The absence of representative Epstein-Barr virus-associated intrahepatic cholangiocarcinoma (EBVaICC) cell lines has limited our understanding of the molecular and immunological characteristics of this cancer subtype.

We reviewed patients with metastatic cholangiocarcinoma at Sun Yat-sen University Cancer Center from January 2015 to August 2023. Among them, 22 patients with EBVaICC and 66 patients with non-EBVaICC who received anti-PD1 treatment were included. Additionally, 2 EBV-positive ICC cell lines, RBE-EBV and HuH28-EBV, were developed through cell-to-cell infection. Stable EBV infection and responsiveness to viral reactivation were confirmed. Transcriptomic and bioinformatics analyses were performed, and in vitro experiments examined the immune effects of EBV-positive ICC. Key immune-related genes and cytokines were validated by reverse transcription quantitative polymerase chain reaction and ELISA in cell lines and patient plasma samples.

In this study, we found that patients with EBVaICC showed enhanced immune responses and improved overall and progression-free survival compared to patients with non-EBVaICC. We first successfully established and validated 2 EBV-positive ICC cell lines (RBE-EBV and HuH28-EBV). These cell lines were confirmed for stable EBV infection and displayed responsiveness to viral reactivation, making them suitable for future studies. Transcriptomic analyses and in vitro studies revealed that EBV activated the cGAS-STING pathway, resulting in MHC-I upregulation and CXCL10 secretion in ICC cells, which collectively enhanced CD8+ T cell chemotaxis and cytotoxicity. Furthermore, ELISA analysis showed higher plasma levels of CXCL10 and IFN-γ in patients with EBVaICC, suggesting a potential role for EBV in enhancing immunotherapy sensitivity in this subtype.

The established EBV-positive ICC cell lines revealed enhanced immunogenicity driven by cGAS-STING pathway activation, providing valuable models for future research and insights into the mechanisms of improved immunotherapy sensitivity in EBVaICC.

We aimed to identify the clinicopathological features of lymphoepithelioma-like intrahepatic cholangiocarcinoma (LEL-ICC), and EBV latency pattern and sequence variations of EBV-associated LEL-ICC. The clinical and pathological information of nine cases of LEL-ICC diagnosed in Department of Pathology, the Third Affiliated Hospital of Sun Yat-sen University from January 2015 to October 2022 were collected. EBV latency pattern and sequence variations of EBV-associated LEL-ICC were investigated. There were 3 males and 6 females with a median age of 47 years in our cases. The morphological feature was the poorly differentiated or undifferentiated tumor cells surrounded by densely tumor infiltrating lymphocytes. Immunohistochemical staining showed the tumor cells were positive for CK7 and/or CK19, negative for HepPar-1 and Arginase-1. Eight cases showed positive nuclear signal in tumor cells by in situ hybridization of EBER. Five surgical specimens of EBV-associated LEL-ICC were positive for EBNA1 and negative for EBNA2, LMP1 and ZEBRA by immunohistochemestry. The type A strain, type f, type I, and del-LMP1 variants were found in EBV-associated LEL-ICC patients. LEL-ICC is a rare subtype of ICC and the accurate diagnosis mainly depends on typical histopathology, immunohistochemistry and in situ hybridization for EBER. The latency pattern in EBV-associated LEL-ICC patients was probably latency type I, the mainly EBV genotypes were perhaps type A strain, type f, type I and del-LMP1 variants.

Epstein-Barr virus (EBV), the first identified human tumor virus, significantly influences the immune microenvironment of associated cancers. EBV-induced expression of viral antigens by tumor cells triggers immune recognition and elicits a pro-inflammatory response. While mild inflammation may help eliminate malignant cells, intense inflammation can accelerate tumor progression. Moreover, EBV can establish lifelong latency in human hosts, characterized by low immunogenicity of its proteins and noncoding RNAs. This enables tumor cells to evade immune detection and impair immune cell function, disrupting immune homeostasis. Consequently, EBV-associated malignancies pose a considerable public health challenge globally, often complicating the prognosis of cancer patients under conventional treatment. With deeper research into the oncogenic expressions and mechanisms of EBV, novel targeted therapies against EBV are gaining prominence. This review discusses recent advancements in understanding how EBV helps tumor cells evade immune surveillance and induce immune dysfunction. It also examines the clinical potential of targeting EBV-associated tumors, providing fresh perspectives on the mechanisms and therapeutic strategies for these cancers.

Epstein-Barr virus (EBV), the first human oncovirus discovered in 1964, has become a focal point in virology, immunology, and oncology because of its unique biological characteristics and significant role in human diseases. As we commemorate the 60th anniversary of EBV's discovery, it is an opportune moment to reflect on the major advancements in our understanding of this complex virus. In this review, we highlight key milestones in EBV research, including its virion structure and life cycle, interactions with the host immune system, association with EBV-associated diseases, and targeted intervention strategies.

WWP1, a member of the C2-WW-HECT E3 ligase family, is an E3 ubiquitin-protein ligase containing WW domains. This enzyme plays a critical role in regulating diverse cellular processes. Its expression is modulated by various factors and non-coding RNAs, resulting in ubiquitination that affects substrate protein degradation. WWP1 demonstrates a dual function, acting predominantly as an oncogene in tumors but occasionally as a tumor suppressor. This review summarizes WWP1's biological roles, therapeutic potential in oncology, upstream regulatory factors, and downstream substrates. It aims to promote research on WWP1's antitumor effects, improve understanding of its role in tumorigenesis, and support the development of targeted therapies.

