Metal-Organic Framework: Fabrication of Nano Fluorescent Composite Materials and Treatment of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumor originating from liver cells, characterized by complex pathogenesis and limited treatment options such as surgery, chemotherapy, and transplantation. Cisplatin, an effective chemotherapeutic agent, disrupts cancer cell DNA but is hindered by side effects and the need for controlled sustained release to optimize efficacy. Metal-organic frameworks (MOFs) have emerged as promising nanocarriers for precise local drug delivery, reducing required doses and mitigating side effects of chemotherapeutic drugs, thus offering a potential avenue for hepatocellular carcinoma (HCC) treatment. In this research, a rectangular channel MOF (Rumgay H, Ferlay J, Martel C, Georges D, Ibrahim AS, Zheng R, Wei W, Lemmens VEPP, Soerjomataram I (2022) Global, regional and national burden of primary liver cancer by subtype. Eur J Cancer 161:108-118) carrier was synthesized using ligand L as the organic linker coordinated with Cu(II) and I(I). The MOF's structure and fluorescence properties were characterized. Additionally, to enhance substrate biocompatibility, composite carrier materials were prepared by incorporating polylactic acid (PLA) with 1, utilized for cisplatin loading. To evaluate the inhibitory effect of PLA-1@cisplatin on HCC, HepG-2 and Huh-7 HCC cell lines were treated with varying concentrations of the drug for 48 h, and their cell viability was assessed. The results demonstrated a significant dose-dependent reduction in cell viability of both HepG-2 and Huh-7 cells. To explore the potential inhibitory mechanism of PLA-1@cisplatin on HCC, the mRNA levels of GADD45A and NACC1 in HepG-2 and Huh-7 cells post-treatment were measured. GADD45A expression, initially low in HCC cells, was significantly upregulated after drug treatment, while NACC1, typically highly expressed in HCC, showed a significant decrease in mRNA levels with increasing concentrations of PLA-1@cisplatin. These findings indicate that PLA-1@cisplatin effectively upregulates GADD45A expression and downregulates NACC1 expression. Overall, the developed cisplatin-loaded nanoparticle system holds promise for HCC treatment by reducing chemotherapy side effects and enhancing drug efficacy.

Distinctive Metabolism-Associated Gene Clusters That Are Also Prognostic in Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma.

Objective: To offer new prognostic evaluations by exploring potentially distinctive genetic features of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Methods: There were 12 samples for gene expression profiling processes in this study. These included three HCC lesion samples and their matched adjacent nontumor liver tissues obtained from patients with HCC, as well as three ICC samples and their controls collected similarly. In addition to the expression matrix generated on our own, profiles of other cohorts from The Cancer Genome Atlas (TCGA) program and the Gene Expression Omnibus (GEO) were also employed in later bioinformatical analyses. Differential analyses, functional analyses, protein interaction network analyses, and gene set variation analyses were used to identify key genes. To establish the prognostic models, univariate/multivariate Cox analyses and subsequent stepwise regression were applied, with the Akaike information criterion evaluating the goodness of fitness. Results: The top three pathways enriched in HCC were all metabolism-related; they were fatty acid degradation, retinol metabolism, and arachidonic acid metabolism. In ICC, on the other hand, additional pathways related to fat digestion and absorption and cholesterol metabolism were identified. Consistent characteristics of such a metabolic landscape were observed across different cohorts. A prognostic risk score model for calculating HCC risk was constructed, consisting of ADH4, ADH6, CYP2C9, CYP4F2, and RDH16. This signature predicts the 3-year survival with an AUC area of 0.708 (95%CI = 0.644 to 0.772). For calculating the risk of ICC, a prognostic risk score model was built upon the expression levels of CYP26A1, NAT2, and UGT2B10. This signature predicts the 3-year survival with an AUC area of 0.806 (95% CI = 0.664 to 0.947). Conclusion: HCC and ICC share commonly abrupted pathways associated with the metabolism of fatty acids, retinol, arachidonic acids, and drugs, indicating similarities in their pathogenesis as primary liver cancers. On the flip side, these two types of cancer possess distinctive promising biomarkers for predicting overall survival or potential targeted therapies.

Silibinin Therapy Improves Cholangiocarcinoma Outcomes by Regulating ERK/Mitochondrial Pathway.

