The coexistence of myosteatosis and the creatinine/cystatin C ratio are determinants of outcomes in cholangiocarcinoma patients undergoing curative surgery.

Background: Myosteatosis is a well-established predictor of poor prognosis in many types of cancer, and a decreased Creatinine/Cystatin C ratio (CCR) is a known indicator of unfavorable outcomes in patients with metabolic disorders and cancer. Despite this knowledge, the significance of concurrent CCR and myosteatosis in predicting the prognosis of patients with cholangiocarcinoma (CCA) who undergo radical surgery remains uncertain. Method: Data from 757 patients with cholangiocarcinoma who underwent the first radical resection in the Affiliated Hospital of Qingdao University from January 2017 to March 2022 were collected. According to the inclusion and exclusion criteria, 149 patients were finally included in the retrospective study cohort. Various clinicopathological, serological, and radiological data were collected at admission. Myosteatosis was evaluated using sliceOmatic software on computed tomography (CT) images. The study used receiver operating characteristic (ROC) curve analysis to determine the critical value of CCR, which predicts overall survival (OS) based on the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were employed to identify the risk factors associated with OS and RFS confidently. Results: The group identified as the myosteatosis cohort consisted of 79 patients with an average age of 64.3 ± 7.8 years. The ROC curve analysis revealed an optimal critical CCR value of 10.834. A low CCR ≤ 10.834 and myosteatosis were found to be associated with poor OS and RFS outcomes (P = 0.022; P = 0.017; P = 0.038; P = 0.030 respectively). Moreover, patients with myosteatosis and a CCR ≤ 10.834 had the worst OS and RFS outcomes (P = 0.035; P = 0.027). Conclusion: After radical excision in CCA patients, the presence of myosteatosis and CCR had a negative correlation with prognosis. A more accurate prediction of OS and RFS was possible by combining CCR and myosteatosis, compared to CCR alone.

Neutrophil extracellular traps are associated with enhanced procoagulant activity in liver cirrhosis patients with portal vein thrombosis.

OBJECTIVE: Patients with liver cirrhosis (LC) commonly exhibit hypercoagulability and tend to develop thrombosis. Neutrophil extracellular traps (NETs) are associated with a variety of thrombotic conditions, but their possible value in portal vein thrombosis (PVT) is not known. We assessed whether NETs promote thrombosis and contribute to the procoagulant state in patients with LC. METHODS: The circulating levels of NETs markers (myeloperoxidase, neutrophil elastase, citrullinated histone H3) were measured in 72 patients (median age, 55 years; 48 [66.7%] men) with LC from September 2020 to February 2021. Then they were divided into two groups: patients with or without PVT. NETs procoagulant activity was assessed based on thrombin-antithrombin complex (TAT complex) and Factor X. The levels of plasma markers were determined by ELISA. RESULTS: There were 28 patients with PVT and 44 patients without PVT. The levels of NETs markers and hypercoagulability markers in the plasma of cirrhosis patients with PVT were significantly higher than those of cirrhosis patients without PVT (p < 0.05). Additionally, the levels of the NETs markers correlated with TAT complex and Factor X (Spearman correlation rho >0.73, p < 0.0001). CONCLUSIONS: Neutrophil extracellular traps seem to enhance procoagulant activity in LC patients with PVT; thus, they may be a practical predictor of PVT as well as a rapid and easy-to-use diagnostic and treatment guide for PVT in patients with cirrhosis.

Prognostic significance of systemic immune-inflammation index and platelet-albumin-bilirubin grade in patients with pancreatic cancer undergoing radical surgery.