Cholangiocarcinoma is the second most common primary liver cancer, and its global incidence has increased in recent years. Radical surgical resection and systemic chemotherapy have traditionally been the standard treatment options. However, the complexity of cholangiocarcinoma subtypes often presents a challenge for early diagnosis. Additionally, high recurrence rates following radical treatment and resistance to late-stage chemotherapy limit the benefits for patients. Immunotherapy has emerged as an effective strategy for treating various types of cancer, and has shown efficacy when combined with chemotherapy for cholangiocarcinoma. Current immunotherapies targeting cholangiocarcinoma have predominantly focused on T lymphocytes within the tumor microenvironment, and new immunotherapies have yielded unsatisfactory results in clinical trials. Therefore, it is essential to achieve a comprehensive understanding of the unique tumor microenvironment of cholangiocarcinoma and the pivotal role of T lymphocytes within it. In this review, we describe the heterogeneous immune landscape and intercellular communication in cholangiocarcinoma and summarize the specific distribution of T lymphocytes. Finally, we review potential immune checkpoints in cholangiocarcinoma.

Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare subtype of non-small-cell lung cancer. This study aims to compare the efficacy and safety of perioperative PD-1/PD-L1 inhibitor plus chemotherapy versus chemotherapy alone in stage II-IIIB PLELC patients.

This retrospective study included stage II-IIIB PLELC patients. Patients received either perioperative immuno-chemotherapy (IO-Chemo) or chemotherapy alone (Chemo). Data on patient characteristics, treatments, efficacy, toxicities, and pathology were collected. Primary endpoints were major pathological response (MPR) and event-free survival (EFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), and adverse events (AEs).

A total of 72 patients were included in this retrospective study. The ORR was 75.0 % in the IO-Chemo group and 58.3 % in the Chemo group (odds ratio [OR] 0.47 [95 % CI 0.15-1.42]; P = 0.200). The percentage of patients achieving major pathological response (MPR) was 54.2 % in the IO-Chemo group and 12.5 % in the Chemo group (OR 1.91 [95 % CI 1.22-2.99]; P < 0.001). Pathological complete response (pCR) was achieved by 33.3 % of patients in the IO-Chemo group compared to 4.2 % in the Chemo group (OR 1.44 [95 % CI 1.08-1.92]; P = 0.002). The median EFS was not reached in the IO-Chemo group, whereas it was 35.0 months in the Chemo group (95 % CI 14.2-55.8; hazard ratio [HR] 0.42 [95 % CI 0.19-0.93]; P = 0.031). Median overall survival (OS) was not reached after a median follow-up of 47.0 months. Multivariate analysis indicated that the PD-1/PD-L1 inhibitor combination was independently associated with longer EFS (HR = 0.32 [95 % CI 0.11-0.95]; P = 0.043). AEs of any grade occurred in 91.7 % of the patients in the IO-Chemo group versus 89.6 % in the Chemo group.

In patients with resectable PLELC, perioperative PD-1/PD-L1 inhibitor plus chemotherapy resulted in significantly longer EFS and a higher percentage of patients achieving MPR and pCR than chemotherapy alone, with a tolerable safety profile.

The prognosis for advanced intrahepatic cholangiocarcinoma (iCCA) is poor, and there remains an urgent need to develop efficient systemic therapy. The efficacy of Pembrolizumab immunotherapy combined with lenvatinibin in iCCA is still unclear. The role of Epstein-Barr-virus (EBV) as a biomarker in iCCA for response to immunotherapy needs further exploration.

We report a case of a 60-year-old female with EBV-associated advanced iCCA (EBVaiCCA) who progressed after first-line therapy. She accomplished an available response to the combination therapy of pembrolizumab with lenvatinib, with overall survival of 20 months.

As far as we know, this is the first case report about the application of Pembrolizumab with lenvatinib for EBVaiCCA patients. This case indicates that the combination of immunotherapy and antiangiogenic therapy provides a glimmer of hope for advanced EBVaiCCA patients.

Intrahepatic cholangiocarcinoma is a primary liver malignancy with poor prognosis and limited treatment options. Lymphoepithelioma-like intrahepatic cholangiocarcinoma is an exceedingly rare variant of intrahepatic cholangiocarcinoma that histologically resembles nasopharyngeal carcinoma, previously known as lymphoepithelioma. It was first reported by Hsu et al in 1996 and they were able to show the presence of Epstein-Barr virus in tumor cells. Even though several risk factors for the development of intrahepatic cholangiocarcinoma have been identified, the association between Epstein-Barr virus and intrahepatic cholangiocarcinoma is relatively rare. This article aims at discussing a female patient's lymphoepithelioma-like intrahepatic cholangiocarcinoma tumor and summarizing the existing literature on Epstein-Barr virus-positiveLymphoepithelioma-like intrahepatic cholangiocarcinoma, including the clinical features, pathogenesis, diagnostic challenges, treatment approaches, prognosis, and histopathologic description.

Pediatric lymphoepithelioma-like carcinoma (pLELC) is a rare neoplasm with unclear prognosis, genome, and tumor microenvironment. Our study aims to elucidate its genomic and clinical characteristics.

Forty-one pLELC patients were enrolled at Sun Yat-sen University Cancer Center from 2012 to 2023. Kaplan-Meier analysis was utilized to estimate progression-free survival (PFS) and overall survival (OS). Baseline plasma protein levels from 16 patients and 9 health controls were analyzed using a Olink proteomic platform and whole exon sequence (WES) was performed on 11 tumor samples from 10 pediatric patients. Immunohistochemistry (IHC) for PD-L1was performed, and the infiltration of CD4+ or CD8+ T cells was evaluated.

