Repurposing diacerein to suppress colorectal cancer growth by inhibiting the DCLK1/STAT3 signaling pathway.

Double cortin-like kinase 1 (DCLK1) exhibits high expression levels across various cancers, notably in human colorectal cancer (CRC). Diacerein, a clinically approved interleukin (IL)-1ß inhibitor for osteoarthritis treatment, was evaluated for its impact on CRC proliferation and migration, alongside its underlying mechanisms, through both in vitro and in vivo analyses. The study employed MTT assay, colony formation, wound healing, transwell assays, flow cytometry, and Hoechst 33342 staining to assess cell proliferation, migration, and apoptosis. Additionally, proteome microarray assay and western blotting analyses were conducted to elucidate diacerein's specific mechanism of action. Our findings indicate that diacerein significantly inhibits DCLK1-dependent CRC growth in vitro and in vivo. Through high-throughput proteomics microarray and molecular docking studies, we identified that diacerein directly interacts with DCLK1. Mechanistically, the suppression of p-STAT3 expression following DCLK1 inhibition by diacerein or specific DCLK1 siRNA was observed. Furthermore, diacerein effectively disrupted the DCLK1/STAT3 signaling pathway and its downstream targets, including MCL-1, VEGF, and survivin, thereby inhibiting CRC progression in a mouse model, thereby inhibiting CRC progression in a mouse model.

Effect of apatinib on the pharmacokinetics of tramadol and O-desmethyltramadol in rats.

Since the combination of anticancer drugs and opioids is very common, apatinib and tramadol are likely to be used in combination clinically. This study evaluated the effects of apatinib on the pharmacokinetics of tramadol and its main metabolite O-desmethyltramadol in Sprague-Dawley (SD) rats and the inhibitory effects of apatinib on tramadol in rat liver microsomes (RLMs), human liver microsomes (HLMs) and recombinant human CYP2D6.1. The samples were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The in vivo results showed that compared with the control group, apatinib increased the AUC(0-t), AUC(0-∞) and Cmax values of tramadol and O-desmethyltramadol, and decreased the values of VZ/F and CLz/F. In addition, the MRT(0-t), MRT(0-∞) values of O-desmethyltramadol were increased. In vitro, apatinib inhibited the metabolism of tramadol by a mixed way with IC50 of 1.927 µM in RLMs, 2.039 µM in HLMs and 15.32 µM in CYP2D6.1. In summary, according to our findings, apatinib has a strong in vitro inhibitory effect on tramadol, and apatinib can increase the analgesic effect of tramadol and O-desmethyltramadol in rats.

Reduced Adenoma Miss Rate With 9-Minute vs 6-Minute Withdrawal Times for Screening Colonoscopy: A Multicenter Randomized Tandem Trial.

INTRODUCTION: Although the 9-minute mean withdrawal time (m-WT) is often reported to be associated with the optimal adenoma detection rate (ADR), no randomized trials of screening colonoscopy have confirmed the impact of a 9-minute m-WT on adenoma miss rate (AMR) and ADR. METHODS: A multicenter tandem trial was conducted in 11 centers. Seven hundred thirty-three asymptomatic participants were randomized to receive segmental tandem screening colonoscopy with a 9-minute withdrawal, followed by a 6-minute withdrawal (9-minute-first group, 9MF, n = 366) or vice versa (6-minute-first group, 6MF, n = 367). The primary outcome was the lesion-level AMR. RESULTS: The intention-to-treat analysis revealed that 9MF significantly reduced the lesion-level (14.5% vs 36.6%, P < 0.001) and participant-level AMR (10.9% vs 25.9%, P < 0.001), advanced adenoma miss rate (AAMR, 5.3% vs 46.9%, P = 0.002), multiple adenomas miss rate (20.7% vs 56.5%, P = 0.01), and high-risk adenomas miss rate (14.6% vs 39.5%, P = 0.01) of 6MF without compromising detection efficiency ( P = 0.79). In addition, a lower false-negative rate for adenomas ( P = 0.002) and high-risk adenomas ( P < 0.05), and a lower rate of shortening surveillance schedule ( P < 0.001) were also found in 9MF, accompanying with an improved ADR in the 9-minute vs 6-minute m-WT (42.3% vs 33.5%, P = 0.02). The independent inverse association between m-WT and AMR remained significant even after adjusting ADR, and meanwhile, 9-minute m-WT was identified as an independent protector for AMR and AAMR. DISCUSSION: In addition to increasing ADR, 9-minute m-WT also significantly reduces the AMR and AAMR of screening colonoscopy without compromising detection efficiency.

