Comparative studies of the Pschorr reaction in the pyrazole series. Access to the new dibenzo(e,g)pyrazolo(1,5-a)(1,3)diazocine system of pharmaceutical interest

The diazonium tetrafluoroborate 11 obtained from 2-amino-N-methyl-N-(1-phenyl-3-methylpyrazol-5-yl)benzamide was transformed in dry acetonitrile via an ionic or radical pathway. Diferences were observed with respect to ionic or radical transformations in aqueous media of the analogous diazonium hydrogen sulfate 1 derived from the same amine. In acetonitrile solution, the ionic pathway was characterized by an increased yield of 1,4-dimethyl-3-phenyl-pyrazolo[3,4-c]isoquinolin-5-one 4 and by the formation of its isomer, the new derivative 7,9-dimethyldibenzo[e,g]pyrazolo[1,5-a][1,3]diazocin-10(9H)-one 12. When the reaction folowed a radical pathway, the pyrazolo[3,4-c]isoquinoline derivative 4 and N-methyl-2-(1-phenyl-3-methylpyrazol-5-yl)benzamide 17, the later due to a 1,4-pyrazolyl transfer proces, were isolated in low yields. Decomposition of the solid diazonium tetrafluoroborate at its melting point gave compounds 4, 12 and the N-(1-phenyl-3-methylpyrazol-5-yl)-2-fluorobenzamide 17. The crystal structure of compound 12 was also determined

Gene expression profiling of advanced ovarian cancer: characterization of a molecular signature involving fibroblast growth factor 2

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Liquid Biopsy as Surrogate to Tissue for Molecular Profiling in Pancreatic Cancer: A Meta-Analysis towards Precision Medicine

Liquid biopsy (LB) is a non-invasive approach representing a promising tool for new precision medicine strategies for cancer treatment. However, a comprehensive analysis of its reliability for pancreatic cancer (PC) is lacking. To this aim, we performed the first meta-analysis on this topic. We calculated the pooled sensitivity, specificity, positive (LR+) and negative (LR−) likelihood ratio, and diagnostic odds ratio (DOR). A summary receiver operating characteristic curve (SROC) and area under curve (AUC) were used to evaluate the overall accuracy. We finally assessed the concordance rate of all mutations detected by multi-genes panels. Fourteen eligible studies involving 369 patients were included. The overall pooled sensitivity and specificity were 0.70 and 0.86, respectively. The LR+ was 3.85, the LR- was 0.34 and DOR was 15.84. The SROC curve with AUC of 0.88 indicated a relatively high accuracy of LB for molecular characterization of PC. The concordance rate of all mutations detected by multi-genes panels was 31.9%. LB can serve as surrogate to tissue in molecular profiling of PC, because of its relatively high sensitivity, specificity and accuracy. It represents a unique opportunity to be further explored towards its introduction in clinical practice and for developing new precision medicine approaches against PC

A Case Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic and Tractable Biomarkers in Male Breast Cancer

Purpose: Breast cancer (BC) affects both genders, but is understudied in men. Although still rare, male BC is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar. Experimental design: A transcriptomic investigation of male and female BC was performed, confirming transcriptomic data in silico. Biomarkers were immunohistochemically assessed in 697 MBCs (n=477, training; n=220, validation set) and quantified in pre- and post-treatment samples from a male BC patient receiving Everolimus and PI3K/mTOR inhibitor. Results: Gender-specific gene expression patterns were identified. eIF transcripts were up-regulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (Log rank; p=0.013; HR=1.77, 1.12-2.8 and p=0.035; HR=1.68, 1.03-2.74, respectively), or when co-expressed (p=0.01; HR=2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis (eIF4E p=0.016; HR 2.38 (1.18-4.8), eIF5 p=0.022; HR 2.55 (1.14-5.7); co-expression p=0.001; HR=7.04 (2.22-22.26)). Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/Everolimus, with extended survival. Conclusions: Translational initiation pathway inhibition could be of clinical utility in male BC patients overexpressing eIF4E and eIF5. With mTOR inhibitors which target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required

4-oxo-n-(4-hydroxyphenyl)retinamide derivatives as therapeutic agents for the treatment of cancer

The invention relates to prepn. of oxohydroxyphenyl retinamide derivs of formula I wherein: X is -\u200bCOOH or NH2; R is a straight or branched C1-\u200bC10 alkylene chain; and R1 is H, straight or branched C1-\u200bC10 alkyl, aryl, or R2CO- wherein R2 is straight or branched C1-\u200bC10 alkyl, or a pharmaceutically acceptable salt thereof for the treatment of cancer. Compds. I belong to retinoid family that are are natural and synthetic derivs. of vitamin A (retinol) which modulate various cell processes, such as proliferation, differentiation and apoptosis