Patients receiving anti PD-1 in combination with chemotherapy had a 1-year PFS of 100%, while the 2-year PFS was 72.92% (95%CI: 46.80‒100%). The 1-year OS for patients receiving anti PD-1 in combination with chemotherapy was 100%, and the 2-year OS was 87.5% (95%CI: 67.34-100%). Significant upregulation of immune checkpoint molecules was detected including LAG-3, PD-L1, and galectin-9 in LELC group by proteomic analysis (P < 0.05). The mutational landscape of pediatric LELC presented more genes mutated in pathways associated with immune, DNA repair, cell cycle and NOTCH. Pathway analysis of mutational profiles indicated DNA repair pathway and SWI/SNF complex were potential drug targets for pLELC patients. All the pediatric LELC patients evaluated exhibited positive PD-L1 expression and CD4+/CD8+ T cells infiltration.

Our findings indicate a promising response rate associated with the combination of PD-1 antibody treatment and chemotherapy in pediatric patients with LELC, providing a theoretical basis for targeting DNA repair pathways. These outcomes suggest that clinical trials involving immune checkpoint inhibitors are warranted in pediatric patients with LELC.

Intrahepatic cholangiocarcinoma (ICC) ranks as the second most primary liver cancer that often goes unnoticed with a high mortality rate. Hepatectomy is the main treatment for ICC, but only 15% of patients are suitable for surgery. Despite advancements in therapeutic approaches, ICC has an unfavorable prognosis, largely due to lymph node metastasis (LNM) that is closely linked to the elevated recurrence rates. Consequently, the identification of precise and suitable techniques for the detection and staging of LNM assumes paramount importance for ICC therapy. While preoperative imaging plays a crucial role in ICC diagnosis, its efficacy in accurately diagnosing LNM remains unsatisfactory. The inclusion of lymph node dissection as part of the hepatectomy procedures is significant for the accurate pathological diagnosis of LNM, although it continues to be a topic of debate. The concept of sentinel lymph node in ICC has presented a novel and potentially valuable approach for diagnosing LNM. This review aims to explore the current state and prospects of LNM in ICC, offering a promising avenue for enhancing the clinical diagnosis and treatment of ICC to improve patient prognosis.

Pancreatic cancer is a common malignancy with poor prognosis and limited treatment. Here we aimed to investigate the role of host chromosomal instability (CIN) and tumor microbiome in the prognosis of pancreatic cancer patients.

One hundred formalin-fixed paraffin-embedded (FFPE) pancreatic cancer samples were collected. DNA extracted from FFPE samples were analyzed by low-coverage whole-genome sequencing (WGS) via a customized bioinformatics workflow named ultrasensitive chromosomal aneuploidy detector.

Samples were tested according to the procedure of ultrasensitive chromosomal aneuploidy detector (UCAD). We excluded 2 samples with failed quality control, 1 patient lost to follow-up and 6 dead in the perioperative period. The final 91 patients were admitted for the following analyses. Thirteen (14.3%) patients with higher CIN score had worse overall survival (OS) than those with lower CIN score. The top 20 microbes in pancreatic cancer samples included 15 species of bacteria and 5 species of viruses. Patients with high human herpesvirus (HHV)-7 and HHV-5 DNA reads exhibited worse OS. Furthermore, we classified 91 patients into 3 subtypes. Patients with higher CIN score (n =13) had the worst prognosis (median OS 6.9 mon); patients with lower CIN score but with HHV-7/5 DNA load (n = 24) had worse prognosis (median OS 10.6 mon); while patients with lower CIN score and HHV-7/5 DNA negative (n = 54) had the best prognosis (median OS 21.1 mon).

High CIN and HHV-7/5 DNA load were associated with worse survival of pancreatic cancer. The novel molecular subtypes of pancreatic cancer based on CIN and microbiome had prognostic value.

The incidence rate of intrahepatic cholangiocarcinoma (ICC), which has a poor prognosis, is rapidly increasing. To investigate the intratumor heterogeneity in ICC, we analyzed single-cell RNA sequencing data from the primary tumor and adjacent normal tissues of 14 treatment-naïve patients. We identified 10 major cell types, along with 45 subclusters of cells. Notably, we identified a fibroblast cluster, Fibroblast_LUM+, which was preferably enriched in tumor tissues and actively interacted with cholangiocytes. LGALS1 was verified as a marker gene of Fibroblast_LUM+, contributing to the malignant phenotype of ICC. Higher amount of LGALS1+ fibroblasts was associated with poorer overall survival of ICC patients. Mechanistically, LGALS1+ fibroblasts activated the proliferation and migration of tumor cells by upregulating the expression levels of CCR2, ADAM15, and β-integrin. Silencing LGALS1 in cancer-associated fibroblasts (CAFs) suppressed CAF-augmented tumor cell migration and invasion in vitro as well as tumor formation in vivo, suggesting that blockade of LGALS1 serves as a potential therapeutic approach for ICC. Taken together, our single-cell analysis provides insight into the interaction between malignant cells and specific subtypes of fibroblasts, which contributes to better understanding of the intratumor heterogeneity in ICC and the development of novel strategies for the treatment of ICC by targeting fibroblasts in the tumor microenvironment.

Cholangiocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts, with poor prognosis and limited treatment options. Traditional therapies, such as surgery, chemotherapy, and radiation, have shown limited efficacy, especially in advanced cases. Recent advancements in immunotherapy, particularly T cell-based therapies like chimeric antigen receptor T (CAR T) cells, tumor-infiltrating lymphocytes (TILs), and T cell receptor (TCR)-based therapies, have opened new avenues for improving outcomes in CCA. This review provides a comprehensive overview of the current state of T cell therapies for CCA, focusing on CAR T cell therapy. It highlights key challenges, including the complex tumor microenvironment and immune evasion mechanisms, and the progress made in preclinical and clinical trials. The review also discusses ongoing clinical trials targeting specific CCA antigens, such as MUC1, EGFR, and CD133, and the evolving role of precision immunotherapy in enhancing treatment outcomes. Despite significant progress, further research is needed to optimize these therapies for solid tumors like CCA. By summarizing the most recent clinical results and future directions, this review underscores the promising potential of T cell therapies in revolutionizing CCA treatment.

Lymphoepithelioma-like intrahepatic cholangiocarcinoma (LEL-ICC) is a rare liver tumor that appears as a hepatic nodule on imaging with a specific pathological pattern, and the definitive diagnosis relies on its pathological histomorphology, immunophenotype, and Epstein-Barr encoding region test. Radical surgical resection is the primary treatment modality, and immunotherapy is expected to be a new adjuvant treatment option. LEL-ICC with massive multinucleated giant cell infiltration has not been reported so far. In this article, we report a patient with LEL-ICC showing massive multinucleated giant cell infiltration, review the relevant literature, and analyze its clinicopathological features and prognosis to accumulate experience for the accurate diagnosis of LEL-ICC.

Biliary tract cancers (BTCs) have rising incidence and mortality rates. Chemotherapy's limited efficacy has led to exploring new treatments like immunotherapy. which offers modest benefits. Moreover, the identification of reliable predictive biomarkers for immune checkpoint therapy in BTCs remains elusive, hindering personalized treatment strategies. This review provides an overview of the current landscape of emerging biomarkers for immunotherapy response in BTCs. We discuss the incremental benefits of combination therapy and the evolving role of immunotherapy in managing advanced BTC. Additionally, we highlight the need for robust predictive biomarkers to optimize treatment outcomes and foster a more individualized approach to patient care. We aim to identify promising research avenues and strategies to enhance therapeutic efficacy and patient survival in BTCs.

Inactivated vaccines lack the capability to serologically differentiate between infected and vaccinated animals, thereby impeding the effective eradication of pathogen. Conversely, vaccines based on virus-like particles (VLPs) emulate natural viruses in both size and antigenic structure, presenting a promising alternative to overcome these limitations. As the complexity of swine infectious diseases increases, the increase of vaccine types and doses may intensify the stress response. This exacerbation can lead to diminished productivity, failure of immunization, and elevated costs. Given the critical dynamics of co-infection and the clinically indistinguishable symptoms associated with foot-and-mouth disease virus (FMDV) and senecavirus A (SVA), there is a dire need for an efficacious intervention. To address these challenges, we developed a combined vaccine composed of three distinct VLPs, specifically designed to target SVA and FMDV serotypes O and A. Our research demonstrates that this trivalent VLP vaccine induces antigen-specific and robust serum antibody responses, comparable to those produced by the respective monovalent vaccines. Moreover, the immune sera from the combined VLP vaccine strongly neutralized FMDV type A and O, and SVA, with neutralization titers comparable to those of the individual vaccines, indicating a high level of immunogenic compatibility among the three VLP components. Importantly, the combined VLPs vaccines-immunized sera conferred efficient protection against single or mixed infections with FMDV type A and O, and SVA viruses in pigs. In contrast, individual vaccines could only protect pigs against homologous virus infections and not against heterologous challenges. This study presents a novel combined vaccines candidate against FMD and SVA, and provides new insights for the development of combination vaccines for other viral swine diseases.

Biliary tract cancer stands as a prevalent illness, posing significant risks to human health, where immune cells are pivotal in both its development and recovery processes. Due to the diverse functionalities exhibited by different immune cell phenotypes within the organism, and the relatively limited research on their relationship with biliary tract cancer, this study employed Mendelian randomization (MR) to explore their potential association, thereby aiding in a better understanding of the causal link between immune cell phenotypes and biliary tract cancer.

In this study, the causative association of 731 immunophenotype with biliary tract cancer was established using publicly accessible genome-wide association study (GWAS) genetic data through two-sample MR analysis. Sensitivity analyses assess horizontal pleiotropy and heterogeneity of the study findings.

Among the 731 immunophenotypes examined, a total of 26 immune cell phenotypes were found to exhibit positive results, indicating a significant association with the risk of biliary tract cancer. We confirmed that among these 26 types of immune cells, there are primarily 13 types of B cells; three types of classical dendritic cells (CDCs), including CD80 on myeloid DC, HLA DR on myeloid DC, and Myeloid DC %DC; one type of mature stage T cell,CD4RA on TD CD4+; six types of regulatory T cells; and three types of myeloid cells.

Cholangiocarcinoma (CCA), a rare yet notably aggressive cancer, has experienced a surge in incidence in recent years. Presently, surgical resection remains the most effective curative strategy for CCA. Nevertheless, a majority of patients with CCA are ineligible for surgical removal at the time of diagnosis. For advanced stages of CCA, the combination of gemcitabine and cisplatin is established as the standard chemotherapy regimen. Despite this, treatment efficacy is often hindered by the development of resistance. In recent times, immune checkpoint inhibitors, particularly those that block programmed death 1 and its ligand (PD1/PD-L1), have emerged as promising strategies against a variety of cancers and are being increasingly integrated into the therapeutic landscape of CCA. A growing body of research supports that the use of PD1/PD-L1 monoclonal antibodies in conjunction with chemotherapy may significantly improve patient outcomes. This article seeks to meticulously review the latest studies on PD1/PD-L1 involvement in CCA, delving into their expression profiles, prognostic significance, contribution to oncogenic processes, and their potential clinical utility.

