Investigation on Quantitative Structure-Activity Relationships of 1,3,4 Oxadiazole Derivatives as Potential Telomerase Inhibitors

The published manuscript is available at EurekaSelect via http://www.eurekaselect.com/164022/article, DOI : 10.2174/1570163815666180724113208. © 2018 Bentham ScienceA series of 1,3,4-oxadiazole derivatives with significant broad-spectrum anticancer activity against different cell lines, and demonstrated telomerase inhibition, was subjected to Quantitative Structure-Activity Relationships (QSAR) analysis. Validated models with high correlation coefficients were developed. The Multiple Linear Regression (MLR) models, by Ordinary Least Squares (OLS), showed good robustness and predictive capability, according to the Multi-Criteria Decision Making (MCDM = 0.8352), a technique that simultaneously enhances the performances of a certain number of criteria. The descriptors selected for the models, such as electrotopological state (E-state) descriptors, and extended topochemical atom (ETA) descriptors, showed the relevant chemical information contributing to the activity of these compounds. The results obtained in this study make sure about the identification of potential hits as prospective telomerase inhibitors.Peer reviewedFinal Accepted Versio

A quantitative structure-permeability relationship model for split-thickness skin absorption, reasoning for the choice of the database.

The skin is the largest organ in the human body, protecting the body from xenobiotic invasion (1). Local and systemic drugs may also be administered through the skin, therefore the need to measure the permeability of the skin to chemicals has long been apparent. The use of in vivo or in vitro techniques is time-consuming, since it is not only necessary to conduct a permeation study, but also to optimize experimental conditions and build analytical methods for each chemical. Moreover, it is not possible to assess the permeability of compounds not yet synthesised. An alternative option can be the development of Quantitative Structure-Permeability Relationships (QSPRs). These in silico models aim to form a relationship between the absorption of chemicals through the skin and their physico-chemical and/or structural properties (2). Knowing that permeability can be affected by different experimental conditions, the aim of this study is to build a QSPR based on uniform and consistent experimental conditions, but with a significant database size. Two different databases were compared: the first one was obtained only from Zhang et al (3), the second one was created from multiple literature sources, fulfilling the following conditions: - Data (log Kp values) were obtained by an in vitro diffusion system; - The membrane was human stratum corneum and viable epidermis; - The donor solvent was an aqueous solution; - No permeation enhancement technologies were used; - No association with other chemicals were considered. The geometrical structures of all chemicals were optimized with MM2 forcefield. Molecular descriptors and fingerprints were generated where possible. For each database, a wide range of Multi Linear Regression models were built using QSARins (4, 5) through a stepwise forward regression process. The models have been validated according to Golbraikh and Tropsha (6) criteria and the best ones have been selected according to the Multi-Criteria Decision Making (7). The model calculated from the data obtained from a single source shows better correlation, robustness, and predictivity, revealing a grade of uncertainty coming from an inter laboratory variability of the different sources used to build the database. REFERENCES 1. Baba H, Takahara J-i, Mamitsuka H. In Silico Predictions of Human Skin Permeability using Nonlinear Quantitative Structure–Property Relationship Models. Pharmaceutical Research. 2015;32(7):2360-71. 2. Moss GP, Cronin MTD. Quantitative structure–permeability relationships for percutaneous absorption: re-analysis of steroid data. International Journal of Pharmaceutics. 2002;238(1):105-9. 3. Zhang K, Chen M, Scriba GKE, Abraham MH, Fahr A, Liu X. Human Skin Permeation of Neutral Species and Ionic Species: Extended Linear Free Energy Relationship Analyses. Journal of Pharmaceutical Sciences. 2012;101(6):2034-44. 4. Gramatica P, Chirico N, Papa E, Cassani S, Kovarich S. QSARINS: A new software for the development, analysis, and validation of QSAR MLR models. Journal of Computational Chemistry. 2013;34(24):2121-32. 5. Gramatica P, Cassani S, Chirico N. QSARINS-chem: Insubria datasets and new QSAR/QSPR models for environmental pollutants in QSARINS. Journal of Computational Chemistry. 2014;35(13):1036-44. 6. Golbraikh A, Tropsha A. Beware of q2! Journal of Molecular Graphics and Modelling. 2002;20(4):269-76. 7. Keller HR, Massart DL, Brans JP. Multicriteria decision making: A case study. Chemometrics and Intelligent Laboratory Systems. 1991;11(2):175-89.Peer reviewedFinal Published versio

Predicting Skin Permeability by means of Computational Approaches : Reliability and Caveats in Pharmaceutical Studies

© 2019 American Chemical Society.The skin is the main barrier between the internal body environment and the external one. The characteristics of this barrier and its properties are able to modify and affect drug delivery and chemical toxicity parameters. Therefore, it is not surprising that permeability of many different compounds has been measured through several in vitro and in vivo techniques. Moreover, many different in silico approaches have been used to identify the correlation between the structure of the permeants and their permeability, to reproduce the skin behavior, and to predict the ability of specific chemicals to permeate this barrier. A significant number of issues, like interlaboratory variability, experimental conditions, data set building rationales, and skin site of origin and hydration, still prevent us from obtaining a definitive predictive skin permeability model. This review wants to show the main advances and the principal approaches in computational methods used to predict this property, to enlighten the main issues that have arisen, and to address the challenges to develop in future research.Peer reviewedFinal Accepted Versio

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

GSK3β as a novel promising target to overcome chemoresistance in pancreatic cancer

