Zolpidem-triggered atrial fibrillation in a patient with cardiomyopathy: a case report.

BACKGROUND: Zolpidem is a non-benzodiazepine hypnotic widely used to manage insomnia. Zolpidem-triggered atrial fibrillation (AF) in patients with cardiomyopathy has never been reported before. CASE PRESENTATION: A 40-year-old man with Duchenne muscular dystrophy-related cardiomyopathy attempted suicide and developed new-onset AF after zolpidem overdose. One year before admission, the patient visited our clinic due to chest discomfort and fatigue after daily walks for 1 month; both electrocardiography (ECG) and 24-hour Holter ECG results did not detect AF. After administration of cardiac medication (digoxin 0.125 mg/day, spironolactone 40 mg/day, furosemide 20 mg/day, bisoprolol 5 mg/day, sacubitril/valsartan 12/13 mg/day), he felt better. AF had never been observed before this admission via continuous monitoring during follow-up. Sixteen days before admission, the patient saw a sleep specialist and started zolpidem tartrate tablets (10 mg/day) due to insomnia for 6 months; ECG results revealed no significant change. The night before admission, the patient attempted suicide by overdosing on 40 mg of zolpidem after an argument, which resulted in severe lethargy. Upon admission, his ECG revealed new-onset AF, necessitating immediate cessation of zolpidem. Nine hours into admission, AF spontaneously terminated into normal sinus rhythm. Results from the ECG on the following days and the 24-hour Holter ECG at 1-month follow-up showed that AF was not detected. CONCLUSIONS: This study provides valuable clinical evidence indicating that zolpidem overdose may induce AF in patients with cardiomyopathy. It serves as a critical warning for clinicians when prescribing zolpidem, particularly for patients with existing heart conditions. Further large-scale studies are needed to validate this finding and to explore the mechanisms between zolpidem and AF.

Temporal trends and risk factors of perioperative cardiac events in patients over 80 years old with coronary artery disease undergoing noncardiac surgery: a high-volume single-center experience, 2014-2022.

BACKGROUND: Temporal trends and risk factors of perioperative cardiac events (PCEs) in patients over 80 years old with coronary artery disease (CAD) undergoing noncardiac surgery are still unclear. METHODS: We retrospectively reviewed 1478 patients over 80 years old, with known CAD undergoing selective noncardiac surgery in a single center (2014-2022). Patients were divided into three equal time groups based on the discharge date (2014-2016, 2017-2019, and 2020-2022), with 367, 473, and 638 patients in Groups 1-3, respectively. Perioperative clinical variables were extracted from the electronic medical records database. The primary outcome was the occurrence of PCEs intraoperatively or during hospitalization postoperatively, defined as any of the following events: myocardial infarction, heart failure, nonfatal cardiac arrest, and death. RESULTS: PCEs occurred in 180 (12.2%) patients. Eight independent risk factors were associated with PCEs, including four clinical factors (body mass index < 22 kg/m2, history of myocardial infarction, history of heart failure, and general anesthesia) and four preoperative laboratory results (hemoglobin < 110 g/L, albumin < 40 g/L, creatinine > 120 µmol/L, and potassium <3.6 mmol/L). Significant rising trends were seen over the 9-year study period in the incidence of PCEs and independent risk factors including history of myocardial infarction, history of heart failure, general anesthesia, preoperative hemoglobin < 110 g/L, preoperative albumin < 40 g/L, and preoperative creatinine > 120 µmol/L (P for trend <0.05). CONCLUSION: The incidence and independent risk factors of PCEs in patients over 80 years old with CAD undergoing noncardiac surgery showed significant rising trends over the last 9-year period.

Emerging biomolecules for practical theranostics of liver hepatocellular carcinoma.