Background: Silibinin is widely utilized drug in various cancer treatments, though its application in cholangiocarcinoma has not yet been explored. For the first time, we evaluated the anticancer potential and underlying molecular mechanism of silibinin in treatment of cholangiocarcinoma treatment. Methods: HuCCT-1 and CCLP-1 cells were chosen to be an in vitro study model and were exposed to various concentrations of silibinin for indicated times. Cell viability was evaluated by the cell counting kit-8 (CCK-8) assay and half maximal inhibitory (IC50) concentrations were calculated. Cell proliferation capacity was determined through the use of colony formation and 5-Ethynyl-2'- deoxyuridine (EdU) assays. Cell apoptosis and cycle arrest were assessed by Live/Dead staining assay and flow cytometry (FCM). The protein levels of extracellular regulated protein kinases (ERK)/mitochondrial apoptotic pathway were evaluated through western blotting (WB). Mitochondrial membrane potential changes were determined via 5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide (JC-1). A cholangiocarcinoma cell line xenograft model was used to assess the anti-tumor activity of silibinin in vivo. Results: Inhibition of the ERK protein by silibinin led to a significant decrease in mitochondrial membrane potential, which, in turn, caused Cytochrome C to be released from the mitochondria. The activation of downstream apoptotic pathways led to apoptosis of cholangiocarcinoma cells. In general, silibinin inhibited the growth of cholangiocarcinoma cell line xenograft tumors. Conclusions: Silibinin is able to inhibit cholangiocarcinoma through the ERK/mitochondrial apoptotic pathway, which makes silibinin a potential anti-tumor drug candidate for cholangiocarcinoma treatment.

BCAT1, a key prognostic predictor of hepatocellular carcinoma, promotes cell proliferation and induces chemoresistance to cisplatin.

BACKGROUND & AIMS: BCAT1 initiates the catabolism of branched-chain amino acids. Here, we investigated the function of BCAT1 and its transcriptional regulatory mechanism in hepatocellular carcinoma (HCC). METHODS: RNASeq was used to evaluate BCAT1 mRNA levels in HCC and normal matched specimens. After the exogenous expression of BCAT1 in BEL-7404 cells and the suppression of endogenous BCAT1 expression with shRNA in HepG2 cells, the cell proliferation, clone-forming ability and cell-cycle changes were measured with MTT assay, colony-forming assay and flow cytometry respectively. A xenograft model was used to investigate the effect of BCAT1 on cancer growth in vivo. Chromatin immunoprecipitation and luciferase reporter technologies were used to confirm the transcriptional regulation of the BCAT1 gene by MYC. The expression of the BCAT1 and MYC proteins in 122 HCC tissues was determined with an immunohistochemical analysis. RESULTS: BCAT1 mRNA was clearly increased in HCC tissues and hepatomas. The ectopic expression of BCAT1 in BEL-7404 cells enhanced their proliferation, clone formation, tumourigenic properties, S-G2 /M phase transition and chemoresistance to cisplatin. The suppression of BCAT1 expression in HepG2 cells significantly inhibited their proliferation, clone formation, and S-G2 /M phase transition and caused their chemosensitization to cisplatin. MYC affected the transcriptional regulation of BCAT1. Clinical data showed that BCAT1 expression correlated with a significantly poorer prognosis. CONCLUSION: BCAT1 plays a pathogenic role in HCC by causing cell proliferation and chemoresistance. The MYC transcription factor is involved in regulating the transcriptional activity of BCAT1. BCAT1 expression has prognostic significance for the survival of patients with HCC.

MicroRNA-145-5p inhibits gastric cancer invasiveness through targeting N-cadherin and ZEB2 to suppress epithelial-mesenchymal transition.

MicroRNA (miR)-145-5p has been reported to function as a suppressor of cancer and plays an important role in cancer invasiveness. Epithelial-mesenchymal transition (EMT) is an important process in cancer invasion and migration. However, the involvement of miR-145-5p in EMT in human gastric cancer (GC) remains unclear. In this study, we aimed to investigate the molecular mechanisms by which miR-145-5p regulates EMT in GC invasiveness. We used quantitative real-time polymerase chain reaction to investigate the miR-145-5p expression level in GC and matched normal tissues. The effects of miR-145-5p on GC cell invasion and migration abilities were evaluated using Transwell models. The relationships among miR-145-5p and zinc-finger E-box binding homeobox 2 (ZEB2), E-cadherin, and N-cadherin were analyzed by quantitative real-time polymerase chain reaction and Western blot analyses. miR-145-5p levels in primary GC tissues obtained from 60 patients were significantly downregulated, compared to those in paired normal tissues. Lauren classification, depth of tumor invasion, lymph node metastasis, lymphatic invasion, and tumor-node-metastasis stage were associated with miR-145-5p expression. miR-145-5p inhibits the expression of the candidate target gene ZEB2 to delay the invasion and migration of GC cells. ZEB2 acts as transcriptional repressor of E-cadherin, while miR-145-5p is known to suppress N-cadherin directly to regulate EMT. Therefore, we concluded that miR-145-5p may target N-cadherin and ZEB2 directly to influence EMT.