Single-cell sequencing reveals heterogeneity between pancreatic adenosquamous carcinoma and pancreatic ductal adenocarcinoma with prognostic value.

Pancreatic adenosquamous carcinoma (ASPC) is a rare subtype of pancreatic cancer with lethal malignancy, and few studies have focused on the heterogeneity of ASPC. Here, we performed a single-cell sequencing procedure on pancreatic tumor tissue from an ASPC patient and a patient with high-grade intraductal papillary mucinous neoplasm (IPMN). Through the combined analysis of single-cell sequencing data from five pancreatic ductal adenocarcinoma (PDAC) patients, one IPMN patient, and one ASPC patient in a public database, we identified 11 main types of cells, including macrophages, B cells, cancer stem cells, ductal cells, fibroblasts, endo/stellate cells, neutrophils, acinar cells, T cells, natural killer (NK) cells, dendritic cells, and mast cells. Then, the different characteristics and differentiation paths of the immune microenvironment among IPMN, ASPC, and PDAC in macrophages, T cells, and cancer-associated fibroblasts (CAFs) were identified through multiple bioinformatics analyses. Two novel special cancer-associated fibroblasts were identified as nCAFs and imCAFs. Then, cancer cells in duct cells were identified using the infercnv software. Two ASPC-specific subgroups of cancer cells with squamous cell features were identified. Finally, the identified specific CAFs and cancer cells were mapped to TCGA-PAAD cohort through the cibersoftx software. All of these identified subgroups were calculated to have a significant prognostic value in pancreatic cancer patients. These findings will promote the clinical application of single-cell sequencing data of pancreatic cancer and deepen our understanding of ASPC.

Simultaneous Recognition of Atrophic Gastritis and Intestinal Metaplasia on White Light Endoscopic Images Based on Convolutional Neural Networks: A Multicenter Study.

INTRODUCTION: Patients with atrophic gastritis (AG) or gastric intestinal metaplasia (GIM) have elevated risk of gastric adenocarcinoma. Endoscopic screening and surveillance have been implemented in high incidence countries. The study aimed to evaluate the accuracy of a deep convolutional neural network (CNN) for simultaneous recognition of AG and GIM. METHODS: Archived endoscopic white light images with corresponding gastric biopsies were collected from 14 hospitals located in different regions of China. Corresponding images by anatomic sites containing AG, GIM, and chronic non-AG were categorized using pathology reports. The participants were randomly assigned (8:1:1) to the training cohort for developing the CNN model (TResNet), the validation cohort for fine-tuning, and the test cohort for evaluating the diagnostic accuracy. The area under the curve (AUC), sensitivity, specificity, and accuracy with 95% confidence interval (CI) were calculated. RESULTS: A total of 7,037 endoscopic images from 2,741 participants were used to develop the CNN for recognition of AG and/or GIM. The AUC for recognizing AG was 0.98 (95% CI 0.97-0.99) with sensitivity, specificity, and accuracy of 96.2% (95% CI 94.2%-97.6%), 96.4% (95% CI 94.8%-97.9%), and 96.4% (95% CI 94.4%-97.8%), respectively. The AUC for recognizing GIM was 0.99 (95% CI 0.98-1.00) with sensitivity, specificity, and accuracy of 97.9% (95% CI 96.2%-98.9%), 97.5% (95% CI 95.8%-98.6%), and 97.6% (95% CI 95.8%-98.6%), respectively. DISCUSSION: CNN using endoscopic white light images achieved high diagnostic accuracy in recognizing AG and GIM.