Most cases of hepatocellular carcinoma (HCC) are able to be diagnosed through regular surveillance in an identifiable patient population with chronic hepatitis B or cirrhosis. Nevertheless, 50% of global cases might present incidentally owing to symptomatic advanced-stage HCC after worsening of liver dysfunction. A systematic search based on PUBMED was performed to identify relevant outcomes, covering newer surveillance modalities including secretory proteins, DNA methylation, miRNAs, and genome sequencing analysis which proposed molecular expression signatures as ideal tools in the early-stage HCC detection. In the face of low accuracy without harmonization on the analytical approaches and data interpretation for liquid biopsy, a more accurate incidence of HCC will be unveiled by using deep machine learning system and multiplex immunohistochemistry analysis. A combination of molecular-secretory biomarkers, high-definition imaging and bedside clinical indexes in a surveillance setting offers a comprehensive range of HCC potential indicators. In addition, the sequential use of numerous lines of systemic anti-HCC therapies will simultaneously benefit more patients in survival. This review provides an overview on the most recent developments in HCC theranostic platform.

Alternate recurrent coronary artery spasm and stress cardiomyopathy: a case report.

BACKGROUND: Coronary artery spasm (CAS) and stress cardiomyopathy (SC) have different characteristic clinical manifestations in the case of suspicious myocardial infarction with nonobstructive coronary arteries. Established recurrence rates of both conditions have been reported, however, alternate recurrent CAS and SC in the same individual have not been described. CASE PRESENTATION: A 59-year-old man suffered from atypical chest pain in the first episode, acute heart attack in the second and third episodes (totally 3 times over a period of approximately 5 years). During the first episode, he visited our hospital with mild paroxysmal chest pain without obvious inducement for approximately 2 years. He was underdiagnosed at that time without other obvious findings except the poor R wave progression in V1-3 leads revealed in electrocardiogram. At 4 months after the first episode, he suffered from a heart attack (the second episode) and was diagnosed with SC based on the coronary angiography (CAG) and left ventriculography findings of nonobstructive coronary arteries combined with a classic apical ballooning shape. At 31 months after the second episode, he suffered another heart attack (the third episode) and was diagnosed with CAS based on the CAG results of recoverable severe multivessel stenoses. During the episodes, partial reversible nature of apical hypokinesis was observed in echocardiogram. In retrospect, the patient suffered silent CAS in the first episode, SC in the second episode, and severe multivessel CAS in the third episode. CONCLUSION: The unusual presentations observed in this case have not been reported. This case suggests that cardiologists should be aware of the possibility of alternate recurrent CAS and SC in the same individual. Provocative tests for spasm and cardiac magnetic resonance imaging might help gain more insights into this issue.

Genomic ERBB2/ERBB3 mutations promote PD-L1-mediated immune escape in gallbladder cancer: a whole-exome sequencing analysis.

OBJECTIVES: Patients with gallbladder carcinoma (GBC) lack effective treatment methods largely due to the inadequacy of both molecular characterisation and potential therapeutic targets. We previously uncovered a spectrum of genomic alterations and identified recurrent mutations in the ErbB pathway in GBC. Here, we aimed to study recurrent mutations of genes and pathways in a larger cohort of patients with GBC and investigate the potential mechanisms and clinical significance of these mutations. DESIGN: We performed whole-exome sequencing (WES) in 157 patients with GBC. Functional experiments were applied in GBC cell lines to explore the oncogenic roles of ERBB2/ERBB3 hotspot mutations, their correlation with PD-L1 expression and the underlying mechanisms. ERBB inhibitors and a PD-L1 blocker were used to evaluate the anticancer activities in co-culture systems in vitro and in vivo. RESULTS: WES identified ERBB2 and ERBB3 mutations at a frequency of 7%-8% in the expanded cohort, and patients with ERBB2/ERBB3 mutations exhibited poorer prognoses. A set of in vitro and in vivo experiments revealed increased proliferation/migration on ERBB2/ERBB3 mutation. Ectopic expression of ERBB2/ERBB3 mutants upregulated PD-L1 expression in GBC cells, effectively suppressed normal T-cell-mediated cytotoxicity in vitro through activation of the PI3K/Akt signalling pathway and contributed to the growth and progression of GBC in vivo. Treatment with an ERBB2/ERBB3 inhibitor or a PD-L1 monoclonal antibody reversed these immunosuppressive effects, and combined therapy revealed promising therapeutic activities. CONCLUSIONS: ERBB2/ERBB3 mutations may serve as useful biomarkers in identifying patients who are sensitive to ERBB2/ERBB3 inhibitors and PD-L1 monoclonal antibody treatment. TRIAL REGISTRATION NUMBER: NCT02442414;Pre-results.

