Galcanezumab in episodic migraine: subgroup analyses of efficacy by high versus low frequency of migraine headaches in phase 3 studies (EVOLVE-1 & EVOLVE-2).

BACKGROUND: Patients with high-frequency episodic migraine (HFEM) have a greater disease burden than those with low-frequency episodic migraine (LFEM). Acute treatment overuse increases the risk of migraine chronification in patients with HFEM. Galcanezumab, a humanized monoclonal antibody binding calcitonin gene-related peptide (CGRP), is effective for migraine prevention with a favorable safety profile. Here, we investigate whether there are differences in galcanezumab efficacy in patients with LFEM or with HFEM. METHODS: Data were pooled from two double-blind, placebo-controlled phase 3 trials; EVOLVE-1 and EVOLVE-2. Patients were 18-65 years old, experienced 4-14 monthly migraine headache days (MHDs) for ≥1 year prior, with onset at \u3c 50 years of age. Migraine headaches were tracked via electronic patient-reported outcome system and randomization was stratified by low (LFEM; 4-7 monthly MHDs) or high (HFEM; 8-14 monthly MHDs) frequency. Subgroup analysis compared the HFEM and LFEM subgroups with a linear or generalized linear mixed model repeated measures approach. RESULTS: The intent-to-treat patients (N = 1773) had a mean age of 41.3 years, were mostly white (75%), female (85%), and 66% of patients had HFEM. In both the LFEM and HFEM subgroups, the overall (Months 1-6) and monthly changes from baseline in monthly MHDs and monthly MHDs with acute medication use compared with placebo were statistically significantly reduced for galcanezumab 120-mg and 240-mg. Galcanezumab (120-mg and 240-mg) significantly decreased the overall and monthly MHDs with nausea and/or vomiting, and with photophobia and phonophobia versus placebo in patients with LFEM or HFEM. In both subgroups, the mean overall (Months 1-6) and monthly percentages of patients with ≥50%, ≥75%, and 100% reduction in monthly MHDs from baseline were statistically significantly greater in patients receiving either dose of galcanezumab versus placebo. Galcanezumab (120-mg and 240-mg) significantly improved the Migraine-Specific Quality of Life Questionnaire role function-restrictive domain score as well as the Migraine Disability Assessment total score versus placebo for patients with LFEM or HFEM. There were no significant subgroup-by-treatment interactions. CONCLUSIONS: Galcanezumab was as effective in patients with HFEM as in those with LFEM. Associated symptoms, quality of life, and disability were similarly improved in patients with HFEM or LFEM. TRIAL REGISTRATION: NCT02614183 , NCT02614196

DNA base sequence effects on bulky lesion-induced conformational heterogeneity during DNA replication

4-Aminobiphenyl (ABP) and its structure analog 2-aminofluorene (AF) are well-known carcinogens. In the present work, an unusual sequence effect in the 5′-CTTCTG1G2TCCTCATTC-3′ DNA duplex is reported for ABP- and AF-modified G. Specifically, the ABP modification at G1 resulted in a mixture of 67% major groove B-type (B) and 33% stacked (S) conformers, while at the ABP modification at G2 exclusively resulted in the B-conformer. The AF modification at G1 and G2 lead to 25%:75% and 83%:17% B:S population ratios, respectively. These differences in preferred conformation are due to an interplay between stabilizing (hydrogen bonding and stacking that is enhanced by lesion planarity) and destabilizing (solvent exposure) forces at the lesion site. Furthermore, while the B-conformer is a thermodynamic stabilizer and the S-conformer is a destabilizer in duplex settings, the situation is reversed at the single strands/double strands (ss/ds) junction. Specifically, the twisted biphenyl is a better stacker at the ss/ds junction than the coplanar AF. Therefore, the ABP modification leads to a stronger strand binding affinity of the ss/ds junction than the AF modification. Overall, the current work provides conformational insights into the role of sequence and lesion effects in modulating DNA replication

Investigation of the magnetic anisotropy in a series of trigonal bipyramidal Mn(II) complexes

