Rapid Detection of Recurrent Non-Muscle Invasive Bladder Cancer in Urine Using ATR-FTIR Technology.

Non-muscle Invasive Bladder Cancer (NMIBC) accounts for 80% of all bladder cancers. Although it is mostly low-grade tumors, its high recurrence rate necessitates three-times-monthly follow-ups and cystoscopy examinations to detect and prevent its progression. A rapid liquid biopsy-based assay is needed to improve detection and reduce complications from invasive cystoscopy. Here, we present a rapid spectroscopic method to detect the recurrence of NMIBC in urine. Urine samples from previously-diagnosed NMIBC patients (n = 62) were collected during their follow-up visits before cystoscopy examination. Cystoscopy results were recorded (41 cancer-free and 21 recurrence) and attenuated total refraction Fourier transform infrared (ATR-FTIR) spectra were acquired from urine samples using direct application. Spectral processing and normalization were optimized using parameter grid searching. We assessed their technical variability through multivariate analysis and principal component analysis (PCA). We assessed 35 machine learning models on a training set (70%), and the performance was evaluated on a held-out test set (30%). A Regularized Random Forests (RRF) model achieved a 0.92 area under the receiver operating characteristic (AUROC) with 86% sensitivity and 77% specificity. In conclusion, our spectroscopic liquid biopsy approach provides a promising technique for the early identification of NMIBC with a less invasive examination.

Design and synthesis of new phthalazine-based derivatives as potential EGFR inhibitors for the treatment of hepatocellular carcinoma.

Searching for new leads in the battle of cancer will never ends, we herein disclose the design and synthesis of new phthalazine derivatives and their in vitro and in vivo testing for their antiproliferative activity. Phthalazine was selected as a privilege moiety that is incorporated in a big number of anticancer drugs in clinical use or that are still under clinical or preclinical studies. We utilized the drug extension strategy to tailor the designed compounds to fit the EGFR hydrophobic sub pocket and cleft region. The designed phthalazine derivatives was synthesized by linking phthalazine moiety with 1,3,4-oxadiazole-thione and 1,2,4-triazole-thione. Alkylation and glycosylation of the new heterocyclic systems were successfully performed to be used in the drug extension. Coupling of some phthalazine derivatives with different amino acids was also performed to improve the drug selectivity. The synthesized compounds were tested for their antiproliferative activity against cancer cells both in vivo and in vitro. The in vitro activity against hepatocellular carcinoma (HepG2 cell line) ranged from 5.7 µg/mL to 43.4 µg/mL. Compounds 31a and 16 were the most active with an IC50 5.7 µg/mL and 7.09 µg/mL, respectively compared to the standard compound doxorubicin (4.0 µg/mL). In vivo, compounds 10 and 16 showed IC50 values 7.25 µg/mL and 7.5 µg/mL, respectively compared to the standard compound cisplatin (IC50 9.0 µg/mL). In silico, testing of the phthalazine derivatives showed that they are good inhibitors for EGFR. The docking studies substantiated compounds 4, 10, 16 and 31a as new lead compounds and identified Arg841 as a key residue in the cleft region for binding stronger inhibitors.

Stemness-related transcriptional factors and homing gene expression profiles in hepatic differentiation and cancer.

Stem cell transcriptional signature activation is an essential event in the development of cancer. This study aimed to investigate the differential expression profile of three pluripotency-associated genes (OCT4, NANOG, and SOX2), G-protein-coupled chemokine receptor 4 (CXCR4) and the ligand (CXCL2), and alpha feto-protein (AFP) in hepatogenic differentiated stem cells and in sera of hepatitis C virus (HCV) and HCV-induced hepatocellular carcinoma (HCC) patients. Mesenchymal stem cells derived from umbilical cord blood were differentiated using hepatogenic differentiation media. Serum specimens were collected from 96 patients (32 cirrhotic HCV, 32 early HCC, and 32 late HCC) and 96 controls. Real-time quantitative reverse transcription polymerase chain reaction was performed for relative quantification of the 6 target genes using LIVAC method. In silico network analysis was also executed to explore the pluripotency and tumorigenic regulatory circuits in liver cancer. The expression levels of all genes declined gradually during the stages of stem cell differentiation. On univariate and multivariate analyses, NANOG, CXCR4 and AFP were significantly up-regulated in HCC patients with late clinical stage. In contrast, SOX2 and CXCL2 were markedly over-expressed in cirrhotic patients and could be used for clear demarcation between cirrhotic and HCC patients in our cases. In conclusion, our data highlight the potential role of SOX2 stem cell marker and CXCL2 chemokine in liver cell degeneration and fibrogenesis in HCV-induced hepatic cirrhosis in our sample of the Egyptian population. In addition, the significant association of NANOG and CXCR4 high-expression with late HCC, could contribute to the acquisition of stem cell-like properties in hepatic cancer and dissemination in late stages, respectively. Taken together, our results could have a potential application in HCC prognosis and treatment.