Background: Systemic inflammatory markers are associated with patient survival in pancreatic cancer (PC). The aim of this study was to investigate the prognostic significance of the systemic immune-inflammation index (SII) in PC patients who underwent radical surgery. Platelet-albumin-bilirubin (PALBI) grade is a composite evaluation index based on liver function. Patients with pancreatic head cancer are prone to obstructive jaundice, which leads to abnormal liver function. Based on this, we also explored the prognostic value of PALBI grade in PC patients. Methods: Patients with pathologically confirmed PC who had undergone radical surgery (with negative surgical margin) for the first time at the Affiliated Hospital of Qingdao University from January 2013 to December 2019 and followed up by December 2020 were retrospectively analyzed. Peripheral blood cell count is easily affected by infection or hematological diseases, which affects the results, so it is excluded. Clinical data and laboratory examination indexes were collected. The SII and PALBI grade were calculated. The cutoff values were determined using the Youden index. The Cox proportional hazards regression model was used to analyze the prognostic value of the SII and PALBI grade through univariate and multivariate survival analysis. Results: A total of 214 patients [median age, 60.29 years; 128 (59.8%) men] met the inclusion criteria. There were 140 patients (65.4%) with pancreatic head cancer according to the tumor location. They were divided into high and low SII or PALBI groups by cutoff values of 705 and -5.6, respectively. According to the multivariate analysis, SII (P<0.001) was an independent factor negatively associated with overall survival (OS) and disease-free survival (DFS). In patients with pancreatic head cancer, PALBI grade was associated with shorter OS (P=0.031). The combination of high SII and high PALBI grade had stronger predictive value for poor prognosis (log-rank test, P<0.001), which the OS was 11.3 months less than the combination of low two groups. Conclusions: SII was a promising prognostic biomarker in PC. And PALBI grade also showed predictive value for patients with pancreatic head cancer. Therefore, it can help predict the treatment outcomes in these patients.

Discovery of DDO-2213 as a Potent and Orally Bioavailable Inhibitor of the WDR5-Mixed Lineage Leukemia 1 Protein-Protein Interaction for the Treatment of MLL Fusion Leukemia.

WD repeat-containing protein 5 (WDR5) is essential for the stability and methyltransferase activity of the mixed lineage leukemia 1 (MLL1) complex. Dysregulation of the MLL1 gene is associated with human acute leukemias, and the direct disruption of the WDR5-MLL1 protein-protein interaction (PPI) is emerging as an alternative strategy for MLL-rearranged cancers. Here, we represent a new aniline pyrimidine scaffold for WDR5-MLL1 inhibitors. A comprehensive structure-activity analysis identified a potent inhibitor 63 (DDO-2213), with an IC50 of 29 nM in a competitive fluorescence polarization assay and a Kd value of 72.9 nM for the WDR5 protein. Compound 63 selectively inhibited MLL histone methyltransferase activity and the proliferation of MLL translocation-harboring cells. Furthermore, 63 displayed good pharmacokinetic properties and suppressed the growth of MV4-11 xenograft tumors in mice after oral administration, first verifying the in vivo efficacy of targeting the WDR5-MLL1 PPI by small molecules.

Design, synthesis and bioevaluation of inhibitors targeting HSP90-CDC37 protein-protein interaction based on a hydrophobic core.

HSP90-CDC37 protein-protein interaction (PPI) works as a kinase specific-molecular chaperone system to regulate the maturation of kinases. Currently, selectively disrupting HSP90-CDC37 PPI, rather than the direct inhibition of the ATPase function of HSP90, is emerging as a promising strategy for cancer therapy by specifically blocking the maturation of kinases. However, due to the limited understanding of HSP90-CDC37 binding interface, design of small molecule inhibitors targeting HSP90-CDC37 PPI is challenging. In this work, based on the binding mode of compound 11 (previously reported by our group), we discovered a hydrophobic pocket centered on Phe213, which was previously unknown, contributing to the binding affinity of HSP90-CDC37 PPI inhibitors. A series of hydrophobic substituted inhibitors were utilized to confirm the importance of Phe213 hydrophobic core. Finally, we obtained an optimum compound DDO-5994 (exhibited an ideal binding pattern on hydrophobic core) with improved binding affinity (KD = 5.52 µM) and antiproliferative activity (IC50 = 6.34 µM). Both in vitro and in vivo assays confirmed DDO-5994 as a promising inhibitor to exhibit ideal antitumor efficacy through blocking HSP90-CDC37 PPI.

Discovery and Optimization of Small Molecules Targeting the Protein-Protein Interaction of Heat Shock Protein 90 (Hsp90) and Cell Division Cycle 37 as Orally Active Inhibitors for the Treatment of Colorectal Cancer.