Understanding how the magnetic anisotropy in simple coordination complexes can be manipulated is instrumental to the development of single-molecule magnets (SMMs). Clear strategies can then be designed to control both the axial and transverse contributions to the magnetic anisotropy in such compounds, and allow them to reach their full potential. Here we show a strategy for boosting the magnetic anisotropy in a series of trigonal bipyramidal Mn(II) complexes – [MnCl3(HDABCO)(DABCO)] (1), [MnCl3(MDABCO)2]·[ClO4] (2), and [MnCl3(H2O)(MDABCO)] (3). These have been successfully synthesised using the monodentate [DABCO] and [MDABCO]+ ligands. Through static (DC) magnetic measurements and detailed theoretical investigation using ab initio methods, the magnetic anisotropy of each system has been studied. The calculations reveal that the rhombic zero-field splitting (ZFS) term (E) can be tuned as the symmetry around the Mn(II) ion is changed. Furthermore, an in silico investigation reveals a strategy to increase the axial ZFS parameter (D) of trigonal bipyramidal Mn(II) by an order of magnitude

A large axial magnetic anisotropy in trigonal bipyramidal Fe(II)

The first trigonal bipyramidal Fe(II) complex to display slow relaxation of magnetisation has been isolated, with this behaviour found to arise through a combination of a large magnetic anisotropy (D = -27.5 cm-1) and a pseudo-D3h symmetry at the Fe(II) centre, as investigated through ab initio and magnetic studies

Computational evaluation of nucleotide insertion opposite expanded and widened DNA by the translesion synthesis polymerase Dpo4

Open accessExpanded (x) and widened (y) deoxyribose nucleic acids (DNA) have an extra benzene ring incorporated either horizontally (xDNA) or vertically (yDNA) between a natural pyrimidine base and the deoxyribose, or between the 5- and 6-membered rings of a natural purine. Far-reaching applications for (x,y)DNA include nucleic acid probes and extending the natural genetic code. Since modified nucleobases must encode information that can be passed to the next generation in order to be a useful extension of the genetic code, the ability of translesion (bypass) polymerases to replicate modified bases is an active area of research. The common model bypass polymerase DNA polymerase IV (Dpo4) has been previously shown to successfully replicate and extend past a single modified nucleobase on a template DNA strand. In the current study, molecular dynamics (MD) simulations are used to evaluate the accommodation of expanded/widened nucleobases in the Dpo4 active site, providing the first structural information on the replication of (x,y)DNA. Our results indicate that the Dpo4 catalytic (palm) domain is not significantly impacted by the (x,y)DNA bases. Instead, the template strand is displaced to accommodate the increased C1’–C1’ base-pair distance. The structural insights unveiled in the present work not only increase our fundamental understanding of Dpo4 replication, but also reveal the process by which Dpo4 replicates (x,y)DNA, and thereby will contribute to the optimization of high fidelity and efficient polymerases for the replication of modified nucleobases.Ye

DNA-protein pi-interactions in nature: abundance, structure, composition and strength of contacts between aromatic amino acids and DNA neucleobases or deoxyribose sugar

Sherpa Romeo green journal, open accessFour hundred twenty-eight high-resolution DNA– protein complexes were chosen for a bioinformatics study. Although 164 crystal structures (38% of those searched) contained no interactions, 574 discrete pi- contacts between the aromatic amino acids and the DNA nucleobases or deoxyribose were identified using strict criteria, including visual inspection. The abundance and structure of the interactions were determined by unequivocally classifying the contacts as either pi–pi stacking, Pi–pi T-shaped or sugar– pi contacts. Three hundred forty-four nucleobase– amino acid pi–pi contacts (60% of all interactions identified) were identified in 175 of the crystal structures searched. Unprecedented in the literature, 230 DNA–protein sugar–pi contacts (40% of all interactions identified) were identified in 137 crystal structures, which involve C–H···pi and/or lone–pair···pi interactions, contain any amino acid and can be classified according to sugar atoms involved. Both pi–pi and sugar–pi interactions display a range of relative monomer orientations and therefore interaction energies (up to –50 (–70) kJ mol−1 for neutral (charged) interactions as determined using quantum chemical calculations). In general, DNA–protein pi-interactions are more prevalent than perhaps currently accepted and the role of such interactions in many biological processes may yet to be uncovered.Ye

The relationship between aortic wall distensibility and rupture of infrarenal abdominal aortic aneurysm

