Real-time Telepathology Is Substantially Equivalent to In-Person Intraoperative Frozen Section Diagnosis

CONTEXT.—: Intraoperative diagnosis by frozen section is a mainstay of surgical pathology practice, providing immediate feedback to the surgical team. Despite good accuracy with modern methods, access to intraoperative surgical pathology with an appropriate turnaround time (TAT) has been a limiting factor for small or remote surgical centers, with negative impacts on cost and patient care. Telepathology offers immediate expert anatomic pathology consultation to sites without an in-house or subspecialized pathologist. OBJECTIVE.—: To assess the utility of live telepathology in frozen section practice. DESIGN.—: Frozen section diagnoses by telemicroscopy from 2 tertiary care centers with combined 3 satellite hospitals were queried for anatomic site, TAT per block, pathologist, and concordance with paraffin diagnosis. TAT and concordance were compared to glass diagnoses in the same period. RESULTS.—: For 748 intraoperative diagnoses by telemicroscopy, 694 had TATs with a mean of 18 minutes 56 seconds ± 8 minutes 45 seconds, which was slower than on glass (14 minutes 25 seconds ± 7 minutes 8 seconds, P \u3c .001). Twenty-two (2.89% of available) were discordant, which was not significantly different from the on-glass rate (P = .44) or categorical distribution (P = .31). Two cases (0.27%) had technical failures. CONCLUSIONS.—: Although in-person diagnoses were statistically faster, the great majority of telemicroscopic diagnoses were returned in less than 20 minutes. This remained true through numerous pathologists, pathology assistants and/or technicians, different hospitals, and during a combined 6 years. The concentration of discordant diagnoses among relatively few pathologists suggests individual comfort with telepathology and/or frozen section diagnosis. In rare cases, technologic issues prevented telemicroscopic diagnosis. Overall, this justifies continued use and expansion of telemicroscopic services in primary intraoperative diagnoses

Molecular docking and inhibition of matrix metalloproteinase-2 by novel difluorinatedbenzylidene curcumin analog

We recently described the synthesis and characterization of a novel difluorinatedbenzylidene analog of curcumin, commonly referred as CDF, which demonstrated significantly enhanced bioavailability and in vivo anticancer activity. CDF targets many factors similar to curcumin, albeit with more potency, as reported previously. To further highlight this differential behavior of CDF, we chose matrix metalloproteinase protein MMP-2 which is involved in the processes of invasion and metastasis of human tumors. Both curcumin and CDF were characterized for their binding characteristics using in silico docking studies; they were also evaluated via biological assays involving gelatin zymography, miRNA analysis, invasion assays and ELISA. CDF was found to inhibit MMP-2 expression and activity in A549 and H1299 NSCLC cells much more effectively than curcumin, validating molecular modeling results. miR-874, an MMP-2-targeting miRNA, was up-regulated by CDF. Thus, it appears that CDF can inhibit MMP-2 through multiple mechanisms. Our results are suggestive of a more potent inhibition of invasion and metastasis by CDF, compared to curcumin, thus warranting its further evaluation as an effective anticancer agent

Inhibition of Hedgehog signaling sensitizes NSCLC cells to standard therapies through modulation of EMT-regulating miRNAs

Abstract Background Epidermal growth factor receptor- tyrosine kinase inhibitors (EGFR-TKIs) benefit Non-small cell lung cancer (NSCLC) patients, and an EGFR-TKIi erlotinib, is approved for patients with recurrent NSCLC. However, resistance to erlotinib is a major clinical problem. Earlier we have demonstrated the role of Hedgehog (Hh) signaling in Epithelial-to-Mesenchymal transition (EMT) of NSCLC cells, leading to increased proliferation and invasion. Here, we investigated the role of Hh signaling in erlotinib resistance of TGF-β1-induced NSCLC cells that are reminiscent of EMT cells. Methods Hh signaling was inhibited by specific siRNA and by GDC-0449, a small molecule antagonist of G protein coupled receptor smoothened in the Hh pathway. Not all NSCLC patients are likely to benefit from EGFR-TKIs and, therefore, cisplatin was used to further demonstrate a role of inhibition of Hh signaling in sensitization of resistant EMT cells. Specific pre- and anti-miRNA preparations were used to study the mechanistic involvement of miRNAs in drug resistance mechanism. Results siRNA-mediated inhibition as well as pharmacological inhibition of Hh signaling abrogated resistance of NSCLC cells to erlotinib and cisplatin. It also resulted in re-sensitization of TGF-β1-induced A549 (A549M) cells as well the mesenchymal phenotypic H1299 cells to erlotinib and cisplatin treatment with concomitant up-regulation of cancer stem cell (CSC) markers (Sox2, Nanog and EpCAM) and down-regulation of miR-200 and let-7 family miRNAs. Ectopic up-regulation of miRNAs, especially miR-200b and let-7c, significantly diminished the erlotinib resistance of A549M cells. Inhibition of Hh signaling by GDC-0449 in EMT cells resulted in the attenuation of CSC markers and up-regulation of miR-200b and let-7c, leading to sensitization of EMT cells to drug treatment, thus, confirming a connection between Hh signaling, miRNAs and drug resistance. Conclusions We demonstrate that Hh pathway, through EMT-induction, leads to reduced sensitivity to EGFR-TKIs in NSCLCs. Therefore, targeting Hh pathway may lead to the reversal of EMT phenotype and improve the therapeutic efficacy of EGFR-TKIs in NSCLC patients

Molecular Targets of Naturopathy in Cancer Research: Bridge to Modern Medicine

The relevance of naturopathy (defined as the practice of medicine for the treatment of human diseases with natural agents) in human cancer is beginning to be appreciated, as documented by renewed interest in nutraceutical research, the natural anticancer agents of dietary origin. Because of their pleiotropic effects and the ability to modulate multiple signaling pathways, which is a good attribute of natural agents, nutraceuticals have frequently been demonstrated to re-sensitize drug-resistant cancers. The effectiveness of nutraceuticals can be further enhanced if the tools for the relative assessment of their molecular targets are readily available. Such information can be critical for determining their most effective uses. Here, we discuss the anticancer potential of nutraceuticals and the associated challenges that have interfered with their translational potential as a naturopathic approach for the management of cancers. In the years to come, an efficient screening and assessment of molecular targets will be the key to make rapid progress in the area of drug design and discovery, especially focusing on evidence-based development of naturopathy for the treatment of human malignancies