Novel Regulatory Factors and Small-Molecule Inhibitors of FGFR4 in Cancer.

Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase receptor that is a member of the fibroblast growth factor receptor family and is stimulated by highly regulated ligand binding. Excessive expression of the receptor and its ligand, especially FGF19, occurs in many types of cancer. Abnormal FGFR4 production explains these cancer formations, and therefore, this receptor has emerged as a potential target for inhibiting cancer development. This review discusses the diverse mechanisms of oncogenic activation of FGFR4 and highlights some currently available inhibitors targeting FGFR4.

Drug-eluting beads transarterial chemoembolization by CalliSpheres is effective and well tolerated in treating intrahepatic cholangiocarcinoma patients: A preliminary result from CTILC study.

This study aimed to investigate the efficacy and safety of drug-eluting beads (DEB) transarterial chemoembolization (TACE) treatment in Chinese intrahepatic cholangiocarcinoma (ICC) patients.37 ICC patients underwent DEB-TACE treatment in CTILC study (registered on clinicaltrials.gov with registry No. NCT03317483) were included in this present study. Treatment response was assessed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Overall survival (OS) was calculated from the time of DEB-TACE operation until the date of death from any causes. Liver function change and adverse events (AEs) were recorded during and after DEB-TACE operation.3 (8.1%) patients achieved complete response (CR) and 22 (59.5%) patients achieved partial response (PR), with objective response rate (ORR) of 67.6%. After DEB-TACE treatment, mean OS was 376 days (95%CI: 341-412 days). Multivariate logistic regression analysis revealed that Bilobar disease (P = .040, OR: 0.105, 95% CI: 0.012-0.898) and portal vein invasion (P = .038, OR: 0.104, 95% CI: 0.012-0.881) could independently predict less possibility of ORR. Patients with ALB abnormal, TP abnormal, ALT abnormal and AST abnormal were increased at 1-week post DEB-TACE treatment (P = .034, P = .001, P < .001, P = .006, respectively), while returned to the levels at baseline after 1 to 3 months (all P > .050). Besides, most of the AEs were mild including pain, fever, vomiting, and nausea in this study.DEB-TACE was effective and well tolerated in treating ICC patients, and bilobar disease as well as portal vein invasion were independently correlated with less probability of ORR achievement.

Efficacy and Safety of Drug-Eluting Beads Transarterial Chemoembolization by CalliSpheres® in 275 Hepatocellular Carcinoma Patients: Results From the Chinese CalliSpheres® Transarterial Chemoembolization in Liver Cancer (CTILC) Study.

The purpose of this study was to investigate the efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) treatment in Chinese hepatocellular carcinoma (HCC) patients and the prognostic factors for treatment response as well as survival. A total of 275 HCC patients were included in this prospective study. Treatment response was assessed by modified Response Evaluation Criteria in Solid Tumors (mRECIST), and progression-free survival (PFS) as well as overall survival (OS) were determined. Liver function and adverse events (AEs) were assessed before and after DEB-TACE operation. Complete response (CR), partial response (PR), and objective response rate (ORR) were 22.9%, 60.7%, and 83.6%, respectively. The mean PFS was 362 (95% CI: 34.9-375) days, the 6-month PFS rate was 89.4 ± 2.1%, while the mean OS was 380 (95% CI: 370-389) days, and the 6-month OS rate was 94.4 ± 1.7%. Multivariate logistic regression revealed that portal vein invasion (p = 0.011) was an independent predictor of worse clinical response. Portal vein invasion (p = 0.040), previous cTACE treatment (p = 0.030), as well as abnormal serum creatinine level (BCr) (p = 0.017) were independent factors that predicted worse ORR. In terms of survival, higher Barcelona Clinic Liver Cancer (BCLC) stage (p = 0.029) predicted for worse PFS, and abnormal albumin (ALB) (p = 0.011) and total serum bilirubin (TBIL) (p = 0.009) predicted for worse OS. The number of patients with abnormal albumin, total protein (TP), TBIL, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were augmented at 1 week posttreatment and were similar at 1-3 months compared with baseline. The most common AEs were pain, fever, nausea, and vomiting, and no severe AEs were observed in this study. DEB-TACE was effective and tolerable in treating Chinese HCC patients, and portal vein invasion, previous cTACE treatment, abnormal BCr, ALB, and TBIL appear to be important factors that predict worse clinical outcome.