LncRNA-HGBC stabilized by HuR promotes gallbladder cancer progression by regulating miR-502-3p/SET/AKT axis.

BACKGROUNDS: Long non-coding RNAs (lncRNAs) are essential factors that regulate tumor development and metastasis via diverse molecular mechanisms in a broad type of cancers. However, the pathological roles of lncRNAs in gallbladder carcinoma (GBC) remain largely unknown. Here we discovered a novel lncRNA termed lncRNA Highly expressed in GBC (lncRNA-HGBC) which was upregulated in GBC tissue and aimed to investigate its role and regulatory mechanism in the development and progression of GBC. METHODS: The expression level of lncRNA-HGBC in GBC tissue and different cell lines was determined by quantitative real-time PCR. The full length of lncRNA-HGBC was obtained by 5' and 3' rapid amplification of the cDNA ends (RACE). Cellular localization of lncRNA-HGBC was detected by fluorescence in situ hybridization (FISH) assays and subcellular fractionation assay. In vitro and in vivo assays were preformed to explore the biological effects of lncRNA-HGBC in GBC cells. RNA pull-down assay, mass spectrometry, and RNA immunoprecipitation (RIP) assay were used to identify lncRNA-HGBC-interacting proteins. Dual luciferase reporter assays, AGO2-RIP, and MS2-RIP assays were performed to verify the interaction between lncRNA-HGBC and miR-502-3p. RESULTS: We found that lncRNA-HGBC was upregulated in GBC and its upregulation could predict poor survival. Overexpression or knockdown of lncRNA-HGBC in GBC cell lines resulted in increased or decreased, respectively, cell proliferation and invasion in vitro and in xenografted tumors. LncRNA-HGBC specifically bound to RNA binding protein Hu Antigen R (HuR) that in turn stabilized lncRNA-HGBC. LncRNA-HGBC functioned as a competitive endogenous RNA to bind to miR-502-3p that inhibits target gene SET. Overexpression, knockdown or mutation of lncRNA-HGBC altered the inhibitory effects of miR-502-3p on SET expression and downstream activation of AKT. Clinically, lncRNA-HGBC expression was negatively correlated with miR-502-3p, but positively correlated with SET and HuR in GBC tissue. CONCLUSIONS: Our study demonstrates that lncRNA-HGBC promotes GBC metastasis via activation of the miR-502-3p-SET-AKT cascade, pointing to lncRNA-HGBC as a new prognostic predictor and a therapeutic target.

NOP2/Sun RNA methyltransferase 2 promotes tumor progression via its interacting partner RPL6 in gallbladder carcinoma.

NOP2/Sun domain family, member 2 (NSUN2) is a nuclear RNA methyl-transferase catalyzing 5-methylcytosine formation. Evidence shows that NSUN2 is correlated with cell unlimited proliferation. However, its functional role in gallbladder carcinoma (GBC), which is the most common biliary tract malignancy and has a poor prognosis, remains to be determined. Here we found that NSUN2 was highly expressed in GBC tissues as well as cell lines. NSUN2 silencing repressed GBC cell proliferation and tumorigenesis both in vitro and in vivo. Conversely, upregulation of NSUN2 enhanced GBC cell growth and colony formation. We further discovered that RPL6 was a closely interacting partner with NSUN2. Silencing RPL6 resulted in insufficient NSUN2 translational level and accumulative NSUN2 transcriptional level. Exogenous expression of NSUN2 partially rescued the effect of RPL6 in gallbladder cancer progression. Taken together, our data provided novel mechanic insights into the function of NSUN2 in GBC, thus pointing to NSUN2 as a potential and effective therapeutic approach to GBC treatment.

LncRNA-PAGBC acts as a microRNA sponge and promotes gallbladder tumorigenesis.