Pancreatic cancer is an aggressive malignancy with increasing incidence and poor prognosis due to its late diagnosis and intrinsic chemoresistance. Most pancreatic cancer patients present with locally advanced or metastatic disease characterized by inherent resistance to chemotherapy. These features pose a series of therapeutic challenges and new targets are urgently needed. Glycogen synthase kinase 3 beta (GSK3β) is a conserved serine/threonine kinase, which regulates key cellular processes including cell proliferation, DNA repair, cell cycle progression, signaling and metabolic pathways. GSK3β is implicated in non-malignant and malignant diseases including inflammation, neurodegenerative diseases, diabetes and cancer. GSK3β recently emerged among the key factors involved in the onset and progression of pancreatic cancer, as well as in the acquisition of chemoresistance. Intensive research has been conducted on key oncogenic functions of GSK3β and its potential as a druggable target; currently developed GSK3β inhibitors display promising results in preclinical models of distinct tumor types, including pancreatic cancer. Here, we review the latest findings about GSK-3β biology and its role in the development and progression of pancreatic cancer. Moreover, we discuss therapeutic agents targeting GSK3β that could be administered as monotherapy or in combination with other drugs to surmount chemoresistance. Several studies are also defining potential gene signatures to identify patients who might benefit from GSK3β-based therapeutic intervention. This detailed overview emphasizes the urgent need of additional molecular studies on the impact of GSK3β inhibition as well as structural analysis of novel compounds and omics studies of predictive biomarkers

Mid- and longer-term follow up of chimney and/or periscope grafts and risk factors for failure

OBJECTIVE: The aim was to report on chimney and periscope grafts (CPGs) and their mid- and longer-term outcomes when they are used to preserve reno-visceral artery (RVA) perfusion in endovascular repair of pararenal (PRAAs) or thoraco-abdominal aortic aneurysm (TAAAs). In addition, factors associated with CPG failure are presented. Limited data exist on the outcomes of CPGs, and mid- and long-term results are generally not reported. METHODS: This was a prospective study in a cohort of 100 patients with PRAA (69) or TAAA (31). A total of 224 (mean 2.24 per patient) RVAs were preserved with 136 (61%) chimney and 88 (39%) periscope grafts. CPGs were constructed mainly using self expandable stent grafts. Patients were followed by clinical examination, CTA (82%), and/or duplex (18%). Data were collected until February 2015. RESULTS: CPG immediate technical success was 99% (222/224 branches). Mean follow up was 29 months (range 0-65; SD 17); 59% patients were followed > 2 years, 30% > 3 years, and 16% > 4 years. Post-operatively, CPG occlusion was observed early (≤30 days) in three (1.3%) branches and during follow up in 10 (4.5%). At 36 and 48 months, the estimated primary patency was 93% and 93%. After corrective percutaneous (10) or surgical (3) re-interventions, the estimated secondary patency was 96% and 96%. Thirty day mortality was 2%; at 36 and 48 months the estimated patient survival was 79%. Significant shrinkage (72 [SD 23] vs. 62 [SD 24] mm; p 5 mm) in 55 patients, and sac enlargement in four. Incomplete aneurysm sac sealing was treated successfully by a secondary intervention in 15 patients. CONCLUSIONS: Self expandable CPGs have proved to be a highly successful and durable treatment for RVA preservation up to 5 years. Incomplete CPG expansion, inadequate length, and CPG use in small and diseased target arteries were risk factors for occlusion. These mid- and longer-term results support CPG use to treat PRAAs or TAAAs in patients unfit for open surgery or fenestrated/branched stent grafts

Chronic Mesenteric Ischemia: Critical review and guidelines for management

BACKGROUND: CMI is caused by chronic occlusive disease of mesenteric arteries. In such an uncommon disease, clear recommendations are strongly needed. Unfortunately, treatment options for symptomatic CMI are still controversial and no guidelines exist. METHODS: A systematic literature review of the last 25-years was conducted through MEDLINE, Embase, and Cochrane Review/Trials register to identify studies reporting on CMI treatment with more than 10 patients. Primary outcomes were perioperative mortality and morbidity rates. Secondary outcomes were survival rates, primary and secondary patency rates, vessels treated, CMI recurrence, follow-up (FU), technical success (TS), and in-hospital length of stay (InH-LOS). Patients were divided into endovascular treatment (ET) or open treatment (OT) groups. Subsequently, primary and secondary outcomes were analyzed by study publication year for the interval periods 1986-2000 ("A") and 2001-2010 ("B"). Differences were assessed using the t-test and the χ(2) test. RESULTS: Forty-three articles with 1,795 patients were included. Perioperative mortality and morbidity rates were lower in the ET group. No difference in survival rate was observed. Primary and secondary patencies were superior in the OT group. A greater number of vessels were revascularized in the OT group. CMI recurrence was more frequent in the ET group. FU was longer in the OT group. TS was superior in the OT group and InH-LOS was shorter in the ET group. A higher number of patients were treated by ET in the period "A." No differences in mortality and morbidity were observed between period "A" and "B" in ET and OT groups. CONCLUSIONS: Considering the lower periprocedural mortality and morbidity after ET, this approach should be considered as the first treatment option in most CMI patients, especially in those with severe malnutrition. Primary OT should be restricted to cases that do not qualify for ET or good surgical risk patients with long life expectancy. Considering better long-term results of OT, ET treatment should be considered as a bridge therapy to OT in some patients requiring retreatment if ET does not preclude subsequent OT