The tumor microbiome has been characterized in several malignancies; however, no previous studies have investigated its role in intrahepatic cholangiocarcinoma (ICC). Hence, we explored the tumor microbiome and its association with prognosis in ICC.

One hundred and twenty-one ICC tumor samples and 89 adjacent normal tissues were profiled by 16S rRNA sequencing. Microbial differences between tumor and adjacent nontumoral liver tissues were assessed. Tumor microbial composition was then evaluated to detect its association with prognosis. Finally, a risk score calculated by the tumor microbiota was accessed by the least absolute shrinkage and selector operator method (Lasso) to predict prognosis of ICC.

The tumor microbiome displayed a greater diversity than that in adjacent nontumoral liver tissues. Tumor samples were characterized by a higher abundance of Firmicutes, Actinobacteria, Bacteroidetes, and Acidobacteriota. Higher tumor microbial α diversity was associated with lymph node metastasis and predicted shortened overall survival (OS) and recurrence-free survival (RFS). A total of 11 bacteria were selected to generate the risk score by Lasso. This score showed potential in predicting OS, and was an independent risk factor for OS.

In conclusion, our study characterized the tumor microbiome and revealed its role in predicting prognosis in ICC.

Renal cell carcinoma is the most common form of kidney cancer which is a global threat to human health, needing to explore effective therapeutic targets and treatment methods. Aurora kinase B acts as an important carcinogenic role in various kinds of tumors, while its mechanism in renal cell carcinoma is indistinct. Herein we explore the underlying mechanism of Aurora kinase B in renal cell carcinoma.

Label-free quantitative proteomics analysis was employed to analyze the differentially expressed proteins in 786-O cells which were treated with si-Aurora kinase B or si-ctrl. In the current study, 169 differentially expressed proteins were identified. The top 10 upregulated proteins were MX2, IFI44L, ISG20, DDX58, F3, IFI44, ECE1, PRIC285, NIT1, and IFIT2. The top 10 downregulated proteins were FKBP9, FSTL1, DDAH1, TGFB2, HMGN3, COIL, FAM65A, PTPN14, ARFGAP2, and EIF2C2. GO enrichment analysis showed that these differentially expressed proteins participated in biological processes, including defense response to virus, response to virus, and type I interferon signaling pathway. These differentially expressed proteins participated in cellular components, including focal adhesion, cell-substrate adherens junction, cell-substrate junction, and endoplasmic reticulum lumen. These differentially expressed proteins participated in molecule functions, including guanyl nucleotide binding, nucleotidase activity, double-stranded RNA binding, 2'-5'-oligoadenylate synthetase activity, and virus receptor activity. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the significantly changed proteins including OAS3, OAS2, JAK1, TAP1, and RAC1 were involved in Epstein-Barr virus infection.

Taken together, our results demonstrate the possible mechanisms that Aurora kinase B may participate in renal cell carcinoma. These findings may provide insights into tumorigenesis and a theoretical basis for developing potential therapies of renal cell carcinoma.

Cholangiocarcinoma represents a malignant neoplasm originating from the hepatobiliary tree, with a subset of tumors developing inside the liver. Intrahepatic cholangiocarcinomas (ICC) commonly exhibit an asymptomatic presentation, rendering both diagnosis and treatment challenging. Cuproptosis, an emerging regulated cell death pathway induced by copper ions, has garnered attention recently. As cancer cells show altered copper metabolism and comparatively higher copper needs, cuproptosis may play a role in the development of ICC. However, studies investigating this possibility are currently lacking.

Single-cell and bulk RNA sequence data were analyzed, and correlations were established between the expression of cuproptosis-related molecules and ICC patient survival. Genes with predicting survival were used to create a CUPT score using Cox and LASSO regression and tumor mutation burden (TMB) analysis. The CIBERSORT software was employed to characterize immune cell infiltration within the tumors. Furthermore, immune infiltration prediction, biological function enrichment, and drug sensitivity analyses were conducted to explore the potential implications of the cuproptosis-related signature. The effects of silencing solute carrier family 39 member 4 gene (SLC39A4) expression using siRNA were investigated using assays measuring cell proliferation, colony formation, and cell migration. Key genes of cuproptosis were detected by western blotting.

The developed CUPT score divided patients into high and low CUPT score groups. Those with a low score had significantly better prognosis and longer survival. In contrast, high CUPT scores were associated with worse clinical outcomes and significantly higher TMB. Comparisons of the two groups also indicated differences in the immune infiltrate present in the tumors. Finally, we were able to identify 95 drugs potentially affecting the cuproptosis pathway. Some of these might be effective in the treatment of ICC. The in vitro experiments revealed that suppressing the expression of SLC39A4 in ICC cell lines resulted in reduced cell proliferation, colony formation, and cell migration. It also led to an increase in cell death and the upregulation of key genes associated with cuproptosis, namely ferredoxin 1 (FDX1) and dihydrolipoyl transacetylase (DLAT). These findings strongly suggest that this cuproptosis-associated molecule may play a pivotal role in the development and metastasis of ICC.

