Predicting Trustworthiness Across Cultures: An Experiment

We contribute to the ongoing debate in the psychological literature on the role of “thin slices” of observable information in predicting others' social behavior, and its generalizability to cross-cultural interactions. We experimentally assess the degree to which subjects, drawn from culturally different populations (France and Japan), are able to predict strangers' trustworthiness based on a set of visual stimuli (mugshot pictures, neutral videos, loaded videos, all recorded in an additional French sample) under varying cultural distance to the target agent in the recording. Our main finding is that cultural distance is not detrimental for predicting trustworthiness in strangers, but that it may affect the perception of different components of communication in social interactions.

Evaluation of Anticonvulsant Activity of Dual COX-2/5-LOX Inhibitor Darbufelon and Its Novel Analogues

Neuroinflammation is an integral part of epilepsy pathogenesis and other convulsive conditions, and non-steroidal anti-inflammatory drugs (NSAIDs) present a potent tool for the contemporary search and design of novel anticonvulsants. In the present paper, evaluation of the anticonvulsant activity of the potential NSAID dual COX-2/5-LOX inhibitor darbufelone methanesulfonate using an scPTZ model in mice in dose 100 mg/kg is reported. Darbufelone possesses anticonvulsant properties in the scPTZ model and presents interest for in-depth studies as a possible anticonvulsant multi-target agent with anti-inflammatory activity. The series of 4-thiazolidinone derivatives have been synthesized following the analogue-based drug design and hybrid-pharmacophore approach using a darbufelone matrix. The synthesized derivatives showed a significant protection level for animals in the scPTZ model and are promising compounds for the design of potential anticonvulsants with satisfactory drug-like parameters.

Mind-Independent Moral Truths and Categorical Moral Reasons

Moral practice embodies the assumptions that moral truths are mind-independent and moral reasons are categorical. According to the practical expressivist account, both assumptions can be understood as claims about the application conditions of moral terms. In both cases, the practical expressivist goes on to understand these claims to voice positions about which moral sensibilities agents ought to adopt. The former voices the claim that agents ought not form their moral attitudes on the basis of their own endorsement of those attitudes; the latter that agents ought not form their structured-approvals purely on the basis of the existing desires of the target agent. In both cases, these substantive moral positions are also constitutive of competence with moral concepts, since agents who generally denied them would not be able to use those concepts to coordinate in the ways distinctive of morality.

Berberine as Potential Multi-Target Agent for Metabolic Diseases: A Review of Investigations for Berberine.

: Berberine (BBR) is a botanic alkaloid extracted from Coptis chinensis (Huanglian), which has various properties, compassing anti-hyperglycemia, anti-obesity, anti-inflammation, and improve insulin resistance, etc. Several researches have confirmed that BBR has effective actions in treating glycolipid metabolic abnormalities. BBR also has beneficial in regulating intestinal flora. Metabolic diseases are strongly associated with metabolic disorders, which are growing in the population and dramatically impacting human health, which also have been considered as a leading cause of diseases and death globally. This review is to evaluate the metabolic properties of BBR, and its potential application to the treatment of metabolic diseases by its effective actions on metabolic disorders.

Nelfinavir Is Active Against SARS-CoV-2 in Vero E6 Cells

Utilizing an integrative computational drug discovery approach, we predicted that nelfinavir is a potential inhibitor of SARS-CoV-2 main protease. Further docking nelfinavir to 30 potential target proteins of COVID-19, we found that nelfinavir is most probably a multi-target agent. The half-maximal effective concentration (EC₅₀) of nelfinavir mesylate against SARS-CoV-2 was 2.89±0.65 μM while that of remdesivir was 1.00±0.34 μM, both drugs showed similar dose-response curves. Based on its high potency against SARS-CoV-2 at cellular level, its higher exposure in lung than in plasma, its good safe profile and its potential to reduce inflammation, nelfinavir deserves further exploration for the treatment of COVID-19.

Nelfinavir Is Active Against SARS-CoV-2 in Vero E6 Cells

Utilizing an integrative computational drug discovery approach, we predicted that nelfinavir is a potential inhibitor of SARS-CoV-2 main protease. Further docking nelfinavir to 30 potential target proteins of COVID-19, we found that nelfinavir is most probably a multi-target agent. The half-maximal effective concentration (EC₅₀) of nelfinavir mesylate against SARS-CoV-2 was 2.89±0.65 μM while that of remdesivir was 1.00±0.34 μM, both drugs showed similar dose-response curves. Based on its high potency against SARS-CoV-2 at cellular level, its higher exposure in lung than in plasma, its good safe profile and its potential to reduce inflammation, nelfinavir deserves further exploration for the treatment of COVID-19.

