Exploring the Carbamazepine Interaction with Human Pregnane X Receptor and Effect on ABCC2 Using <Emphasis Type="BoldItalic">in Vitro</Emphasis> and <Emphasis Type="BoldItalic">in Silico</Emphasis> Approach

Purpose

Over expression of ATP-binding cassette transporters is considered one of the major reasons for non-responsiveness to antiepileptic drugs. Carbamazepine (CBZ), one of first line antiepileptic drug is known to influence ABCC2 expression but its exact molecular mechanism is unknown.

Methods

We investigated the effect of CBZ on expression of ABCC2 and pregnane X receptor (PXR) in HepG2 cell line and compared with hyperforin (agonist of PXR) and ketoconazole (antagonist of PXR) through realtime PCR and western blot assay. Involvement of PXR was demonstrated through nuclear translocation and RNA interference and related effect of CBZ on ABCC2 through functional activity assay. Molecular docking and dynamic simulation approach was used to understand the interaction of CBZ with PXR.

Results

CBZ and hyperforin increased the PXR and ABCC2 expression whereas reversed when present it in combination with ketoconazole. Experiments confirmed CBZ induced ABCC2 expression is PXR dependent. Molecular dynamic (MD) simulation and in vitro experiment indicated possibility of CBZ to be PXR agonist and PXR residue Gln285 to be important for CBZ-PXR interaction.

Conclusions

CBZ alters the functional activity of ABCC2 through PXR, which in turn can interfere with therapy. Mutational analysis of residues revealed the importance of Gln285 in ligand interaction.

     

Mucoepidermoid carcinoma ex pleomorphic adenoma of the lacrimal gland: A rare presentation

Carcinoma ex pleomorphic adenoma in lacrimal gland is a rare entity unlike its salivary gland counterpart. This rare tumor poses a diagnostic challenge to clinicians as pre-operative diagnosis is difficult and diagnosis is only by careful pathological assessment. We report this uncommon lesion in a 62-year-old lady, wherein the malignant component was mucoepidermoid carcinoma. The elderly patient remained clinically and radiologically free of the tumor for two years after complete excision of the tumor but computed tomography at the end of two and a half years showed a recurrent lesion in the region of the lacrimal gland. This makes long term follow up of patients with these rare lacrimal tumors imperative with a minimum period of at least five years.     

A Survey of Expert Practice and Attitudes Regarding Advanced Imaging Modalities in Surveillance of Barrett’s Esophagus

Background

Published guidelines do not address what the minimum incremental diagnostic yield (IDY) for detection of dysplasia/cancer is required over the standard Seattle protocol for an advanced imaging modality (AIM) to be implemented in routine surveillance of Barrett’s esophagus (BE) patients. We aimed to report expert practice patterns and attitudes, specifically addressing the minimum IDY in the use of AIMs in BE surveillance.

Methods

An international group of BE experts completed an anonymous electronic survey of domains relevant to surveillance practice patterns and use of AIMs. The evaluated AIMs were conventional chromoendoscopy (CC), virtual chromoendoscopy (VC), volumetric laser endomicroscopy (VLE), confocal laser endomicroscopy (CLE), and wide-area transepithelial sampling (WATS^3D). Responses were recorded using five-point balanced Likert items and analyzed as continuous variables.

Results

The survey response rate was 84% (61/73)—41 US and 20 non-US. Experts were most comfortable with and routinely use VC and CC, and least comfortable with and rarely use VLE, CLE, and WATS^3D. Experts rated data from randomized controlled trials (1.4?±?0.9) and guidelines (2.6?±?1.2) as the two most influential factors for implementing AIMs in clinical practice. The minimum IDY of AIMs over standard biopsies to be considered of clinical benefit was lowest for VC (15%, IQR 10–29%) and highest for VLE (30%, IQR 20–50%). Compared to US experts, non-US experts reported higher use of CC for BE surveillance (p?<?0.001).

Conclusion

These results should inform benchmarks that need to be met for guidelines to recommend the routine use of AIMs in the surveillance of BE patients.