Changes in the expression of a cuproptosis-related gene signature can predict the clinical prognosis of ICC with considerable accuracy. This supports the notion that cuproptosis influences the diversity and complexity of the immune microenvironment, mutational landscape, and biological behavior of ICC. Understanding this pathway better may hold promise for the development of innovative strategies in the management of this disease.

Cholangiocarcinoma (CCA) is a highly aggressive hepatobiliary malignancy, second only to hepatocellular carcinoma in prevalence. Despite surgical treatment being the recommended method to achieve a cure, it is not viable for patients with advanced CCA. Gene sequencing and artificial intelligence (AI) have recently opened up new possibilities in CCA diagnosis, treatment, and prognosis assessment. Basic research has furthered our understanding of the tumor-immunity microenvironment and revealed targeted molecular mechanisms, resulting in immunotherapy and targeted therapy being increasingly employed in the clinic. Yet, the application of these remedies in CCA is a challenging endeavor due to the varying pathological mechanisms of different CCA types and the lack of expressed immune proteins and molecular targets in some patients. AI in medical imaging has emerged as a powerful tool in this situation, as machine learning and deep learning are able to extract intricate data from CCA lesion images while assisting clinical decision making, and ultimately improving patient prognosis. This review summarized and discussed the current immunotherapy and targeted therapy related to CCA, and the research progress of AI in this field.

Myosin heavy chain gene 7 (MYH7), a sarcomeric gene encoding the myosin heavy chain (myosin-7), has attracted considerable interest as a result of its fundamental functions in cardiac and skeletal muscle contraction and numerous nucleotide variations of MYH7 are closely related to cardiomyopathy and skeletal muscle myopathy. These disorders display significantly inter- and intra-familial variability, sometimes developing complex phenotypes, including both cardiomyopathy and skeletal myopathy. Here, we review the current understanding on MYH7 with the aim to better clarify how mutations in MYH7 affect the structure and physiologic function of sarcomere, thus resulting in cardiomyopathy and skeletal muscle myopathy. Importantly, the latest advances on diagnosis, research models in vivo and in vitro and therapy for precise clinical application have made great progress and have epoch-making significance. All the great advance is discussed here.

Cholangiocarcinoma (CHOL) is a malignant disease that affects the digestive tract, and it is characterized by a poor prognosis. This research sought to explore the involvement of cuproptosis-related lncRNAs (CRLs) in the prognostic prediction and immune infiltration of cholangiocarcinoma.

The expression profiles and clinical data of CHOL patients were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and CRLs were defined via co-expression analysis. Two molecular clusters distinguished by cuproptosis-related genes (CRGs) were produced. Then a risk signature consisted by four CRLs was formed, and all samples were separated into low- and high-risk groups using a risk score. Kaplan-Meier survival analysis, principal component analysis, differentially expressed analysis, immune cell infiltration analysis, and sensitivities analysis of chemotherapy drugs were conducted between the two groups. Simultaneously, the expression values of four lncRNAs confirmed by real-time PCR in our own 20 CHOL samples were brought into the risk model.

The CHOL samples could be differentiated into two molecular clusters, which displayed contrasting survival times. Additionally, patients with higher risk scores had significantly worse prognosis compared to those in the low-risk group. Furthermore, both immune infiltration and enrichment analysis revealed significant discrepancies in the tumor immune microenvironment (TIME) between different risk groups. Moreover, the predictive power and the correlation with CA19-9 and CEA of risk signature were validated in our own samples.

We developed a risk signature which could serve as an independent prognostic factor and offer a promising prediction for not only prognosis but also TIME in CHOL patients.

Classical swine fever virus (CSFV) is a highly contagious pathogen causing significant economic losses in the swine industry. Conventional inactivated or attenuated live vaccines for classical swine fever (CSF) are effective but face biosafety concerns and cannot distinguish vaccinated animals from those infected with the field virus, complicating CSF eradication efforts. It is noteworthy that nanoparticle (NP)-based vaccines resemble natural viruses in size and antigen structure, and offer an alternative tool to circumvent these limitations. In this study, we developed an innovative vaccine delivery scaffold utilizing self-assembled mi3 NPs, which form stable structures carrying the CSFV E2 glycoprotein. The expressed yeast E2-fused protein (E2-mi3 NPs) exhibited robust thermostability (25 to 70 °C) and long-term storage stability at room temperature (25 °C). Interestingly, E2-mi3 NPs made with this technology elicited enhanced antigen uptake by RAW264.7 cells. In a rabbit model, the E2-mi3 NP vaccine against CSFV markedly increased CSFV-specific neutralizing antibody titers. Importantly, it conferred complete protection in rabbits challenged with the C-strain of CSFV. Furthermore, we also found that the E2-mi3 NP vaccines triggered stronger cellular (T-lymphocyte proliferation, CD8+ T-lymphocytes, IFN-γ, IL-2, and IL-12p70) and humoral (CSFV-specific neutralizing antibodies, CD4+ T-lymphocytes, and IL-4) immune responses in pigs than the E2 vaccines. To sum up, these structure-based, self-assembled mi3 NPs provide valuable insights for novel antiviral strategies against the constantly infectious agents.