Long noncoding RNAs (lncRNAs) play roles in the development and progression of many cancers; however, the contributions of lncRNAs to human gallbladder cancer (GBC) remain largely unknown. In this study, we identify a group of differentially expressed lncRNAs in human GBC tissues, including prognosis-associated gallbladder cancer lncRNA (lncRNA-PAGBC), which we find to be an independent prognostic marker in GBC Functional analysis indicates that lncRNA-PAGBC promotes tumour growth and metastasis of GBC cells. More importantly, as a competitive endogenous RNA (ceRNA), lncRNA-PAGBC competitively binds to the tumour suppressive microRNAs miR-133b and miR-511. This competitive role of lncRNA-PAGBC is required for its ability to promote tumour growth and metastasis and to activate the AKT/mTOR pathway. Moreover, lncRNA-PAGBC interacts with polyadenylate binding protein cytoplasmic 1 (PABPC1) and is stabilized by this interaction. This work provides novel insight on the molecular pathogenesis of GBC.

The PLGF/c-MYC/miR-19a axis promotes metastasis and stemness in gallbladder cancer.

Gallbladder cancer (GBC) is the most common malignant tumor of the biliary tract system. Epithelial-mesenchymal transition (EMT) plays a vital role in the process of tumor metastasis. Mesenchymal-like cells can serve as a source of cancer stem cells, which can confer the EMT phenotype. Placental growth factor (PLGF) belongs to the vascular endothelial growth factor family and plays a vital role in cancer. However, the underlying molecular mechanisms about the influence of PLGF on EMT in GBC remain unknown. Here we show that PLGF expression levels were higher in GBC tissues than in normal adjacent tissues and were associated with poor prognosis in GBC patients. Exogenous PLGF enhanced the migration, invasion, and tumorsphere formation of GBC cells. Conversely, knockdown of PLGF decreased the aggressive phenotype of GBC cells. Mechanistically, exogenous PLGF upregulated microRNA-19a (miR-19a) expression through the activation of c-MYC. Moreover, Spearman's correlation analysis showed a positive pairwise correlation among PLGF, c-MYC, and miR-19a expression in GBC tissues. Taken together, these results suggest that PLGF promotes EMT and tumorsphere formation through inducing miR-19a expression by upregulating c-MYC. Thus, PLGF could be a promising molecular therapeutic target for GBC.

Chloride intracellular channel 1 regulates the antineoplastic effects of metformin in gallbladder cancer cells.

Metformin is the most commonly used drug for type 2 diabetes and has potential benefit in treating and preventing cancer. Previous studies indicated that membrane proteins can affect the antineoplastic effects of metformin and may be crucial in the field of cancer research. However, the antineoplastic effects of metformin and its mechanism in gallbladder cancer (GBC) remain largely unknown. In this study, the effects of metformin on GBC cell proliferation and viability were evaluated using the Cell Counting Kit-8 (CCK-8) assay and an apoptosis assay. Western blotting was performed to investigate related signaling pathways. Of note, inhibition, knockdown and upregulation of the membrane protein Chloride intracellular channel 1 (CLIC1) can affect GBC resistance in the presence of metformin. Our data demonstrated that metformin apparently inhibits the proliferation and viability of GBC cells. Metformin promoted cell apoptosis and increased the number of early apoptotic cells. We found that metformin can exert growth-suppressive effects on these cell lines via inhibition of p-Akt activity and the Bcl-2 family. Notably, either dysfunction or downregulation of CLIC1 can partially decrease the antineoplastic effects of metformin while upregulation of CLIC1 can increase drug sensitivity. Our findings provide experimental evidence for using metformin as an antitumor treatment for gallbladder carcinoma.

A new agent for contrast-enhanced intravascular ultrasound imaging in vitro: polybutylcyanoacrylate nanoparticles with drug-carrying capacity.

