Physicochemical and functional characterization of trastuzumab-dkst, a trastuzumab biosimilar

Aims: Preclinical comparative similarity studies of trastuzumab-dkst, a Herceptin® biosimilar, are reported. Materials & methods: Primary sequence and higher-order structure and pharmacological mechanisms of action were compared using multiple techniques. Pharmacokinetics and repeat-dose toxicity were assessed in cynomolgus monkeys. Results: Primary structures were identical; secondary and tertiary structures were highly similar. Non-significant differences were observed for charge heterogeneity. Twelve of 13 glycan species were highly similar, with slightly higher total mannose levels in trastuzumab-dkst. FcγR and FcRn binding activity was highly similar. Each drug equally inhibited HER2+ cell proliferation, demonstrating equivalent relative potency in mediating HER2+ cell cytolysis by antibody-dependent cellular cytotoxicity. Pharmacokinetic and toxicological profiles in cynomolgus monkeys were similar. Conclusion: Trastuzumab-dkst, US-licensed trastuzumab and EU-approved trastuzumab demonstrate high structural and functional similarity.

Counterfactuals and Undefinedness: Homogeneity vs. Supervaluations

Theories of counterfactuals agree on appealing to a relation of comparative similarity, but disagree on the quantificational force of counterfactuals. We report on two experiments testing the predictions of three main approaches: universal theories, homogeneity theories, and single-world selection theories (plus supervaluations over selection functions). The critical cases in our experiment were constructed so as to discriminate between the three theories. Our results provide empirical support for the selectional theories, while challenging the other two approaches.

How to choose a fuzzy similarity measure in decision-making?

Purpose The paper is dedicated to the analysis of fuzzy similarity measures in uncertainty analysis in general, and in economic decision-making in particular. The purpose of this paper is to explain how a similarity measure can be chosen to quantify a qualitative description of similarities provided by experts of a given domain, in the case where the objects to compare are described through imprecise or linguistic attribute values represented by fuzzy sets. The case of qualitative dissimilarities is also addressed and the particular case of their representation by distances is presented. Design/methodology/approach The approach is based on measurement theory, following Tversky’s well-known paradigm. Findings A list of axioms which may or may not be satisfied by a qualitative comparative similarity between fuzzy objects is proposed, as extensions of axioms satisfied by similarities between crisp objects. They enable to express necessary and sufficient conditions for a numerical similarity measure to represent a comparative similarity between fuzzy objects. The representation of comparative dissimilarities is also addressed by means of specific functions depending on the distance between attribute values. Originality/value Examples of functions satisfying certain axioms to represent comparative similarities are given. They are based on the choice of operators to compute intersection, union and difference of fuzzy sets. A simple application of this methodology to economy is given, to show how a measure of similarity can be chosen to represent intuitive similarities expressed by an economist by means of a quantitative measure easily calculable. More detailed and formal results are given in Coletti and Bouchon-Meunier (2020) for similarities and Coletti et al. (2020) for dissimilarities.

Molecular Interaction of Cytotoxic Anticancer Analogues as Inhibitors of β-tubulin Protein Against UACC-62 Melanoma Cell

Background In previous research, a series of cytotoxic anticancer analogues related to 2-acylamino-1,4-naphthoquinone derivatives has been demonstrated. As microtubule plays an important role in many essential cellular processes such as mitosis, tubulin is an important target of anticancer drug. Methods This study performed molecular docking simulation, pharmacophore model, comparative force field analysis model, and comparative similarity indices analysis model to investigate the relationship between inhibitory activities and the properties of compounds, in order to further progress the development of cytotoxic anticancer analogues. Results These compounds have common H-bond interactions with key residues Lys254 and Lys352, but compounds with large R2 substituent have different docking poses than compounds with small R2 substituent. Some of derivatives such as compound 18 formed the H-bonds with residue Lys254 using the oxygen atoms in R1 substituent and formed π-cation interactions with residue Lys352 using phenyl moiety of 1,4-naphthoquinone. The R1 substituent of these compounds preferred to have disfavored hydrophobic fields and favorable space toward the direction of residue Asn258, while the R2 substituent of these compounds preferred to have about 2–3 carbon chain length hydrophobic substituent toward the direction of residues Ala316 and Lys352. Conclusion These results offer some beneficial advices for further study in anticancer drug development process.

