Examining the importance of the level of computational theory used in solution-phase structural determinations by NMR using residual dipolar couplings

Abstract

The structures of many small molecules have been determined using residual dipolar couplings (RDCs) and the singular value decomposition method (SVD). Here, a key part of the SVD method is examined. The methods used to predict the 3-dimensional structures of molecules used in the SVD methodology for comparison with RDCs were examined for their impact on the quality of agreement that those structures had with observed RDCs. It was observed that the method of generating a proposed structure had a great impact on the quality of agreement with observed spectral data and that more computationally intensive methods of proposing structures provided better agreement with the observed RDCs in the control molecule.

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Transcription Factors as Critical Players in Melanoma Invasiveness, Drug Resistance and Opportunities for Therapeutic Drug Development

Abstract

Resistance to targeted therapy in cancer is often coupled with the acquisition of a pro-invasive phenotype by tumors cells and a highly permissive tumor microenvironment promoting drug resistance. Transcription factors are frequently shown as major points of convergence of multiple dysregulated receptors and signaling pathways in cancer. Several transcription factors are now incriminated as drivers of both drug resistance and invasiveness. We focused this review on critical transcription factors playing a causal role in both the resistance to BRAF V600E targeted therapy and the pro-invasive behavior of melanoma cells. Simultaneous rewiring of pro-oncogenic signaling pathways, phenotype switching or phenotypic plasticity supporting pro-invasive/pro-metastatic behavior, actin remodeling, bidirectional interactions between tumor microenvironment and melanoma cells represent major challenges for overcoming resistance to BRAF V600E inhibitors (BRAFi) and will be discussed. Although it represents an underdeveloped area of translational investigation, inhibition of transcription factors may open new avenues to combat resistance to BRAFi.

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PDCD1 Gene Polymorphisms as Regulators of T-Lymphocyte Activity in Cutaneous Melanoma Risk and Prognosis

Summary

This study aimed to evaluate whether PD1.1 (c.-606G>A), PD1 (c.627+252C>T), PD1.5 (c.804C>T) and PD1.9 (c.644C>T) single nucleotide polymorphisms of PDCD1 gene influence the risk, clinicopathological aspects and survival of cutaneous melanoma (CM). Individuals with phototype I or II and PD1 CC genotype were under 5.89-fold increased risk of developing CM. PD1.5 TT genotype increased PDCD1 expression (2.49 vs. 1.28 arbitrary units, P= 0.03) and PD1.5 CT or TT genotype and allele T increased PD1 expression in TCD4⁺ lymphocytes (16.6 vs. 12.5%, P= 0.01; 17.0 vs. 13.1%, P= 0.006). At 60 months of follow-up, short recurrence-free survival was seen in patients with PD1.1 AA genotype (33.3 vs. 71.8%, P= 0.03). Patients with PD1.1 AA and PD1.5 CC genotype had 4.21 and 2.62 more chances of presenting relapse and evolving death by disease in Cox analyses, respectively. Our data provides preliminary evidence that abnormalities in regulation of T-lymphocyte alter CM risk, clinical aspects and prognosis.

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Examining the importance of the level of computational theory used in solution-phase structural determinations by NMR using residual dipolar couplings

Abstract

The structures of many small molecules have been determined using residual dipolar couplings (RDCs) and the singular value decomposition method (SVD). Here, a key part of the SVD method is examined. The methods used to predict the 3-dimensional structures of molecules used in the SVD methodology for comparison with RDCs were examined for their impact on the quality of agreement that those structures had with observed RDCs. It was observed that the method of generating a proposed structure had a great impact on the quality of agreement with observed spectral data and that more computationally intensive methods of proposing structures provided better agreement with the observed RDCs in the control molecule.

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Comparative Efficacy of Once-Daily Umeclidinium/Vilanterol and Tiotropium/Olodaterol Therapy in Symptomatic Chronic Obstructive Pulmonary Disease: A Randomized Study

Abstract

Introduction

We report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting β₂-agonist (LAMA/LABA) combinations umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD.

Methods

This was a randomized, two-period crossover open-label study in symptomatic patients with COPD [age 40 years or older, postbronchodilator forced expiratory volume in 1 s (FEV₁) of 70% or less and 50% or more of predicted normal values, and modified Medical Research Council Dyspnoea Scale score of 2 or greater] not receiving inhaled corticosteroid therapy. Patients were randomized to receive UMEC/VI (62.5/25 µg once daily) via a multidose dry powder inhaler (ELLIPTA) followed by TIO/OLO (5/5 µg once daily) via a soft mist inhaler (Respimat), each for 8 weeks with an interim 3-week washout or vice versa. The primary end point was the change from baseline in trough FEV₁ at week 8 with a noninferiority margin of − 50 mL in the per-protocol (PP) population. The incidence of adverse events was also assessed.

Results

In total, 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat population and 227 were included in the PP population. UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV₁ at week 8 [FEV₁ change from baseline 180 mL vs 128 mL; difference 52 mL (95% confidence interval 28–77 mL); p < 0.001]. Patients receiving UMEC/VI had twofold increased odds of experiencing a clinically meaningful increase (100 mL or more) from baseline in trough FEV₁ at week 8 compared with patients receiving TIO/OLO (odds ratio 2.05; 95% confidence interval 1.34–3.14). Adverse events occurred in 25% of patients in the UMEC/VI group and in 31% of patients in the TIO/OLO group.

Conclusion

In this first direct comparison of two once-daily fixed-dose LAMA/LABA combinations, superiority was observed for the primary end point of trough FEV₁ at week 8 with UMEC/VI compared with TIO/OLO in patients with symptomatic COPD. Both treatments had similar safety profiles. These findings confirm the results of previous indirect LAMA/LABA comparisons, and show that an efficacy gradient exists within the LAMA/LABA class.

Trial Registration

ClinicalTrials.gov identifier NCT02799784.

Funding

GlaxoSmithKline.

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A model of disturbed eating behavior in men: The role of body dissatisfaction, emotion dysregulation and cognitive distortions

Comprehensive models, targeting the development of eating disorders (EDs) in males, often employ a sociocultural perspective and empathize the importance of body dissatisfaction (BD). To further illuminate psychological factors contributing to the development of ED pathology, we propose a mediator model of disturbed eating and compensatory behavior (DECB) for men. This model suggests that emotion dysregulation and the susceptibility to body-related cognitive distortions (thought-shape fusion, TSF) mediate the relationship between BD and DECB. Based on data from a cross-sectional online-survey we tested our model in a non-clinical community sample of young men (N=123, 18-37 years). We found a significant positive association between BD and DECB, accounting for participant's body mass index (BMI), age and depressive symptoms. While TSF partially mediated the relationship between BD and DECB, we did not detect a corresponding effect for emotion dysregulation. Based on our findings, we concluded that TSF, which describes specific distorted cognitions with respect to one's own body triggered by fattening/ forbidden food, contributes to the pathological eating- and body-related behavior in men who are dissatisfied with their body. We suggest that TSF should be included in etiological models as a relevant aspect of cognitive information processing with emotional and behavioral consequences.

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La transformació del medi natural en el paisatge agrícola durant l’època antiga. L’exemple del jaciment de Foneria (Barcelona)

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