This study prepared and evaluated polymeric polybutylcyanoacrylate (PBCA) nanoparticles (NPs) that can be used as a new agent for contrast-enhanced intravascular ultrasound (IVUS) imaging with drug delivery capacity. The nanoformulation was successfully developed using suspension polymerisation and characterised in terms of size, size distribution, zeta potential, morphology, stability, toxicity effects, imaging effects and drug release study. The results showed that the nanoparticles were round and hollow, with a particle diameter of 215.8 ± 25.3 nm and a zeta potential of -22.2 ± 4.1 mV. In vitro experiments, the nanoparticles were safe, non-toxic, and stable in nature with the capacity to carry and release drug (ant-miR-126). Moreover, the nanoparticles can match the high-frequency probe of commercially IVUS as a contrast agent to improve the resolution of imaging (the mean echo intensity ratio in the vascular wall increased significantly from 10.89 ± 1.10 at baseline, to 24.51 ± 1.91 during injection and 43.70 ± 0.88 after injection, respectively p < .0001). Overall, a new nano agent with drug-carrying capacity was prepared, which can be used in combination with IVUS for simultaneous diagnosis and targeted therapy of coronary atherosclerosis.

Development and validation of a novel score for predicting perioperative major adverse cardiovascular events in patients with stable coronary artery disease undergoing noncardiac surgery.

BACKGROUND: A model developed specifically for stable coronary artery disease (SCAD) patients to predict perioperative major adverse cardiovascular events (MACE) has not been previously reported. METHODS: The derivation cohort consisted of 5780 patients with SCAD undergoing noncardiac surgery at the First Affiliated Hospital of Zhejiang University School of Medicine, from January 1, 2013 until May 31, 2021. The validation cohort consisted of 2677 similar patients from June 1, 2021 to May 31, 2023. The primary outcome was a composite of MACEs (death, resuscitated cardiac arrest, myocardial infarction, heart failure, and stroke) intraoperatively or during hospitalization postoperatively. RESULTS: Six predictors, including Creatinine >90 µmol/L, Hemoglobin <110 g/L, Albumin <40 g/L, Leukocyte >10 ×109/L, high-risk Surgery (general abdominal or vascular), and American Society of Anesthesiologists (ASA) class (III or IV), were selected in the final model (CHALSA score). Each patient was assigned a CHALSA score of 0, 1, 2, 3, or > 3 according to the number of predictors present. The incidence of perioperative MACEs increased steadily across the CHALSA score groups in both the derivation (0.5%, 1.4%, 2.9%, 6.8%, and 23.4%, respectively; p < 0.001) and validation (0.3%, 1.5%, 4.1%, 9.2%, and 29.2%, respectively; p < 0.001) cohorts. The CHALSA score had a higher discriminatory ability than the revised cardiac risk index (C statistic: 0.827 vs. 0.695 in the validation dataset; p < 0.001). CONCLUSIONS: The CHALSA score showed good validity in an external dataset and will be a valuable bedside tool to guide the perioperative management of patients with SCAD undergoing noncardiac surgery.

Metal-organic framework bearing new viologen ligand for ammonia and Cr2O7 2- sensing.

Three anionic metal-organic frameworks (MOFs) {[Zn3(BTEC)2(H2O)(4-BCBPY)]·(H2O)} n (1-3) (BTEC4- = 1,2,4,5-benzenetetracarboxylic acid anion, 4-BCBPY2+ = 1,1'-bis(4-cyanobenzyl)-4,4'-bipyridinium dication) were synthesized in the reaction of 1,2,4,5-benzenetetracarboxylic acid with different metal salts such as ZnNO3, ZnCl2, and ZnSO4, under solvothermal conditions in the presence of 1,1'-bis(4-cyanobenzyl)-4,4'-bipyridinium chloride. Single crystal X-ray diffraction analysis shows that compounds 1, 2 and 3 have MOF structures based on binuclear metal building units, which are connected by two protonated BTEC4- ligands and three zinc ions, and the viologen cation 4-BCBPY2+ is located in the channel to achieve charge balance. Compounds 1, 2 and 3 have good photosensitivity, respond to sunlight, UV light and blue ray, and turn blue. The D-A distance and π-π stacking distance of the discolored samples (1P, 2P and 3P) changed. In addition, the three compounds showed visible color changes to ammonia vapor, rapidly changing from white to blue. At the same time, the three compounds exhibited fluorescence quenching to ammonia vapor and Cr2O7 2-. It is further proved that compounds 1, 2 and 3 are fluorescent sensors with a low detection limit (for Cr2O7 2-: 10-5 M) and high sensitivity for ammonia vapor and Cr2O7 2-. It was found that photochromic behavior, ammonia sensing properties can be tuned by the nature of metal salts.

