Synthesis of New Chromene Derivatives Targeting Triple-Negative Breast Cancer Cells

Breast cancer continues to be the leading cause of cancer-related deaths among women worldwide. The most aggressive type of breast cancer is triple-negative breast cancer (TNBC). Indeed, not only does TNBC not respond well to several chemotherapeutic agents, but it also frequently develops resistance to various anti-cancer drugs, including taxane mitotic inhibitors. This necessitates the search for newer, more efficacious drugs. In this study, we synthesized two novel chromene derivatives (C1 and C2) and tested their efficacy against a battery of luminal type A and TNBC cell lines. Our results show that C1 and C2 significantly and specifically inhibited TNBC cell viability but had no effect on the luminal A cell type. In addition, these novel compounds induced mitotic arrest, cell multinucleation leading to senescence, and apoptotic cell death through the activation of the extrinsic pathway. We also showed that the underlying mechanisms for these actions of C1 and C2 involved inhibition of microtubule polymerization and disruption of the F-actin cytoskeleton. Furthermore, both compounds significantly attenuated migration of TNBC cells and inhibited angiogenesis in vitro. Finally, we performed an in silico analysis, which revealed that these novel variants bind to the colchicine binding site in β-tubulin. Taken together, our data highlight the potential chemotherapeutic properties of two novel chromene compounds against TNBC.Scopu

Postoperative outcomes in oesophagectomy with trainee involvement

BACKGROUND: The complexity of oesophageal surgery and the significant risk of morbidity necessitates that oesophagectomy is predominantly performed by a consultant surgeon, or a senior trainee under their supervision. The aim of this study was to determine the impact of trainee involvement in oesophagectomy on postoperative outcomes in an international multicentre setting. METHODS: Data from the multicentre Oesophago-Gastric Anastomosis Study Group (OGAA) cohort study were analysed, which comprised prospectively collected data from patients undergoing oesophagectomy for oesophageal cancer between April 2018 and December 2018. Procedures were grouped by the level of trainee involvement, and univariable and multivariable analyses were performed to compare patient outcomes across groups. RESULTS: Of 2232 oesophagectomies from 137 centres in 41 countries, trainees were involved in 29.1 per cent of them (n = 650), performing only the abdominal phase in 230, only the chest and/or neck phases in 130, and all phases in 315 procedures. For procedures with a chest anastomosis, those with trainee involvement had similar 90-day mortality, complication and reoperation rates to consultant-performed oesophagectomies (P = 0.451, P = 0.318, and P = 0.382, respectively), while anastomotic leak rates were significantly lower in the trainee groups (P = 0.030). Procedures with a neck anastomosis had equivalent complication, anastomotic leak, and reoperation rates (P = 0.150, P = 0.430, and P = 0.632, respectively) in trainee-involved versus consultant-performed oesophagectomies, with significantly lower 90-day mortality in the trainee groups (P = 0.005). CONCLUSION: Trainee involvement was not found to be associated with significantly inferior postoperative outcomes for selected patients undergoing oesophagectomy. The results support continued supervised trainee involvement in oesophageal cancer surgery

Guillain-Barré Syndrome Following a Malignant Varicella in Immunocompetent Adult

Varicella zoster virus (VZV) infection may trigger Guillain-Barre syndrome (GBS), but this is rare and almost always in the context of reactivation disease from latent VZV, ‘shingles’. We report here a case of severe GBS following primary VZV infection in an immunocompetent adult

Harlequin Ichthyosis: A Rare Case Report

Harlequin fetus is a rare and the most severe genetic form of the congenital ichthyosis with an autosomal recessive inheritance. Incidence of the disease is nearly 1 in 3,00,000 live births. The disease might be lethal at birth and the affected babies are often premature. Harlequin ichthyosis [HI] is marked by severe keratinized and alligator-like horned skin. The present study reports a new case of harlequin fetus born to the consanguineous parents. He had the typical skin manifestations of thick armour like scales with fissures, complete ectropion and eclabium, atrophic and crumpled ears and swollen extremities. Supportive treatment was given but the neonate died on the 7th day. Adds to the collective knowledge of this rare skin disorder. HI has been linked to mutation in the ABCA12 gene; which cause a deficiency of the epidermal lipid transporter, resulting in hyperkeratosis and abnormal barrier function. Therefore, genetic counseling and mutation screening of this gene should be considered

Comparison of Explicit and Implicit Time Advancing in the Simulation of a 2D Sediment Transport Problem

The simulation of sediment transport, based on the shallow-water equations coupled with Grass model for the sediment transport equation is considered. The aim of the present paper is to investigate the behavior of implicit linearized schemes in this context. A finite-volume method is considered and second-order accuracy in space is obtained through MUSCL reconstruction. A second-order time accurate explicit version of the scheme is obtained through a two step Runge-Kutta method. Implicit linearized schemes of second-order of accuracy in time are derived thanks to a BDF method associated with a Defect Correction technique. The different time-advancing schemes are compared, using a 2D sediment transport problem, with different types of flow/bed interactions. The implicit one largely outperforms the explicit version for slow flow/bed interactions while in the case of fast flow/bed interactions, the CPU time of both time integration schemes are comparable. Thus, the implicit scheme turns out to be a good candidate to simulate flows with sediment transport in practical applications

Linearized implicit time advancing and defect correction applied to sediment transport simulations

The numerical simulation of sediment transport problems is considered in this paper. The physical problem is modeled through the shallow-water equations coupled with the Exner equation to describe the time evolution of the bed profile. The spatial discretization of the governing equations is carried out by a finite-volume method and a modified Roe scheme designed for non-conservative systems. As for the time advancing, starting from an explicit method, a linearized implicit scheme is generated, in which the flux Jacobian is computed through automatic differentiation. Second-order accuracy in space is then obtained through MUSCL reconstruction and in time through a backward differentiation formula associated with a defect-correction approach. The implicit time advancing is compared in terms of accuracy and computational time with the explicit approach for one-dimensional and two-dimensional sediment transport problems, characterized by different time scales for the evolution of the bed and of the water flow. It is shown that, whenever the use of large time steps is compatible with the capture of the water flow dynamics and of the bedload evolution, the implicit scheme is far more efficient than its explicit counterpart with a CPU reduction up to more than two orders of magnitude. This makes implicit time differencing an attractive option for complex real life applications in this area

Implicit time advancing applied to shallow water problems coupled with different models of sediment transport

The numerical simulation of sediment transport problems is considered. The physical problem is modeled through the shallow-water equations coupled with the Exner equation to describe the time evolution of the bed profile. Different models of solid transport discharge of increasing complexity are considered. The spatial discretisation of the governing equations is carried out by a finite-volume method and a modified Roe scheme designed for non-conservative systems. Linearized implicit schemes for time advancing are built through a recently proposed strategy, based on automatic differentiation to compute the flux Jacobians and on the defect correction approach to reach second-order accuracy. Explicit schemes for time advancing are compared with implicit ones in one-dimensional sediment transport problems, characterized by different time scales for the evolution of the bed. It is shown that, independently of the model used for the solid transport discharge, for slow and intermediate speeds of interaction bewteen the bedload and the water flow, for which the use of large time steps is compatible with the capture of the bed evolution, implicit time advancing is far more efficient than explicit one with a computational cost reduction up to more than three orders of magnitude