Expansive Posture

Much can be gleaned about the affective, cognitive, and motivational states of others by attending to various channels of nonverbal communication. Although there are a variety of ways to organize the body of research on the psychological correlates of nonverbal behavior, researchers in social psychology and communication often distinguish between two dimensions: the hierarchical dimension (status/dominance/power) and the affiliative dimension (liking/romantic interest). Most nonverbal cues have implications for both of these dimensions, and postural expansion is not an exception. Postural expansion includes “enlarging” behaviors such as sitting more erectly, opening up the torso, and extending limbs away from the body. In contrast, postural constriction involves postures that ultimately make an organism appear smaller (such as slumping the shoulders, wrapping limbs around the body, or averting the gaze downward). Numerous researchers have noted the comparative similarity between postural expansion and constriction in humans and, respectively, dominance and submission displays in animals. For example, the bristling of a cat’s fur (piloerection) in response to threat serves to make the animal look larger and more threatening, while the exposure of a dog’s stomach in submission or appeasement serves to make the animal appear smaller, less threatening, or more vulnerable. Substantially more literature has investigated the association between postural expansion and the hierarchical dimension than the affiliative dimension, a bias that is duplicated here. Furthermore, it is important to note that the “hierarchical” literature addresses several related, but unique, questions: (1) How does postural expansion affect perceptions of others’ status/dominance/power? (2) Is postural expansion linked with actual differences in status/dominance/power or other relevant dependent measures? (3) Is postural expansion reliably linked with an important universal nonverbal expression?

Comparative Responses to Squats Completed with Free Weights and an Exoskeleton

To assess the comparative similarity of squat data collected as they wore a robotic exoskeleton, female athletes (n=14) did two exercise bouts spaced 14 days apart. Data from their exoskeleton workout was compared to a session they did with free weights. Each squat workout entailed a four-set, four-repetition paradigm with 60-second rest periods. Sets for each workout involved progressively heavier (22.5, 34, 45.5, 57 kg) loads. The same physiological, perceptual, and exercise performance dependent variables were measured and collected from both workouts. Per dependent variable, Pearson correlation coefficients, t-tests, and Cohen's d effect size compared the degree of similarity between values obtained from the exoskeleton and free weight workouts. Results show peak O2, heart rate, and peak force data produced the least variability. In contrast, far more inter-workout variability was noted for peak velocity, peak power, and electromyography (EMG) values. Overall, an insufficient amount of comparative similarity exists for data collected from both workouts. Due to the limited data similarity, the exoskeleton does not exhibit an acceptable degree of validity. Likely the cause for the limited similarity was due to the brief amount of familiarization subjects had to the exoskeleton prior to actual data collection. A familiarization session that accustomed subjects to squats done with the exoskeleton prior to actual data collection may have considerably improved the validity of data obtained from that device.

Knowing that Pain is Bad

This chapter shows how moral knowledge is possible according to Compassionate Moral Realism, and how that view is able to sidestep the two most influential worries about moral realism’s ability to account for moral knowledge. First, an analogous case of knowledge is considered: knowing that two color experiences are similar in comparison to some third. The latter form of knowledge is hard to deny, and can be naturally explained in terms of a conceptual analysis of comparative similarity and reflection on conscious experiences. A parallel explanation, it is argued, can be given of moral knowledge of the badness of pain according to Compassionate Moral Realism. It is then shown that this explanation is not threated by considerations concerning the evolution of our capacities and concerning moral disagreement—in part because of the view’s compatibility with judgment pluralism.

Measuring shared variants in cohorts of discordant siblings with applications to autism

We develop a method of analysis [affected to discordant sibling pairs (A2DS)] that tests if shared variants contribute to a disorder. Using a standard measure of genetic relation, test individuals are compared with a cohort of discordant sibling pairs (CDS) to derive a comparative similarity score. We ask if a test individual is more similar to an unrelated affected than to the unrelated unaffected sibling from the CDS and then, sum over such individuals and pairs. Statistical significance is judged by randomly permuting the affected status in the CDS. In the analysis of published genotype data from the Simons Simplex Collection (SSC) and the Autism Genetic Resource Exchange (AGRE) cohorts of children with autism spectrum disorder (ASD), we find strong statistical significance that the affected are more similar to the affected than to the unaffected of the CDS (P value ∼ 0.00001). Fathers in multiplex families have marginally greater similarity (P value = 0.02) to unrelated affected individuals. These results do not depend on ethnic matching or gender.