Development of a novel nomogram-based online tool to predict axillary status after neoadjuvant chemotherapy in cN+ breast cancer: A multicentre study on 1,950 patients

Background: Type of axillary surgery in breast cancer (BC) patients who convert from cN + to ycN0 after neoadjuvant chemotherapy (NAC) is still debated. The aim of the present study was to develop and validate a preoperative predictive nomogram to select those patients with a low risk of residual axillary disease after NAC, in whom axillary surgery could be minimized. Patients and methods: 1950 clinically node-positive BC patients from 11 Breast Units, treated by NAC and subsequent surgery, were included from 2005 to 2020. Patients were divided in two groups: those who achieved nodal pCR vs. those with residual nodal disease after NAC. The cohort was divided into training and validation set with a geographic separation criterion. The outcome was to identify independent predictors of axillary pathologic complete response (pCR). Results: Independent predictive factors associated to nodal pCR were axillary clinical complete response (cCR) after NAC (OR 3.11, p < 0.0001), ER-/HER2+ (OR 3.26, p < 0.0001) or ER+/HER2+ (OR 2.26, p = 0.0002) or ER-/HER2- (OR 1.89, p = 0.009) BC, breast cCR (OR 2.48, p < 0.0001), Ki67 > 14% (OR 0.52, p = 0.0005), and tumor grading G2 (OR 0.35, p = 0.002) or G3 (OR 0.29, p = 0.0003). The nomogram showed a sensitivity of 71% and a specificity of 73% (AUC 0.77, 95%CI 0.75\u20130.80). After external validation the accuracy of the nomogram was confirmed. Conclusion: The accuracy makes this freely-available, nomogram-based online tool useful to predict nodal pCR after NAC, translating the concept of tailored axillary surgery also in this setting of patients

Whole body vibration: What is all the fuss about?

Whole body vibration (WBV) has been promoted in the market as a new method for exercising, by which 10min are more than enough for the fitness training of busy, modern people. Several companies have been over-stating the positive effects that this type of exercise has on the human body, advertising the general improvement in strength, flexibility and neuromuscular performance granted through it. The question needs to be asked: ‘Does WBV do what it is said to be doing?’. © 2010, MA Healthcare Ltd. All rights reserved

Theoretical and experimental study of flavones as inhibitors of xanthine oxidase

Inhibitory activities of 19 polyhydroxylated and polymethoxylated flavones towards xanthine oxidase have been obtained by accurate measurements of the dissociation constants of enzyme-inhibitor complexes (K-EI). A topological description of the congeneric series has been adopted to derive quantitative structure-activity relationships (QSAR) with the use of multiple linear regression analysis. For interpretative purposes, molecular orbital calculations have also been performed. Inhibition appears to involve flavones as donors and the anion at the C-7 hydroxyl as the most active form in solution. Substituents in the 4H-1-benzopyran-4-one moiety can directly affect the availability of the C-7 anion in solution; substituents in the 2-phenyl moiety are probably involved in secondary local interactions with the enzyme

Physico-chemical properties of anthocyanidins. Part 1. Theoretical evaluation of the stability of the neutral and anionic tautomeric forms

Quantum chemical (AM1) and solvation model calculations have been applied to the study of tautomeric stabilities in three anthocyanidins, so as to single out the dominant tautomeric forms (neutral and anionic) at physiological pH. The theoretical information concerning the tautomeric stabilities and electronic structures of anthocyanidins are essential for the development of quantitative structure-activity relationships. The present results allow us to discriminate between the wide variety of tautomeric forms, and to infer that, depending on the pH, only two neutral tautomers and two anionic tautomers should be present in solution. On interpretative grounds, the main factors determining stability are chiefly ascribable to the extent of pi-electron delocalization and to the possibility of classical resonance structures. Several theoretical descriptors have been calculated for use in quantitative structure-activity relationships