Epstein-Barr virus (EBV)-positive plasma cell neoplasms (PCNs) in immunocompetent patients are a rare entity, the clinicopathological and prognostic features of which have not been well characterized. Fifteen cases of EBV-positive PCN arising in immunocompetent patients from south China were retrospectively analyzed, and an additional 44 cases from the literature were reviewed. The overall EBV-positive rate defined by EBV-encoded small RNAs (EBERs) in-situ hybridization of PCNs was 12.3% (15/122), and it was significantly higher in plasmacytoma (17.1%, 13/76) than in plasma cell myeloma/multiple myeloma (4.3%, 2/46; P=0.031). The age of the patients ranged from 17 to 79 years, with a median age of 56 years. There was a large preponderance of men, with a male-to-female ratio of 4:1. Solitary plasmacytoma of bone (23.8%, 5/21) had comparable EBV-encoded small RNAs-positive rates with extramedullary plasmacytoma arising in the upper respiratory tract (19.5%, 8/41; P=0.949). Anaplastic and classic cytologic appearance was observed in 61.5% (8/13) and 38.5% (5/13) of EBV-positive plasmacytomas, respectively. Cases with an anaplastic cytologic appearance had a significantly higher Ki-67 proliferation index than those with a classic cytologic appearance (median: 55% vs. 10%, P=0.001). In the combined cohorts, anaplastic/plasmablastic cytologic appearance was significantly more common in extramedullary plasmacytoma arising in the upper respiratory tract (72.0%, 18/25) than outside the upper respiratory tract (11.1%, 1/9; P=0.006). Among the 59 cases of EBV-positive PCN, survival data of 34 cases were available for analysis, including 30 cases of plasmacytoma and 4 cases of plasma cell myeloma/multiple myeloma. There was no statistically significant difference in overall survival between patients with EBV-positive plasmacytomas in the combined cohorts and EBV-negative plasmacytomas in the present cohort. The prevalence of EBV in PCN in immunocompetent patients varies according to histologic subtype and tumor location. Compared with EBV-negative cases, EBV-positive plasmacytomas tend to have an anaplastic/plasmablastic cytologic appearance. No significant impact of EBV infection on clinical outcomes is observed in the limited number of reported cases.

IL-33/ST2 signaling plays crucial roles in the development and progression of various human malignancies. However, its significance in intrahepatic cholangiocarcinoma (ICC) still remains unclear.

This study aimed to investigate the expression of IL-33/ST2 signaling and its correlations with macrophage heterogeneity and ICC patients' clinicopathologic features.

The expression of different phenotype macrophage markers and IL-33/ST2 signalingrelated markers was detected. The correlation between L-33/ST2 signaling and different phenotype macrophage markers as well as ICC patients' clinicopathologic data was evaluated.

Massive heterogeneous cancer cells and PAS-positive cells were observed in tumor tissues. CD68-positive cells accumulated in tumor tissues and expression of both M1 phenotype markers and M2 phenotype macrophage markers was higher in tumor samples than para-carcinoma samples. However, M2 phenotype macrophages represented the dominant macrophage population in ICC tissues. Plasma levels of IL-33, ST2, and MIF were evidently enhanced in ICC patients compared to healthy controls. IL-33/ST2 signaling-related markers exhibited a massive increase in tumor samples than para-carcinoma samples. IL-33 and ST2 expression in ICC tissues was positively associated with M1 and M2 phenotype macrophages. Plasma levels of IL-33, ST2, and MIF were correlated with the diameter of tumor lesions, lymph node metastasis, TNM stage, and tumor differentiation degree. Multivariate analysis demonstrated IL-33 expression to exhibit a correlation with the diameter of tumor lesions, lymph node metastasis, and TNM stage. Additionally, there was a relationship observed between ST2, MIF expression, and diameter of tumor lesions plus TNM stage.

IL-33/ST2 signaling exhibited a positive relationship with macrophage heterogeneity in ICC tissues, and upregulated levels of IL-33, ST2, and MIF were associated with aggressive clinicopathologic characteristics. These findings may provide promising diagnostic biomarkers and potential therapeutic strategies for ICC patients targeting IL-33/ST2 signaling.

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.

Gastrointestinal (GI) cancers are an increasing global health challenge. Viral diseases play an important role in the development of GI cancers. For example, Epstein-Barr virus, which belongs to the human herpesvirus family, is a well-recognized risk factor for the development of gastric cancer. The purpose of this study was to investigate a possible association between varicella-zoster virus reactivation and subsequent diagnosis of GI cancer.

In this retrospective cohort study, a total of 103,123 patients with a first diagnosis of herpes zoster (HZ) between 2005 and 2021 were propensity score matched to a cohort of 103,123 patients without HZ. Patient data was extracted from the Disease Analyzer database (IQVIA). The incidence of GI cancer was compared as a function of HZ. Cox regression analysis was used to examine the association between HZ and GI cancer.

Over a follow-up period of up to 10 years, the incidence of GI cancer did not differ between the two cohorts (HZ cohort 2.26 cases per 1000 patient-years vs. non-HZ cohort 2.37 cases per 1000 patient-years, p = 0.548). In regression analysis, HZ was not associated with an increased risk of developing GI cancer (HR: 0.97; 95% CI 0.89-1.05). Furthermore, no significant effect of the presence of HZ on the incidence of different GI cancer entities was found.

In this retrospective cohort study consisting of well-matched patients, we observed no significant association between a HZ infection and the development of GI cancer during a long-term follow-up.

Epstein-Barr virus-related lymphoepithelioma-like cholangiocarcinoma (EBV-LELCC), a subtype of intrahepatic cholangiocarcinoma (IHCC), is an extremely rare cancer. To date, only few cases have been reported. Therefore, more studies are needed to provide new insights into its clinicopathological characteristics and treatment.

We retrospectively collected data from 16 EBV-LELCC patients admitted to our hospital between January 2013 and February 2022. We summarized their clinical characteristics and analyzed the genomic features of 5 patients by whole-exon sequencing. In addition, the Kaplan-Meier method was used to assess the prognostic differences between EBV-LELCC and EBV-negative IHCC.