Cell division cycle 37 (Cdc37) is known to work as a kinase-specific cochaperone, which selectively regulates the maturation of kinases through protein-protein interaction (PPI) with Hsp90. Directly disrupting the Hsp90-Cdc37 PPI is emerging as an alternative strategy to develop anticancer agents through a specific inhibition manner of kinase clients of Hsp90. Based on a first specific small-molecule inhibitor targeting Hsp90-Cdc37 PPI (DDO-5936), which was previously reported by our group, we conducted a preliminary investigation of the structure-activity relationships and pharmacodynamic evaluations to improve the potency and drug-like properties. Here, our efforts resulted in the currently best inhibitor 18h with improved binding affinity (Kd = 0.5 µM) and cellular inhibitory activity (IC50 = 1.73 µM). Both in vitro and in vivo assays revealed that 18h could efficiently block the Hsp90-Cdc37 interaction to specifically inhibit kinase clients of Hsp90. Furthermore, 18h showed ideal physiochemical properties with favorable stability, leading to an oral efficacy in vivo.

Notch1 and PI3K/Akt signaling blockers DAPT and LY294002 coordinately inhibit metastasis of gastric cancer through mutual enhancement.

PURPOSE: Blockade of either Notch1 or PI3K/Akt pathway inhibits metastasis of gastric cancer. However, whether blockade of both pathways coordinately exerts such an effect remains unknown. In this study, we aimed to investigate the effects of combined treatment with Notch1 signaling blocker DAPT and PI3K/Akt signal blocker LY294002 on metastasis of gastric cancer. METHODS: Notch intracellular domain (NICD) and phosphorylated Akt (p-Akt) levels in gastric cancer tissues and their adjacent normal tissue samples and gastric cancer SGC7901 and AGS cells and normal GES-1 cells were determined using immunohistochemistry and Western blotting. The effects of combined DAPT and LY294002 on metastasis of gastric cancer were evaluated by examining migration and invasion potential of SGC7901 cells using wound healing and transwell assays, determining changes in the levels of epithelial-mesenchymal transition biomarkers and MMP-9, Notch1, HES1, and phosphorylation of Akt in gastric cancer SGC7901 cells and/or AGS cells in vitro using Western blotting, and metastasis of gastric cancer to lungs in BALB/c nude mice after treatment. RESULTS: NICD and p-Akt levels were significantly higher in gastric cancer tissues and SGC7901 and AGS cells than those in the normal control and GES-1 cells. Migration and invasion potential of SGC7901 cells, EMT biomarkers and MMP-9 in SGC7901 cells, and metastasis of gastric cancer to lungs in mice were coordinately inhibited by DAPT and LY294002. In addition, DAPT and LY294002 coordinately inhibited the levels of Notch1, HES1, and p-Akt in gastric cancer cells. CONCLUSION: DAPT and LY294002 coordinately inhibited metastasis of gastric cancer through mutual enhancement.

Circular RNA hsa_circ_0000885 Levels are Increased in Tissue and Serum Samples from Patients with Osteosarcoma.

BACKGROUND Circular RNAs (circRNAs) are novel non-coding RNAs that have important roles in tumor progression. This study aimed to measure the levels of hsa_circ_0000885 in serum samples and tumor tissue from patients with osteosarcoma compared with controls and to evaluate the findings with disease-free survival and overall survival. MATERIAL AND METHODS Fifty pairs of osteosarcoma tissues and matched adjacent normal tissue were obtained from patients who underwent the same chemotherapy regimen before surgery. Blood samples were obtained from 30 patients with osteosarcoma before and after chemotherapy, 25 patients with osteosarcoma before and after surgery, 27 patients with benign bone tumors, and 25 age-matched and sex-matched healthy controls. Circular RNA sequencing and quantitative real-time polymerase chain reaction (qRT-PCR) were used to analyze hsa_circ_0000885 expression. RESULTS Hsa_circ_0000885 expression was significantly increased in tissue and serum samples from patients with osteosarcoma, compared with controls, with significantly increased expression levels in patients with Enneking stage IIB and III osteosarcoma, compared with early-stage osteosarcoma. Patients with high serum and tumor levels of hsa_circ_0000885 had lower rates of disease-free survival and overall survival. The serum expression levels of hsa_circ_0000885 were significantly higher in patients with osteosarcoma compared with patients with benign bone tumors or healthy controls. CONCLUSIONS Hsa_circ_0000885 was upregulated in osteosarcoma, and it could serve as a good prognostic biomarker indicating poor clinical outcomes of osteosarcoma. Hsa_circ_0000885 was upregulated in serum of osteosarcoma patients and could serve as a good diagnostic biomarker for osteosarcoma.