Bone Marrow Mesenchymal Stem Cell-Derived Exosomal MicroRNA-133a Restrains Myocardial Fibrosis and Epithelial-Mesenchymal Transition in Viral Myocarditis Rats Through Suppressing MAML1.

Myocarditis is a disease characterized by localized or diffuse inflammation of the myocardium without efficient treatment. This study explored the regulatory mechanism of microRNA-133 (miR-133) secreted from bone marrow mesenchymal stem cell-derived exosome (BMSC-Exo) on myocardial fibrosis and epithelial-mesenchymal transition (EMT) in viral myocarditis (VMC) rats through regulating mastermind-like 1 (MAML1). BMSCs in rats were isolated and cultured to identify their immune phenotype and osteogenic and adipogenic ability, and BMSC-Exo were extracted and identified. Exosomes were obtained through ultracentrifugation, which were identified by transmission electron microscope and western blot analysis. The rats were injected with Coxsackie B3 virus for preparation of VMC model, and cardiomyocytes were isolated, cultured and grouped in the same way as animal experiments (NCExo, Ad-miR-133aExo, Adas-miR-133aExo). In vivo and in vitro experiments were conducted to figure out the roles of exosomal miR-133a and MAML1 in inflammation, apoptosis, EMT, fibrosis, and cell viability. The targeting relationship between miR-133a and MAML1 was verified by dual luciferase reporter gene assay. BMSC-Exo raised miR-133a expression in VMC rats and effectively improved the VMC rat cardiac function and myocardial fibrosis, increased cardiomyocyte viability and inhibited the EMT process. Elevated miR-133a in exosomes strengthened the improvements. Silenced miR-133a effectively reversed the effects of BMSC-Exo on VMC rats. miR-133a targeted MAML1. Inhibition of MAML1 improved cardiac function and myocardial fibrosis in VMC rats and could reverse the effect of miR-133a-silenced exosomes on VMC rats. Our study suggests that elevated exosomal miR-133a suppresses myocardial fibrosis and EMT in rats with VMC via down-regulating MAML1, thereby inhibiting the progression of myocarditis.

The impact of delayed heart rate recovery on prevalent hypertension.

Objectives: Delayed heart rate recovery (HRR) is considered an indicator of autonomic nervous dysfunction, which is a primary pathological mechanism of hypertension. The present study aimed to explore the independent association between delayed HRR and prevalent hypertension.Methods: In this cross-sectional study, 314 inpatients were recruited between January 2018 and December 2019. HRR was defined as the peak heart rate during exercise minus the 2nd-minute heart rate after exercise in the treadmill exercise test.Results: The mean HRR in the hypertension group was lower than that in the non-hypertension group (41 bpm vs. 46 bpm; P < 0.001). After full adjustment, each standard deviation increase in HRR was associated with a 35% decrease in the risk of prevalent hypertension (OR: 0.65, 95% CI: 0.48-0.87; P = 0.004). When the HRR was divided into quartiles, the risk in the top quartile was 26% of that in the bottom quartile (OR: 0.26, 95% CI: 0.12-0.56; P = 0.001). Furthermore, smooth curve fitting showed that the risk of prevalent hypertension decreased linearly with the increase in HRR.Conclusion: Delayed HRR was independently associated with prevalent hypertension. The association was linear and robust over the entire range of HRR. The present study suggested that delayed HRR could be used to optimize hypertension risk stratification.

Multiple Non-coding ANRIL Transcripts Are Associated with Risk of Coronary Artery Disease: a Promising Circulating Biomarker.