Bis(acridine-9-carboxylate)-nitro-europium(III) dihydrate complex a new apoptotic agent through Flk-1 down regulation, caspase-3 activation and oligonucleosomes DNA fragmentation.

New bis(acridine-9-carboxylate)-nitro-europium(III) dihydrate complex was synthesized and characterized. In vivo anti-angiogenic activities of bis(acridine-9-carboxylate)-nitro-europium(III) dihydrate complex against Ehrlich ascites carcinoma (EAC) cells are described. The newly synthesized complex resulted in inhibition of proliferation of EAC cells and ascites formation. The anti-tumor effect was found to be through anti-angiogenic activity as evident by the reduction of microvessel density in EAC solid tumors. The anti-angiogenic effect is mediated through down-regulation of VEGF receptor type-2 (Flk-1). The complex was also found to significantly increase the level of caspase-3 in laboratory animals compared to the acridine ligand and to the control group. This was also consistent with the DNA fragmentation detected by capillary electrophoresis that proved the apoptotic effect of the new complex. Our complex exhibited anti-angiogenic and apoptotic activity in vivo, a thing that makes it a potential effective chemotherapeutic agent. The interaction of calf thymus DNA (ct-DNA) with bis(acridine-9-carboxylate)-nitro-europium(III) dihydrate complex has been investigated using fluorescence technique. A competitive experiment of the europium(III)-acridine complex with ethidium bromide (EB) to bind DNA revealed that interaction between the europium(III)-acridine and DNA was via intercalation. The interaction of the synthesized complex with tyrosine kinases was also studied using molecular docking simulation to further substantiate its mode of action.

Synthesis of novel Eu(III) luminescent probe based on 9- acridinecarboxylic acid skelton for sensing of ds-DNA.

Eu(III)-9-acridinecarboxylate (9-ACA) complex was synthesized and characterized by elemental analysis, conductivity measurement, IR spectroscopy, thermal analysis, mass spectroscopy, (1)H-NMR, fluorescence and ultraviolet spectra. The results indicated that the composition of this complex is [Eu(III)-(9-ACA)(2)(NCS)(C(2)H(5)OH)(2)] 2.5 H(2)O and the oxygen of the carbonyl group coordinated to Eu(III). The interaction between the complex with nucleotides guanosine 5'- monophosphate (5'-GMP), adenosine 5'-diphosphates (5'-ADP), inosine (5'-IMP) and CT-DNA was studied by fluorescence spectroscopy. The fluorescence intensity of Eu(III)-9-acridinecarboxylate complex was enhanced with the addition of CT-DNA. The effect of pH values on the fluorescence intensity of Eu(III) complex was investigated. Under experimental conditions, the linear range was 9-50 ng mL(-1) for calf thymus DNA (CT- DNA) and the corresponding detection limit was 5 ng mL(-1). The results showed that Eu(III)-(9-ACA)(2) complex binds to CT-DNA with stability constant of 2.41 × 10(4) M.

A novel anti-tumor agent, Ln(III) 2-thioacetate benzothiazole induces anti-angiogenic effect and cell death in cancer cell lines.

New complexes with a potent DNA-binding anti-tumor agent, europium(III)- and terbium(III)-2-thioacetate benzothiazole were synthesized and characterized. These complexes showed strong binding affinity to calf thymus DNA using fluorometric and electronic absorption spectroscopy. The synthesized complexes resulted in inhibition of proliferation of EAC cells and ascites formation. Their anti-tumor effect was found to be through anti-angiogenic activity as was evident by the reduction of microvessel density and down-regulation of VEGF receptor type-2 (Flk-1). It was found that EAC cells had distinct DNA fragmentation patterns analyzed by capillary electrophoresis in the treated animals. Moreover, the synthesized complexes exhibited significant cytotoxic activity against HepG2 and MCF7 cell lines. Furthermore, complexes showed a potent anti-bacterial activity against two pathogenic bacteria Escherichia coli and Salmonella.