PLAS-5k: Dataset of Protein-Ligand Affinities from Molecular Dynamics for Machine Learning Applications

Computational methods and recently modern machine learning methods have played a key role in structure-based drug design. Though several benchmarking datasets are available for machine learning applications in virtual screening, accurate prediction of binding affinity for a protein-ligand complex remains a major challenge. New datasets that allow for the development of models for predicting binding affinities better than the state-of-the-art scoring functions are important. For the first time, we have developed a dataset, PLAS-5k comprised of 5000 protein-ligand complexes chosen from PDB database. The dataset consists of binding affinities along with energy components like electrostatic, van der Waals, polar and non-polar solvation energy calculated from molecular dynamics simulations using MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) method. The calculated binding affinities outperformed docking scores and showed a good correlation with the available experimental values. The availability of energy components may enable optimization of desired components during machine learning-based drug design. Further, OnionNet model has been retrained on PLAS-5k dataset and is provided as a baseline for the prediction of binding affinities

Implementing a theory-based intradialytic exercise programme in practice: a quality improvement project

Background Research evidence outlines the benefits of intradialytic exercise (IDE), yet implementation into practice has been slow, ostensibly due to lack of patient and staff engagement. The aim of this quality improvement project was to improve patient outcomes via the introduction of an IDE programme; evaluate patient uptake, sustainability and enhance the engagement of routine haemodialysis (HD) staff with the delivery of the IDE programme. Methods We developed and refined an IDE programme, including interventions designed to increase patient and staff engagement that were based upon the Theoretical Domains Framework, using a series of ‘Plan, Do, Study, Act’ cycles. The programme was introduced at two UK NHS HD units. Process measures included patient uptake, withdrawals, adherence and HD staff involvement. Outcomes measures were patient-reported functional capacity, anxiety, depression and symptomology. All measures were collected over 12 months. Results 95 patients enrolled in the IDE programme. 64 (75%) were still participating at three months, dropping to 41 (48%) at 12 months. Adherence was high (78%) at three months, dropping to 63% by 12 months. Provision of IDE by HD staff accounted for a mean of 2 (5%) sessions per three-month time point. Patients displayed significant improvements in functional ability (p=0.01), and reduction in depression (p=0.02) over 12 months, but effects seen were limited to those who completed the programme. Conclusions A theory-based IDE programme is feasible and leads to improvement in functional capacity and depression. Sustaining IDE over time is marred by high levels of patient withdrawal from the programme. Significant change at an organisational level is required to enhance sustainability by increasing HD staff engagement or access to exercise professional support

Reconstitution of mammalian ion channels in droplet bilayers

Ion channel studies are important for scientific characterization of cellular processes and for the purpose of drug discovery. The sessile droplet bilayer platform allows for simple, fast, inexpensive and high-yield formation of artificial lipid bilayers and reconstitution of ion channels. We validated this bilayer formation platform with mammalian ion channels like Chloride Intracellular Channel 1 (CLIC1) and Voltage-gated potassium channel 1.2 (Kv1.2). Ion channel synthesis using traditional bacterial expression systems is a complex and time consuming process and it limits the number of eukaryotic proteins that can be expressed therein. We explored the use of in vitro protein synthesis and plasma membrane fractionation of commercially available mammalian cells for expressing and reconstituting ion channel proteins in planar lipid bilayers

Complete Response after Treatment with Neoadjuvant Chemoradiation with Prolonged Chemotherapy for Locally Advanced, Unresectable Adenocarcinoma of the Pancreas

Surgery is the only chance for cure in pancreatic ductal adenocarcinoma. In unresectable, locally advanced pancreatic cancer (LAPC), the National Comprehensive Cancer Network (NCCN) suggests chemotherapy and consideration for radiation in cases of unresectable LAPC. Here we present a rare case of unresectable LAPC with a complete histopathological response after chemoradiation followed by surgical resection. A 54-year-old female presented to our clinic in December 2013 with complaints of abdominal pain and 30-pound weight loss. An MRI demonstrated a mass in the pancreatic body measuring 6.2×3.2 cm; biopsy revealed proven ductal adenocarcinoma. Due to splenic vein/artery and contiguous celiac artery encasement, she was deemed surgically unresectable. She was started on FOLFIRINOX therapy (three cycles), intensity modulated radiation to a dose of 54 Gy in 30 fractions concurrent with capecitabine, followed by FOLFIRI, and finally XELIRI. After 8 cycles of ongoing XELIRI completed in March 2015, restaging showed a remarkable decrease in tumor size, along with PET-CT revealing no FDG-avid uptake. She was reevaluated by surgery and taken for definitive resection. Histopathological evaluation demonstrated a complete R0 resection and no residual tumor. Based on this patient and literature review, this strategy demonstrates potential efficacy of neoadjuvant chemoradiation with prolonged chemotherapy, followed by surgery, which may improve outcomes in patients deemed previously unresectable