Multiple ANRIL transcriptional isoforms, such as lncANRIL and circANRIL have been identified. We sought to explore their diagnostic value in patients with coronary artery disease (CAD). First, we selected six target ANRIL isoforms and measured their expression in CAD patients and controls in the peripheral blood. Their diagnostic values were evaluated. circANRIL(exon14-4) was identified as the best potential biomarker. Afterwards, we validated its diagnostic value and evaluated its prognostic value in a larger clinical cohort. Among six tested ANRILs, lncANRIL(exon1) and lncANRIL(exon4-6) in the CAD patients were significantly increased, while circANRIL(exon14-4) was downregulated. circANRIL(exon14-4) had the highest diagnostic value among the three isoforms. The combination of circANRIL(exon14-4) and other factors resulted in a more accurate differentiation of CAD patients. Moreover, lower expression of circANRIL(exon14-4) was associated with higher incidence of MACE. circANRIL(exon14-4) is closely associated with CAD risk and severity, which provides a promising circulating biomarker for CAD diagnosis and prognosis.

Combining Immunoscore with Clinicopathologic Features in Cholangiocarcinoma: An Influential Prognostic Nomogram.

PURPOSE: The aim of this study was to determine the Immunoscore as an independent prognostic factor for cholangiocarcinoma and establish a useful prognostic model for postoperative patients. METHODS: This retrospective study was performed to assess the correlation between the clinicopathological features, tumor immune microenvironment, and prognosis of 76 patients with cholangiocarcinoma. Multivariate analysis was used to identify independent factors significantly associated with local recurrence-free survival (LRFS) and overall survival (OS). Finally, we constructed a nomogram combining the Immunoscore with clinicopathologic features to predict postoperative recurrence and OS. RESULTS: The present study showed that immune cell infiltration was negatively correlated with tumor size, peripheral vascular invasion, lymph node metastasis, and tumor staging. Kaplan-Meier curves indicated that a decreased Immunoscore was associated with poor prognosis. Multivariate analysis demonstrated that resection type, number of tumors, lymph node metastasis, TNM staging, and the Immunoscore were significantly associated with LRFS. For OS, the significantly correlated factors included resection type, peripheral vascular invasion, TNM staging, and the Immunoscore. Immunoscore was superior to TNM staging in predicting both LRFS and OS according to the receiver operating characteristic analysis. Based on the results of the Cox regression analysis, a prognostic nomogram for the postoperative recurrence of cholangiocarcinoma and OS of patients was established. CONCLUSION: The results of this study suggest that the Immunoscore may be used as an independent predictor of postoperative recurrence and OS of patients with cholangiocarcinoma. The Immunoscore appears to offer distinct advantages over the TNM staging system. By combining the Immunoscore and clinicopathological features, the proposed nomogram provides a more accurate predictive tool for postoperative patients with cholangiocarcinoma.

Long noncoding RNA lncGALM increases risk of liver metastasis in gallbladder cancer through facilitating N-cadherin and IL-1ß-dependent liver arrest and tumor extravasation.

BACKGROUND: Long noncoding RNAs (lncRNA) represent significant factors of the mammalian transcriptome that mediates varied biological and pathological processes. The liver is the most common site for gallbladder cancer (GBC) distant metastasis and contributes to the majority of GBC-related death. How lncRNA affects GBC metastasis is not completely understood. RESULTS: A novel lncRNA termed lncGALM (lncRNA in GBC associated with liver metastasis) was discovered to be highly expressed in cancer patients and xenografted tumors with liver metastasis. Elevated lncGALM in GBC patients also correlated to decreased survival. Invasion and migration of GBC cells were enhanced through lncGALM, both in vitro and in vivo. lncGALM functioned as sponges by competitively binding to and inactivating miR-200 family members, which increase epithelial-mesenchymal transition-associated transcription factor ZEB1 and ZEB2, leading to a fibroblastic phenotype and increased expression of N-cadherin. In addition, lncGALM bound to IL-1ß mRNA and stabilized the IL-1ß gene that mediates liver sinusoidal endothelial cell (LSECs) apoptosis. lncGALM-expressing LiM2-NOZ cells acquired a strong ability to migrate and adhere to LSECs, promoting LSECs apoptosis and therefore facilitating tumor cell extravasation and dissemination. CONCLUSIONS: lncGALM promotes GBC liver metastasis by facilitating GBC cell migration, invasion, liver arrest, and extravasation via the invasion-metastasis cascade. Targeting lncGALM may be protective against the development of liver metastasis in GBC patients.