A total of 16 EBV-LELCC patients aged between 35 and 70 were included in this study and were characterized by female predominance. Eight genetic mutations including KMT2C, ARID1B, BAZ1A, NPM1, POLE, PER3, TOPBP1, USP1 were identified from 5 patients. There were 11 stage I, 2 stage III and 3 stage IV patients in this study. The overall survival of stage I and stage III EBV-LELCC patients after radical surgery was significantly better than that of EBV-negative IHCC patients with matched stage (p = 0.0119). Notably, a stage IV patient treated with a variety of antitumor modalities including surgery, interventional therapy, radiotherapy, chemotherapy, targeted therapy and immunotherapy achieved long-term survival of more than seven years.

Altogether, EBV-LELCC presents a more favorable prognosis than IHCC. This study suggests that patients with early EBV-LELCC have a good prognosis after radical surgery, and even patients with advanced EBV-LELCC are expected to have a longer survival under appropriate and timely treatment. For such a rare cancer with unique clinicopathological features and molecular patterns, more research is needed to facilitate its diagnosis and treatment.

Lymphoepithelioma like cholangiocarcinoma (LELCC) is a rare low-grade malignancy with a favorable prognosis. This sarcoma has a strong association with Epstein-Barr virus (EBV). Most of these have been benign, with some malignant instances noted as well. In our case, this tumor exhibited imaging characteristics of HCC. When patients showed recurrent tonsillitis at an early age, AFP did not change significantly, and there was no previous history of hepatitis B. In such scenario, diagnosis of LELCC should be considered.

The development of cholangiocarcinoma spans years, if not decades, during which the immune system becomes corrupted and permissive to primary tumor development and metastasis. This involves subversion of local immunity at tumor sites, as well as systemic immunity and the wider host response. While immune dysfunction is a hallmark of all cholangiocarcinoma, the specific steps of the cancer-immunity cycle that are perturbed differ between patients. Heterogeneous immune functionality impacts the evolutionary development, pathobiological behavior, and therapeutic response of these tumors. Integrative genomic analyses of thousands of primary tumors have supported a biological rationale for immune-based stratification of patients, encompassing immune cell composition and functionality. However, discerning immune alterations responsible for promoting tumor initiation, maintenance, and progression from those present as bystander events remains challenging. Functionally uncoupling the tumor-promoting or tumor-suppressing roles of immune profiles will be critical for identifying new immunomodulatory treatment strategies and associated biomarkers for patient stratification. This review will discuss the immunogenomics of cholangiocarcinoma, including the impact of genomic alterations on immune functionality, subversion of the cancer-immunity cycle, as well as clinical implications for existing and novel treatment strategies.

Epstein-Barr virus-associated intrahepatic cholangiocarcinoma (EBVaICC) has a distinct genomic profile and increased CD3+ and CD8+ T cells infiltration. However, the efficacy of immunotherapy in EBVaICC remains largely unknown. This study aimed to assess the efficacy of programmed cell death protein 1 (PD-1) antibody therapy in EBVaICC.

Patients with metastatic biliary tract cancer (BTC) diagnosed at Sun Yat-sen University Cancer Center from January 2016 to December 2021 were identified. In situ hybridisation was performed to detect EBV. Overall survival (OS) and progression-free survival (PFS) were measured.

A total of 698 patients with metastatic BTC were identified, of whom 39 (5.6%) had EBVaICC. Among the 136 patients who were not administered PD-1 antibody, the OS was similar between patients with EBVaICC and EBV-negative ICC (median OS 12.5 versus 9.5 months, respectively; P = 0.692). For the 205 patients who were administered PD-1 antibody, patients with EBVaICC had significantly longer OS than patients with EBV-negative ICC (median OS 24.9 versus 11.9 months, respectively; P = 0.004). Seventeen patients with EBVaICC were administered PD-1 antibody. Eight patients (47%) achieved a partial response, and 17 patients achieved disease control. The median PFS was 17.5 months.

This study identified a clinically actionable subset of patients with EBVaICC with a promising response to the PD-1 antibody.

Spindle assembly checkpoint (SAC) plays an essential part in facilitating normal cell division. However, the clinicopathological and biological significance of mitotic arrest deficient 2 like 1 (MAD2/MAD2L1), a highly conserved member of SAC in cholangiocarcinoma (CCA) remain unclear. We aim to determine the role and mechanism of MAD2 in CCA progression. In the study, we found up-regulated MAD2 facilitated CCA progression and induced lymphatic metastasis dependent on USP44/LIMA1/PI3K/AKT pathway. MAD2 interfered the binding of USP44 to LIMA1 by sequestrating more USP44 in nuclei, causing impaired formation of USP44/LIMA1 complex and enhanced LIMA1 K48 (Lys48)-linked ubiquitination. In therapeutic perspective, the data combined eleven cases of CCA PDTX model showed that high-MAD2 inhibits tumor necrosis and diminishes the inhibition of cell viability after treated with gemcitabine-based regimens. Immunohistochemistry (IHC) analysis of tissue microarray (TMA) for CCA patients revealed that high-MAD2, low-USP44 or low-LIMA1 level are correlated with worse survival for patients. Together, MAD2 activates PI3K/AKT pathway, promotes cancer progression and induces gemcitabine chemo-resistance in CCA. These findings suggest that MAD2 might be an excellent indicator in prognosis analysis and chemotherapy guidance for CCA patients.