AbstractObjective: A more accurate means of prediction of abdominal aortic aneurysm (AAA) rupture would improve the clinical and cost effectiveness of prophylactic repair. The purpose of this study was to determine whether AAA wall distensibility can be used to predict time to rupture independently of other recognized risk factors. Methods: A prospective, six-center study of 210 patients with AAA in whom blood pressure (BP), maximum AAA diameter (Dmax), and AAA distensibility (pressure strain elastic modulus [Ep] and stiffness [β]) were measured at 6 months with an ultrasound scan-based echo-tracking technique. A stepwise, time-dependent, Cox proportional hazards model was used to determine the effect on time to rupture of age, gender, BP, Dmax, BP, Ep, β, and change in Dmax, Ep, and β adjusted for time between follow-up visits. Results: Median (interquartile range) AAA diameter was 48 mm (41 to 54 mm), median age was 72 years (68 to 77 years), and median follow-up period was 19 months (9 to 30 months). In the Cox model, female gender (hazards ratio [HR], 2.78; 95% CI, 1.23 to 6.28; P =.014), larger Dmax (HR, 1.36 for 10% increase in Dmax; 95% CI, 1.12 to 1.66; P =.002), higher diastolic BP (HR, 1.13 for 10% increase in BP; 95% CI, 1.13 to 1.92; P =.004), and a decrease in Ep (increase in distensibility) over time (HR, 1.38 for 10% decrease in Ep over 6 months; 95% CI, 1.08 to 1.78; P =.010) significantly reduced the time to rupture (had a shorter time to rupture). Conclusion: Women have a shorter time to AAA rupture. The measurement of AAA distensibility, diastolic BP, and diameter may provide a more accurate assessment of rupture risk than diameter alone. (J Vasc Surg 2003;37:112-7.

The relationship between aortic wall distensibility and rupture of infrarenal abdominal aortic aneurysm

AbstractObjective: A more accurate means of prediction of abdominal aortic aneurysm (AAA) rupture would improve the clinical and cost effectiveness of prophylactic repair. The purpose of this study was to determine whether AAA wall distensibility can be used to predict time to rupture independently of other recognized risk factors. Methods: A prospective, six-center study of 210 patients with AAA in whom blood pressure (BP), maximum AAA diameter (Dmax), and AAA distensibility (pressure strain elastic modulus [Ep] and stiffness [β]) were measured at 6 months with an ultrasound scan-based echo-tracking technique. A stepwise, time-dependent, Cox proportional hazards model was used to determine the effect on time to rupture of age, gender, BP, Dmax, BP, Ep, β, and change in Dmax, Ep, and β adjusted for time between follow-up visits. Results: Median (interquartile range) AAA diameter was 48 mm (41 to 54 mm), median age was 72 years (68 to 77 years), and median follow-up period was 19 months (9 to 30 months). In the Cox model, female gender (hazards ratio [HR], 2.78; 95% CI, 1.23 to 6.28; P =.014), larger Dmax (HR, 1.36 for 10% increase in Dmax; 95% CI, 1.12 to 1.66; P =.002), higher diastolic BP (HR, 1.13 for 10% increase in BP; 95% CI, 1.13 to 1.92; P =.004), and a decrease in Ep (increase in distensibility) over time (HR, 1.38 for 10% decrease in Ep over 6 months; 95% CI, 1.08 to 1.78; P =.010) significantly reduced the time to rupture (had a shorter time to rupture). Conclusion: Women have a shorter time to AAA rupture. The measurement of AAA distensibility, diastolic BP, and diameter may provide a more accurate assessment of rupture risk than diameter alone. (J Vasc Surg 2003;37:112-7.

Computational insights into the molecular basis for the replication of flexible tobacco-derived DNA lesions

DNA is damaged by many agents in the environment and this affects many cellular processes, including DNA replication. The present thesis uses a multiscale computational modeling approach to study the intrinsic conformational and base-pairing preferences of flexible O6-G and O2-T alkyl DNA lesions, and the corresponding properties within DNA duplexes and polymerase active sites. Specifically, the replication of O6-benzylguanine (Bz-G) by a prototypical DNA polymerase, DNA polymerase IV, as well as the replication of the tobacco-derived carcinogens, O6-[4-oxo-4-(3-pyridyl)butyl]guanine (POB-G), O6-[4-hydroxy-4-(3-pyridyl)butyl]guanine (PHB-G), and O2-[4-oxo-4-(3-pyridyl)butyl] thymine (POB-T), by human DNA polymerases η and κ, were investigated. This work uncovers structural bases for the reported lesion mutagenicity and biological processing. Additionally, a consistent theoretical framework was used to provide insight into the previously unidentified general base for the nucleotidyl transfer reaction catalyzed by polymerase η. Overall, this thesis emphasizes the complex interplay between many factors that are required to replicate damaged DNA