Binding mode of conformations and structure-based pharmacophore development for farnesyltransferase inhibitors

Farnesyltransferase (FTase) is one of the prenyltransferase family enzymes that catalyse the transfer of 15-membered isoprenoid (farnesyl) moiety to the cysteine of CAAX motif-containing proteins including Rho and Ras family of G proteins. Inhibitors of FTase act as drugs for cancer, malaria, progeria and other diseases. In the present investigation, we have developed two structure-based pharmacophore models from protein–ligand complex (3E33 and 3E37) obtained from the protein data bank. Molecular dynamics (MD) simulations were performed on the complexes, and different conformers of the same complex were generated. These conformers were undergone protein–ligand interaction fingerprint (PLIF) analysis, and the fingerprint bits have been used for structure-based pharmacophore model development. The PLIF results showed that Lys164, Tyr166, TrpB106 and TyrB361 are the major interacting residues in both the complexes. The RMSD and RMSF analyses on the MD-simulated systems showed that the absence of FPP in the complex 3E37 has significant effect in the conformational changes of the ligands. During this conformational change, some interactions between the protein and the ligands are lost, but regained after some simulations (after 2 ns). The structure-based pharmacophore models showed that the hydrophobic and acceptor contours are predominantly present in the models. The pharmacophore models were validated using reference compounds, which significantly identified as HITs with smaller RMSD values. The developed structure-based pharmacophore models are significant, and the methodology used in this study is novel from the existing methods (the original X-ray crystallographic coordination of the ligands is used for the model building). In our study, along with the original coordination of the ligand, different conformers of the same complex (protein–ligand) are used. It concluded that the developed methodology is significant for the virtual screening of novel molecules on different targets.     

Erratum to: Specific stressors in endonasal skull base surgery with and without navigation

European Archives of Oto-Rhino-Laryngology -     

Myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes: a focused review

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Comparison of outcomes between minimally invasive and median sternotomy for double and triple valve surgery: A meta-analysis

Background

Limited data exists demonstrating the efficacy of minimally invasive surgery (MIS) compared to median sternotomy (MS) for multiple valvular disease (MVD). This systematic review and meta-analysis aims to compare operative and peri-operative outcomes of MIS vs MS in MVD.

Methods

PubMed, Ovid, and Embase were searched from inception until August 2019 for randomized and observational studies comparing MIS and MS in patients with MVD. Clinical outcomes of intra- and postoperative times, reoperation for bleeding and surgical site infection were evaluated.

Results

Five observational studies comparing 340 MIS vs 414 MS patients were eligible for qualitative and quantitative review. The quality of evidence assessed using the Newcastle-Ottawa scale was good for all included studies. Meta-analysis demonstrated increased cardiopulmonary bypass time for MIS patients (weighted mean difference [WMD], 0.487; 95% confidence interval [CI], 0.365-0.608; P < .0001). Similarly, aortic cross-clamp time was longer in patients undergoing MIS (WMD, 0.632; 95% CI, 0.509-0.755; P < .0001). No differences were found in operative mortality, reoperation for bleeding, surgical site infection, or hospital stay.

Conclusions

MIS for MVD have similar short-term outcomes compared to MS. This adds value to the use of minimally invasive methods for multivalvular surgery, despite conferring longer operative times. However, the paucity in literature and learning curve associated with MIS warrants further evidence, ideally randomized control trials, to support these findings.

     

The longitudinal validity,reproducibility and responsiveness of the Brisbane Burn Scar Impact Profile (caregiver report for young children version) for measuring health-related quality of life in children with burn scars

BackgroundThe measurement of health-related quality of life (HRQoL) provides information about the perceived burden of the health condition and treatments from a lived experience. The Brisbane Burn Scar Impact Profile (caregiver report for young children, BBSIP^0–8), developed in 2013, is a proxy-report measure of burn scar-specific HRQoL. The aim of this study was to report its psychometric properties in line with an evaluative purpose.MethodsCaregivers of children up to 8 years of age at risk of burn scarring were recruited into a prospective, longitudinal cohort study. Caregivers completed the BBSIP^0–8, Pediatric Quality of Life Inventory and Patient Observer Scar Assessment Scale at baseline (approximately ≥85% of the total body surface area re-epithelialised), 1–2 weeks after baseline and 1-month after baseline. Psychometric properties measured included internal consistency, test–retest reliability, validity and responsiveness.ResultsEighty-six caregivers of mostly male children (55%), of a median age (IQR) of 1 year, 10 months (2 years, 1 month) and total body surface area burn of 1.5% (3.0%) were recruited. Over one third of participants were grafted and 15% had contractures or skin tightness at baseline. Internal consistency of ten item groups ranged from 0.73 to 0.96. Hypothesised correlations of changes in the BBSIP^0–8 items with changes in criterion measures supported longitudinal validity (ρ ranging from ?0.73 to 0.68). The majority of item groups had acceptable reproducibility (ICC = 0.65–0.83). The responsiveness of five item groups was supported (AUC = 0.71–0.90).ConclusionThe psychometric properties tested support the use of the BBSIP^0–8 as an evaluative measure of burn scar-related health-related quality of life for children aged below eight years in the early post-acute period of rehabilitation. Further investigation at longer time period after burn injury is indicated.