A rare case of xanthogranulomatous pyelonepheritis with hepatic angiomyolipoma.

Xantogranulomatous pyelonephritis (XGP) is a rare and chronic variant of pyelonephritis typically associated with obstruction and infection. Xantogranulomatous pyelonephritis can infiltrate liver and connect with hepatic dysfunction. Here we report on a 52-year-old female with a liver mass and a left renal mass detected by uitrasonography and magnetic resonance imaging. Right lobectomy and partial nephrectomy were successively performed. Subsequent pathologic examination indicated hepatic angiomyolipoma and xanthogranulomatous pyelonepheritis, respectively. To the best of our knowledge, this is the first case of such rare combination.

Association Between IL-17, IL-8 and IL-18 Expression in Peripheral Blood and Helicobacter Pylori Infection in Mongolian Gerbils.

BACKGROUND: Persistent Helicobacter pylori infection confers an increased risk for serious illnesses such as peptic ulcers and gastric cancer. Various cytokines are involved in the regulation of inflammatory immune response in H. pylori-infected gastric mucosa. OBJECTIVES: The current study aimed to obtain evidence regarding the association between IL-17, IL-8 and IL-18 expression in peripheral blood and H. pylori infection in Mongolian gerbils. MATERIALS AND METHODS: Mongolian gerbils were inoculated with H. pylori by a metal stomach catheter. After sacrifice, their gastric mucosae were examined in macroscopic, histological and electron microscopy levels. In addition, enzyme linked immunosorbent assay (ELISA) assay was performed on the IL-17, IL-8 and IL-18 cytokines in the blood samples. RESULTS: Serum levels of IL-17, IL-8 and IL-18 were remarkably up-regulated compared to those of the control group. There was an obvious correlation between the increase of IL-17 and the serious extent of gastritis in the current study. However, the serum levels of IL-8 and IL-18 without getting increasingly more for repetitive intragastric administration. There were plenty of neutrophils infiltrating in the infected group mucosal. Intestinal metaplasia and gastric ulcers were also founded in H. pylori infected animals after enhanced inoculation. The edema, degeneration and necrosis changes could be found in organelles by transmission electron microscopy. More serious pathological changes were detected in the enhanced inoculation groups compared to the cycle group. CONCLUSIONS: The serum levels of IL-17, but not IL-8 and IL-18 may serve as a potential biomarker for diagnosis and predicting the prognosis of gastritis caused by H. pylori.

Bone marrow mesenchymal stem cells promote osteosarcoma cell proliferation and invasion.

BACKGROUND: Bone marrow-derived stem cells (BMSCs) are locally adjacent to the tumor tissues and may interact with tumor cells directly. The purpose of this study was to explore the effects of BMSCs on the proliferation and invasion of osteosarcoma cells in vitro and the possible mechanism involved. METHODS: BMSCs were co-cultured with osteosarcoma cells, and CCK-8 assay was used to measure cell proliferation. The ELISA method was used to determine the concentration of stromal cell-derived factor-1 (SDF-1) in the supernatants. Reverse transcription polymerase chain reaction (RT-PCR) was performed to detect the expression of CXCR4 in osteosarcoma cells and BMSCs. Matrigel invasion assay was performed to measure tumor cell invasion. RESULTS: SDF-1 was detected in the supernatants of BMSCs, but not in osteosarcoma cells. Higher CXCR4 mRNA levels were detected in the osteosarcoma cell lines compared to BMSCs. In addition, conditioned medium from BMSCs can promote the proliferation and invasion of osteosarcoma cells, and AMD3100, an antagonist for CXCR4, can significantly downregulate these growth-promoting effects. CONCLUSIONS: BMSCs can promote the proliferation and invasion of osteosarcoma cells, which may involve the SDF-1/CXCR4 axis.

Sarcopenia as a prognostic factor in hepatolithiasis-associated intrahepatic cholangiocarcinoma patients following hepatectomy: a retrospective study.