The Comprehensive Analysis of Efficacy and Safety of CalliSpheres® Drug-Eluting Beads Transarterial Chemoembolization in 367 Liver Cancer Patients: A Multiple-Center, Cohort Study.

This study aimed to investigate the efficacy, safety, and prognostic factors of drug-eluting beads transarterial chemoembolization (DEB-TACE) in treating Chinese patients with liver cancer. A total of 367 liver cancer patients from 24 medical centers were consecutively enrolled in this multiple-center, prospective cohort study, including 275 hepatocellular carcinoma (HCC) cases, 37 intrahepatic cholangiocarcinoma (ICC) cases, and 55 secondary liver cancer cases. All the patients received CalliSpheres® DEB-TACE treatment. Treatment response, overall survival (OS), change of liver function, and adverse events (AEs) were assessed. DEB-TACE treatment achieved 19.9% complete response (CR) and 79.6% objective response rate (ORR), with mean OS of 384 days [95% confidence interval (CI): 375-393 days]. CR and ORR were both higher in HCC patients compared with primary ICC patients and secondary liver cancer patients, while no difference was discovered in OS. Portal vein invasion was an independent risk factor for CR, while portal vein invasion, previous conventional TACE (cTACE) treatment, and abnormal blood creatinine (BCr) were independent risk factors for ORR. In addition, largest nodule size ≥5.0 cm, abnormal albumin (ALB), and abnormal total bilirubin (TBIL) independently correlated with unfavorable OS. Most liver function indexes were recovered to baseline levels at 1-3 months after DEB-TACE. Common AEs were pain, fever, vomiting, and nausea; most of them were at mild grade. CalliSpheres® DEB-TACE is efficient and well tolerated in Chinese liver cancer patients. Portal vein invasion, previous cTACE treatment, largest nodule size, abnormal BCr, ALB, and TBIL correlate with worse prognosis independently.

Efficacy and safety of CalliSpheres® drug-eluting beads transarterial chemoembolization in patients with secondary liver cancer: a preliminary result from CTILC study.

BACKGROUND: This study aimed to assess the treatment response, short-term overall survival (OS) and safety profiles of drug-eluting beads transarterial chemoembolization (DEB-TACE) in patients with secondary liver cancer. METHODS: Fifty-five patients with secondary liver cancer underwent DEB-TACE were enrolled in this prospective cohort study. Treatment response was assessed by modified Response Evaluation Criteria in Solid Tumors (mRECIST). OS was calculated from the time of DEB-TACE operation until the date of death. RESULTS: The complete response (CR) and objective response rate (ORR) at 1-3 months post DEB-TACE were 12.7% and 67.3%. Mean OS was 383 d (95% CI: 360-406), and 6-month OS rate was 93.4%±3.7%. Subgroup analysis revealed previous conventional TACE (cTACE) treatment was correlated with worse ORR (P=0.028), and it was a risk factor for ORR achievement (P=0.021). As for liver function, the percentages of abnormal TP (P=0.031), TBIL (P=0.022), ALT (P=0.002) and AST (P=0.035) were increased at 1 week post DEB-TACE compared to baseline, while these four indexes returned to baseline (all P>0.05) at 1-3 months post DEB-TACE. As to safety profiles, 41 (66.1%), 28 (45.2%), 17 (27.4%), 8 (12.9%) and 6 (9.7%) cases had pain, vomiting, fever, nausea and other adverse events (AEs) respectively during DEB-TACE operation, while 26 (41.9%), 9 (14.5%), 8 (12.9%), 4 (6.5%), 1 (1.6%) and 2 (3.2%) cases had pain, fever, vomiting, nausea, bone marrow toxicity and other AEs respectively at 1 month after DEB-TACE operation. CONCLUSIONS: DEB-TACE was efficient and well tolerated in treating patients with secondary liver cancer.