A rational approach to the design of flavones as xanthine oxidase inhibitors

In the light of previous QSAR studies on flavones as inhibitors of xanthine oxidase, we synthesized and tested a new series of 7-hydroxyflavones carrying a wide and balanced variety of substituents (pi, sigma(p)) at the 4' position in order to explore the effect of substituents at this position on the xanthine oxidase inhibitory activity. The results of pK(a) determinations show that the electronic effects of the substituents are not transferred to the hydroxyl at C7, previously found to be fundamental for activity. An excellent correlation is found between molar refractivity of the substituents and the inhibitory activity. These results, applied to the more active 5,7-dihydroxyflavones, allowed the design and synthesis of a very active inhibitor, with an IC50 in the nanomolar range. On interpretative grounds, C4' substituents of flavones are involved in dispersion interactions with the enzyme. The calculation of quantum chemical polarizabilities and solvent accessible surface areas suggests the existence of pi-pi stacking interactions with an aromatic aminoacidic residue of the enzyme

Solvent effects on the tautomerism of apigeninidin

Solvent effects are found to be responsible for the predominance in water solution of a highly unstable tautomer of apigeninidin in vacuo. We present free energy perturbation in molecular dynamics simulations and self-consistent reaction field calculations of the relative solvation of the anionic tautomers of apigeninidin

A model of the interaction of substrates and inhibitors with xanthine oxidase

A model of the interaction of substrates and inhibitors with xanthine oxidase (XO) based on similarity concepts and molecular modeling is introduced and discussed, and previous literature is reexamined in the light of recent insights into the mechanism and structure of XO. Use is made of quantum-chemical calculations with the inclusion of solvent effects, molecular superimposition with least-squares fitting algorithms, and molecular electrostatic potentials. First, the relative stabilities of the tautomeric forms of the physiological substrates, xanthine and hypoxanthine, are calculated both in vacuo and in water in order to select the most abundant form(s) at physiological pH: the two substrates prove to be stable in their lactam forms, with a dominance of the N-7-H tautomer for xanthine and of N-9-H for hypoxanthine. The structures of xanthine and hypoxanthine are then superimposed, and their relative orientation with respect to the molybdenum center of XO is suggested. The criteria used for superimposition reflect the importance of functional groups of xanthine and hypoxanthine, as inferred from experimental work. In particular, the carbonyl oxygen common to the two substrates is given special consideration on account of its determinant role. The results show that the most important functional groups of the two substrates can be successfully superimposed by means of a rotation that exchanges the five-membered with the six-membered rings of xanthine and hypoxanthine with respect to molybdenum. The close similarity of the electrostatic potentials of the two superimposed molecules adds weight to the proposed orientation of the substrates in the binding site. The model of interaction is then tested and further developed using a series of previously-synthesized dimensional analogs of xanthine and hypoxanthine. The results confirm that the correct positioning of the carbonyl group is essential if a productive interaction with XO is to be achieved and allow us to map the dimensions of the active site starting from the superimposition of the physiological substrates. Two hypotheses regarding the amino acid residues interacting with the important carbonyl oxygen of the substrates are then put forward on the basis of spectroscopic and biochemical evidence: they are postulated to be one lysine or one protonated glutamic acid residue. In an attempt to unify the binding of substrates and inhibitors, the model is extended to the inhibitors of XO by superimposing the most interesting inhibitors developed by Robins on xanthine and hypoxanthine. This allows us to define the most suitable location of the phenyl rings of these inhibitors with respect to the superimposition of the substrates. Intriguingly, the superimpositions of the most active inhibitors are consistent with a unique location of their phenyl rings, even though they are in different positions on the purine ring. Finally, the flavone, which is a potent inhibitor of XO and is currently under investigation by the authors, is accounted for by these findings and successfully included in the model. This model incorporates many important insights into XO and can be of general interest. Moreover, it represents a clear-cut alternative to a previous model developed by Robins on the basis of the coordination of substrates and inhibitors to molybdenum