BACKGROUND: Sarcopenia is closely associated with poor performance status and high mortality in cancer patients. The present study is to determine the correlation between sarcopenia and prognosis of hepatectomy for hepatolithiasis-associated intrahepatic cholangiocarcinoma (IHHCC). METHODS: Sixty-seven eligible IHHCC patients who underwent hepatectomy, between January 2000 and August 2014 were retrospectively evaluated. Sarcopenia was determined from skeletal muscle index (SMI), assessed by skeletal muscle mass on axial computed tomography images. Factors contributing to overall survival (OS) and recurrence-free survival (RFS) were analyzed by univariate and multivariate analyses. RESULTS: Sarcopenia occurred in 33 (49.3%) out of 67 patients. Median OS of the enrolled patients was 12 months. Sarcopenic patients had a shorter OS compared with non-sarcopenic patients (P < 0.001). On univariate analyses, sarcopenia was significantly associated with overall survival (OS) and recurrence-free survival (RFS; both P < 0.05). On multivariate analysis, sarcopenic patients suffered poor overall survival (P < 0.001) and recurrence-free survival (P = 0.011) compared with non-sarcopenic patients. CONCLUSIONS: Preoperative sarcopenia is an independent biomarker of poor prognosis in IHHCC patients following hepatectomy. The identification of sarcopenia may enhance a clinical consideration on decision making for IHHCC patients before surgery.

Neutrophil-lymphocyte ratio: a controversial marker in predicting Crohn's disease severity.

Peripheral blood-derived inflammation-based scores such as the neutrophil-lymphocyte ratio (NLR) have recently been proposed as prognostic markers in ulcerative colitis. In some previous serological markers are commonly used to detect the severity of the Crohn's disease (CD), but their sensitivity and specificity are relatively low. So we want to use simple indicators which are easy to obtain to predict disease severity. Now, we investigated and compared the capacity of NLR and other inflammatory markers in detecting CD activity and differentiating CD patients from healthy controls. These CD patients had not received corticosteroid or immunosuppressive drugs within a defined period of time. Data from our hospital between 2010 and 2012 was used. Neutrophil-lymphocyte ratio (NLR), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cells (WBC), platelet count and albumin were measured in 44 patients with active CD, 66 patients with inactive CD, and 55 healthy blood donors. Disease activity was assessed by the Crohn's Disease Activity Index. In the active CD group, NLR values were found to be elevated compared to inactive CD patients and controls (6.00±7.38, 5.53±6.18 and 1.84±0.85, respectively), but statistical difference was not found between active and inactive CD groups. The overall accuracy of NLR (cutoff: 2.13 fl), CRP (cutoff: 10.5 mg/dl), ESR (cutoff: 19.5 mm/hour) and WBC (cutoff: 9.2 × 10(9)/l) in differentiating CD patients from healthy controls was 80.9%, 67.3%, 71% and 60% respectively. NLR values were found to be correlated with WBC and CRP levels. NLR increased in CD patients compared with healthy subjects. NLR had the best accuracy in determination of CD patients and healthy controls. NLR did not show a discriminative value in disease activity.

Clinical investigation on application of water swallowing to MR esophagography.

OBJECTIVE: To verify the clinical outcomes of applying water swallowing to MR esophagography. METHODS: Thirty patients confirmed postoperatively or histopathologically with thoracic esophageal carcinoma by endoscopic biopsy and 10 healthy volunteers with normal esophagus underwent respectively conventional magnetic resonance imaging (MRI) detection and water swallowing MR esophagography. Of those patients, 4 underwent second examination after radiotherapy. Assessment on imaging effects of MR esophagography was performed. Assessment on definition on MR esophagography of the tumor in both upper and lower ends, specific localization, tumor size finally measured, coincidence with the gross pathologic types and tumor staging were respectively performed by comparison with conventional MRI. Additionally, we evaluated the outcomes of radiotherapy by comparing the previous MR esophagography with the second one with interventional technique. RESULTS: Of the total 44 images of MR esophagography, 97.7% (43/44) were in high resolution by sagittal view and 81.8% (36/44) by cross-section. 93.3% (56/60) of the MR esophagography were clearly defined with the neoplastic lesion ends in the 30 patients with thoracic esophageal carcinoma, compared with 11.7% (7/60) by conventional MRI. The results were totally different in statistics (P<0.005). Preoperative conventional MRI detection of the 22 cases in 25 undergone radical resection suggested vague diameter of the primary tumor and impossibly identified it at middle-lower thoracic esophagus in 5, and even failed to confirm gross pathologic types in 19 cases. Yet, MR esophagography with water swallowing represented accurate tumor length (graded as excellent) in 88% (22/25), localization in 100% (25/25), exact gross pathologic types in 88% (22/25), and accuracy for tumor staging in 80.8% (21/26) compared to 92.3% (24/26) by conventional MRI. Therapeutic effects achieved in 4 patients with radiotherapy. CONCLUSIONS: MR esophagography with water swallowing makes optimal esophagram and is of great value in the preoperative diagnosis of thoracic esophageal cancer and assessment of the radiotherapy effects for patients with such neoplasm, which may serve as an alternative for conventional MRI.