Hyperparathyroidism in multiple endocrine neoplasia type II A

Primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia (MEN) 2A occurs in only 15-30% of patients. It is rarely the first feature recognized in the syndrome, is generally mild and is sometimes expressed only as parathyroid tumors discovered during surgery for medullary thyroid carcinoma. A predisposition to MEN 2 is caused by germline mutations of the RET proto-oncogene on chromosome 10q11.2. Genetic studies have demonstrated the association of PHPT with a specific mutation at codon 634 (C634R). Therefore, all codon 634 mutation carriers are at some risk for hyperparathyroidism and should be submitted to an early screening of the disease. The rarity of MEN 2A-related PHPT has prevented the establishment of a well-defined therapeutic strategy for treating this condition, so that recommendations about the surgical approach have been controversial. Patients with MEN 2A should have annual screenings for hyperparathyroidism by serum calcium and intact parathyroid hormone level measurements. Parathyroidectomy should be considered in all patients who have some evidence of symptomatic disease. The objectives of parathyroid surgery are to a) obtain and maintain normocalcemia for the longest time possible, b) avoid iatrogenic hypoparathyroidism, and c) facilitate future surgery for recurrent disease. Finally, most of the patients with MEN 2A-related PHPT have mild disease and they could be classified as asymptomatic based on the NIH consensus conference regarding the diagnosis and management of asymptomatic PHPT. Therefore, these patients can be followed up safely without parathyroid surger

Free Energy-Based Virtual Screening and Optimization of RNase H Inhibitors of HIV‑1 Reverse Transcriptase

We report the results of a binding free energy-based virtual screening campaign of a library of 77 α-hydroxytropolone derivatives against the challenging RNase H active site of the reverse transcriptase (RT) enzyme of human immunodeficiency virus-1. Multiple protonation states, rotamer states, and binding modalities of each compound were individually evaluated. The work involved more than 300 individual absolute alchemical binding free energy parallel molecular dynamics calculations and over 1 million CPU hours on national computing clusters and a local campus computational grid. The thermodynamic and structural measures obtained in this work rationalize a series of characteristics of this system useful for guiding future synthetic and biochemical efforts. The free energy model identified key ligand-dependent entropic and conformational reorganization processes difficult to capture using standard docking and scoring approaches. Binding free energy-based optimization of the lead compounds emerging from the virtual screen has yielded four compounds with very favorable binding properties, which will be the subject of further experimental investigations. This work is one of the few reported applications of advanced-binding free energy models to large-scale virtual screening and optimization projects. It further demonstrates that, with suitable algorithms and automation, advanced-binding free energy models can have a useful role in early-stage drug-discovery programs

Underlying Event measurements in pp collisions at s=0.9 \sqrt {s} = 0.9 and 7 TeV with the ALICE experiment at the LHC

We present measurements of Underlying Event observables in pp collisions at s√=0.9 and 7TeV. The analysis is performed as a function of the highest charged-particle transverse momentum p T,LT in the event. Different regions are defined with respect to the azimuthal direction of the leading (highest transverse momentum) track: Toward, Transverse and Away. The Toward and Away regions collect the fragmentation products of the hardest partonic interaction. The Transverse region is expected to be most sensitive to the Underlying Event activity. The study is performed with charged particles above three different p T thresholds: 0.15, 0.5 and 1.0 GeV/c. In the Transverse region we observe an increase in the multiplicity of a factor 2–3 between the lower and higher collision energies, depending on the track p T threshold considered. Data are compared to Pythia 6.4, Pythia 8.1 and Phojet. On average, all models considered underestimate the multiplicity and summed p T in the Transverse region by about 10–30%