Trastuzumab in the Treatment of Pregnant Breast Cancer Patients – an Overview of the Literature

Breast cancer is one of the most common malignancies which appear during pregnancy. Since women are increasingly not giving birth until they are at a more advanced age, it can be assumed that the incidence of pregnancy-related breast cancers will continue to increase in the future. Because of pregnancy-induced changes and conservative diagnosis, these carcinomas are frequently not detected until they are at an advanced stage and thus generally require systemic adjuvant therapy. The available data on optimal chemotherapeutic management are limited. Particularly for the use of the target agent trastuzumab which could crucially contribute to improving the prognosis in the therapy of HER2-overexpressing breast cancer in non-pregnant women, there is a lack of definitive information regarding the profile of action and safety in pregnancy as well as with regard to any long-term effects on the child. Thirty-eight pregnancies on trastuzumab for the treatment of breast cancer were able to be analysed in the literature currently available. Information can be gained from this and conclusions can be drawn which can individualise and decisively improve therapeutic options in the future for the pregnant breast cancer patient.

Accounting for the Unique Molecular Landscape of Pediatric Malignancies Improves Target-Agent Pair Identification for Pediatric Precision Oncology

Precision medicine has significant potential to improve therapy options for patients who have exhausted treatment options for their relapsed or refractory cancers. Next-generation sequencing has enabled the detection of genetic abnormalities in individual tumours that bestow sensitivity to selective agents targeting these dysregulated cellular pathways. Several programs have recently launched that utilize sequencing technology to identify patient mutations and match the patients to clinical trials for agents that target the dysregulted pathway. The Pediatric MATCH trial initiated by the National Cancer Institute (NCI) and Children's Oncology Group (COG) exemplifies this approach, but also emphasizes the numerous obstacles involved in molecularly-guided therapies The target and agent prioritization strategy for the Pediatric MATCH trial was recently outlined. It employs an amplicon-based targeted sequencing panel (OCAV3) that was originally developed to capture informative variants for adult tumours, with the current version 3 including a set of pediatric-specific variants. However, the landscape of genomic alterations across pediatric malignancies differs from adult malignancies, which translate to distinct oncogenic drivers. The fundamental differences in the genomic landscapes observed in adult and pediatric malignancies must therefore be considered in the optimization of target identification for precision oncology. We hypothesized that a pediatric-focused targeted sequencing panel (OCCRA) will be more informative than an adult-focused panel (OCAV3) for pediatric malignancies. To compare target-agent pairs identified by OCAV3 and OCCRA, we performed a retrospective analysis of 28 childhood tumour samples, 10 B-ALL, 4 T-ALL, 6 neuroblastomas, and 8 additional solid tumours. For 12 of these tumours, whole genome sequencing (WGS) was performed on matched samples and all sequencing results were filtered for pediatric cancer driver genes. For the 12 samples tested by all three sequencing modalities, we found that the greatest discordance occurred in samples with low (<25%) tumour content. In these samples, however, all three modalities gave highly concordant detection of pediatric driver mutations, indicating the robustness of amplicon-based sequencing. Following the prioritization strategies outlined by the Pediatric MATCH committee, at least one target-agent pair was detected for 16 of 28 samples sequenced by the OCAV3 panel with 23 total agents identified due to multiple variants per sample. Using the OCCRA panel, however, we detected at least one target-agent pair for 19 of 28 samples with 25 total agents. Importantly, a fusion was detected by OCCRA in 3 samples, whereas OCAV3 was unable to detect these fusions due to panel content. Of particular note was the detection of homozygous loss in CDKN2A, which was the most commonly identified target, assigned seven times for OCAV3 and 11 times for OCCRA. Although genomic loss in CDKN2A or CDKN2B is not validated by the manufacturer, orthologous verification through clinical reports and WGS indicates that the OCCRA panel called nine of nine verifiable losses in these genes across the 28 samples. Variants were also detected within targetable pathways currently not included in the Pediatric MATCH trial, such as the JAK/STAT or tyrosine kinase pathways; inclusion of inhibitors targeting these pathways increased the total number of agents to 25 for OCAV3 and 29 for OCCRA. In addition, use of the OCCRA panel enabled detection of potentially targetable cancer driver mutations, including gains in RUNX1, ABL2, or ERBB2 and a SMARCA4 SNV, in several samples for which no established target-agent pairing was assigned. Overall, amplicon-based sequencing was highly reproducible across independent panels, robust to low tumour content, and enabled cost-effective target-agent pairing with short 2-3 day turnaround times. Furthermore the pediatric cancer-specific OCCRA panel improved the identification rate of target-agent pairs and resulted in more frequent matching with multiple agents. Disclosures No relevant conflicts of interest to declare.