Benzodiazepine drug use and cancer risk: a dose-response meta analysis of prospective cohort studies.

Conflicting results identifying the relationship between benzodiazepine drug use and cancer risk. Therefore, we conducted a dose-response meta-analysis of prospective cohort studies to clarify and quantitative assessed the relationship between benzodiazepine drug use and cancer risk. Up to July 2017, 22 original publications were included in current meta-analysis. Our results showed statistically significant association between benzodiazepine drug use and cancer risk (RR:1.25; 95% CI, 1.15-1.36). Subgroup analysis showed benzodiazepine using was associated with significantly a higher risk of breast cancer (RR:1.15; 95% CI, 1.05-1.26), ovarian cancer (RR:1.17; 95% CI, 1.09-1.25), colon cancer (RR:1.07; 95% CI, 1.02-1.13), renal cancer (RR:1.31; 95% CI, 1.15-1.49), malignant melanoma (RR:1.10; 95% CI, 1.03-1.17), brain cancer (RR:2.06; 95% CI, 1.76-2.43), esophagus cancer (RR:1.55; 95% CI, 1.30-1.85), prostate cancer (RR:1.26; 95% CI, 1.16-1.37), liver cancer (RR:1.22; 95% CI, 1.13-1.31), stomach cancer (RR:1.17; 95% CI, 1.03-1.32), pancreatic cancer (RR:1.39; 95% CI, 1.17-1.64) and lung cancer (RR:1.20; 95% CI, 1.12-1.28). Furthermore, a significant dose-response relationship was observed between benzodiazepine drug use and cancer risk (likelihood ratio test, P < 0.001). Our results showed per 500 mg/year, per 5 year of time since first using, per 3 prescriptions and per 3 year of duration incremental increase in benzodiazepine drug use was associated with a 17%, 4%, 16% and 5% in cancer risk increment. Considering these promising results, increasing benzodiazepine using might be harmful for health.

Association between nonsteroidal anti-inflammatory drugs use and risk of central nervous system tumors: a dose-response meta analysis.

Although studies have examined the association between nonsteroidal anti-inflammatory drugs (NSAIDs) use and central nervous system (CNS) tumors risk, the results are inconclusive. Here, we conducted a dose-response meta-analysis in order to investigate the correlation between NSAIDs use and CNS tumors risk. Up to July 2017, 12 studies were included in current meta-analysis. NSAIDs use was significantly associated with a lower risk of CNS tumors. Furthermore, non-aspirin NSAIDs or aspirin use are significantly associated with a lower risk of CNS tumors. Additionally, NSAIDs use was associated with significantly a lower risk of glioma, glioblastoma but not meningioma. Subgroup analysis showed consistent findings. Furthermore, a significant dose-response relationship was observed between NSAIDs use and CNS tumors risk. Increasing cumulative 100 defined daily dose of NSAIDs use was associated with a 5% decrement of CNS tumors risk, increasing NSAIDs or non-aspirin NSAIDs or aspirin use (per 3 prescriptions increment) was associated with a 7%, 7%, 10% decrement of CNS tumors risk, increasing per 2 year of duration of NSAIDs or non-aspirin NSAIDs or aspirin use was associated with a 6%, 8%, 6% decrement of CNS tumors risk. Considering these promising results, NSAIDs use might provide helpful for reducing CNS tumors risk. Large sample size and different ethnic population are warranted to validate this association.