures is valuable for the prognosis of HCC patients. However, our findings require further validation.

Epilepsy is a neural disorder that occurs because of a disruption in neural conductions in various parts of the brain and is mainly characterized by seizures, pensive gaze, involuntary mimics, contractions, meaningless speeches, repetitive movements, and loss of consciousness. The serious side effects of conventional drug delivery systems due to high applied doses, low transition rates to the brain, and limitations of drug application during seizures result in the urgent need for novel drug delivery systems for the enhanced treatment of epilepsy.

In this study, Lacosamide was selected because of its high therapeutic dose, which is due to its low transition to the target site. Microneedle patches were formulated by micromolding of polymers of carboxymethyl cellulose (CMC) and Eudragit S 100 (ES100) for a unique route for applications to reduce the applied dose to minimize the severe side effects. This strategy enhanced brain transition via the nasal route and overcame the blood-brain barrier (BBB) to minimize the applied dose. Characterization studies were performed in detail.

The results revealed that the releases of Lacosamide extended to 96 h with ES100 microneedle patches. In contrast, CMC microneedles released almost all the active ingredients within 1 h due to the hydrophilic nature of the polymer. Stability studies indicated that the formulations were stable at 25 ± 2°C (60 ± 5% Relative Humidity; RH), 40 ± 2°C (75 ± 5% RH) and 5 ± 3°C for 6 months.

By considering the film like structures, polymeric microneedle patches have the potential for Lacosamide delivery through the unconventional nasal route for the improved treatment of epilepsy.

High Mobility Group A2 gene (HMGA2), an oncofetal protein, is normally expressed in fetal development and completely shuts down in almost all organs and tissue types during adulthood. It is upregulated or overexpressed again in certain mesenchymal neoplasms due to chromosomal translocations and in malignant epithelial tumors through transcription regulation. HMGA2 overexpression can either drive tumor development or promote the aggressiveness of tumor growth. Many gynecologic neoplasms, including uterine smooth muscle tumors and ovarian cancer, are associated with HMGA2 overexpression. In this article, we review recent developments in the study of HMGA2 and its expression as a potential biomarker for gynecologic neoplasms and clinic application.

Novel biological agents including cytokines and recombinant fusion proteins are increasingly prescribed for cancer, rheumatologic, autoimmune, and inflammatory diseases, and are currently being evaluated in hepatocellular carcinoma (HCC). They are classified by their mechanism of action and include tumor necrosis factor-alpha (TNF-α) antagonists, T cell mediated antitumor inhibitors, interleukin receptor antagonists, and immune checkpoint inhibitors (ICIs). Some ICIs cause frequent hepatotoxicity with a variable clinical, biochemical, and serological presentation, especially in patients receiving another immunomodulatory agent. Half of the cases of liver damage induced by biological agents spontaneously regress after drug withdrawal, but the others require steroid therapy. Unfortunately, there are no widely accepted recommendation for the use of corticosteroids in these patients, even though international cancer societies have their own guidelines. Differentiating drug-induced autoimmune hepatitis (DIAIH) from classic AIH is challenging for pathologists, but liver biopsy is valuable, particularly in cases with unclear clinical presentation. Interesting, novel histological patterns have been described in liver damage induced by these agents (i.e., endothelitis, ring granuloma and secundary sclerosing cholangitis associated with lymphocytic infiltration of cytotoxic CD8+T cells). Here, we describe the clinical and biochemical characteristics of patients with hepatotoxicity induced by TNF-α antagonists and ICIs. Controversial issues involved in the administration of corticosteroid therapy, and hepatitis B virus (HBV) reactivation induced by immunosuppressive therapy are also discussed.