Ethypharm (France)

Human cytochrome P450 (CYP450) enzymes play a crucial role in drug metabolism and pharmacokinetics. CYP450 inhibition can lead to toxicity, in particular when drugs are co-administered with other drugs and xenobiotics or in the case of polypharmacy. Predicting CYP450 inhibition is also important for rational drug discovery and development, and precision in drug repurposing. In this overarching context, digital transformation of drug discovery and development, for example, using machine and deep learning approaches, offers prospects for prediction of CYP450 inhibition through computational models. We report here the development of a majority-voting machine learning framework to classify inhibitors and noninhibitors for seven major human liver CYP450 isoforms (CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). For the machine learning models reported herein, we employed interaction fingerprints that were derived from molecular docking simulations, thus adding an additional layer of information for protein-ligand interactions. The proposed machine learning framework is based on the structure of the binding site of isoforms to produce predictions beyond previously reported approaches. Also, we carried out a comparative analysis so as to identify which representation of test compounds (molecular descriptors, molecular fingerprints, or protein-ligand interaction fingerprints) affects the predictive performance of the models. This work underlines the ways in which the structure of the enzyme catalytic site influences machine learning predictions and the need for robust frameworks toward better-informed predictions.

<div>AbstractPurpose:<p>Debio 1143 is an oral antagonist of inhibitor of apoptosis proteins, which enhances tumor response with concomitant chemoradiotherapy. Addition of Debio 1143 to cisplatin-based chemoradiotherapy in locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN) was evaluated in a phase I/II study to determine the MTD and recommended phase II dose (RP2D). Here, phase I results are reported.</p>Patients and Methods:<p>Treatment-naïve patients with LA-SCCHN (stages III/IVA/IVB) received Debio 1143 (100, 200, 300 mg/day), for 14 days every 3 weeks, with cisplatin (100 mg/m², every 3 weeks), for three cycles, and concomitant conventional fractionation radiotherapy (70 Gy/7 weeks). Dose-limiting toxicity (DLT) was evaluated over 9 weeks using continual reassessment.</p>Results:<p>Fourteen patients were treated/evaluable for DLT. Median age was 64.5 years, and all patients were current/former smokers. Primary tumors were hypopharynx, oropharynx (all human papillomavirus/p16 negative), larynx, and oral cavity. Two of six patients at 200 mg/day had DLT (grade 3 tubular necrosis, grade 3 aspartate aminotransferase/alanine aminotransferase increase, grade 4 febrile neutropenia, and grade 3 lipase increase), which was considered the MTD and RP2D. Common grade 3–4 adverse events were dysphagia (36%) and mucositis (29%). Laboratory abnormalities were frequent and generally mild, including anemia, white blood cell decrease, and increased creatinine. Addition of Debio 1143 did not compromise chemotherapy administration. Overall locoregional control rate at 18 months was 85%. Overall response rate was 85%, including 69% complete responses. Progression-free survival rate at 24 months was 74%.</p>Conclusions:<p>The RP2D of Debio 1143 is 200 mg/day for 14 days, every 3 weeks, when combined with concomitant high-dose cisplatin chemoradiotherapy in LA-SCCHN. Debio 1143 addition to chemoradiotherapy was safe and manageable. Preliminary efficacy is encouraging and supports further development.</p></div>

While the first case of COVID-19 was declared on March 2 2020 in Senegal, the government banned the attendance of places of worship on 14 March, as a first measure. On March 23, it introduced a curfew, a ban on movement between regions, and the closure of markets. The objective of this study is to measure and understand the acceptability of these four governmental measures as well as the level of public trust in the state to fight the pandemic. We carried out a mixed-method research. The acceptability variables were defined using the theoretical framework of acceptability (TFA). At the quantitative level, we carried out a telephone survey (June/July 2020) at the national level (n = 813) with a sampling strategy by marginal quotas. We conducted a qualitative survey (August/September 2020) with a nested sample (n = 30). The results show a relatively high acceptability of the measures but a heterogeneity of responses. People considered curfews to be much more important (85.7% [83.2%; 88.0%]) than the closure of places of worship (55.4%; [51.9%; 58.7%]), which is least in line with the values and positive affective attitude. Several positive unintended effects of the curfew were stated (security and social/family cohesion). People over the age of 60 have more confidence in the government to fight the pandemic than people under the age of 25, although not significant (7.72 ± 3.12 vs. 7.07 ± 3.11, p = 0.1); and they are more in favour of the closure of places of worship. The more regions are affected by the pandemic, the less confidence respondents report in the government and the less they perceive the measures as effective. The results confirm the importance of government communication and trust in the state to strengthen the acceptability of pandemic measures. Important differences in acceptability show the need to adapt measures and their explanations, instead of unqualified universal action.

In France, Diffuse Large B-Cell Lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL). Health-related quality of life (HRQoL) is a multi-dimensional concept including physical, emotional, social functions, disease symptoms and side effects of treatments. Differences in HRQoL due to gender are little explored in NHL. To investigate whether differences in HRQoL between women and men exist after diagnosis of their lymphoma, we evaluated several facets of HRQoL. One year after DLBCL diagnosis, 141 patients, enrolled in the RT3 (Real Time Tailored Therapy) Study in 2018 and 2019, were invited to answer self-administrated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), Hospital Anxiety and Depression Scale (HADS), and Post Traumatic Growth Inventory (PTGI) questionnaires. Adjusted means and their 95% confidence intervals (95% CI) were calculated in multivariate linear regression models, and compared between female and male survivors. 68% of eligible patients agreed to participate and 82% of them answered all questionnaires. Participants and non participants did not differ significantly regarding socio-demographic and clinical variables, as did female and male participants (mean age of 58.5 years). The adjusted means of the EORTC QLQ-C30 subscales were not different between women and men, excepting for insomnia, significantly higher in women than in men (38.3 vs. 17.2, P = 0.04). Anxiety scores of HADS and several subscales of PTGI were significantly higher in women compared to men (Table). Women seem to be more prone to anxiety, insomnia, and a post traumatic growth after DLBCL than men. The explanation of these disparities is unclear. Specific qualitative approaches should be set up for women with DLBCL. The research was funded by: Calym Keywords: Cancer Health Disparities No conflicts of interests pertinent to the abstract.

(1) Background: Premature infants require mothers’ milk fortification to meet nutrition needs, but breast milk composition may be variable leading to a risk of inadequate nutrition. We aimed at determining factors influencing mothers’ milk macronutrients. (2) Methods: Milk samples were analyzed for the first 5 weeks after premature delivery, by infrared spectroscopy. Mothers’ nutritional intake data were obtained during standardized interviews with dieticians then analyzed with reference software. (3) Results: Composition of 367 milk samples from 81 mothers was (Median [range]g/100mL): Carbohydrates 6.8[4.4-7.3], lipids 3.4[1.3-6.4], proteins 1.3[0.1-3.1]. There was a relationship of milk composition with mothers’ carbohydrates intake only (r=0.164; p<.01). Postnatal age was correlated with milk proteins (r=-0.505 p<.001) & carbohydrates (r=+0.202, p<.001). Multiple linear regression analyses showed (coefficient) a relationship between milk proteins r=0.547 and postnatal age (-0.028), carbohydrates intake (+0.449) and the absence of maturation (-0.066); and between milk lipids r=0.295 and carbohydrates intake (+1.279) and smoking (-0.557). Finally, between milk carbohydrates concentration r=0.266 and postnatal age (+0.012) and smoking (-0.167). (4) Conclusions: Variability of mothers’ milk composition is differentially associated for each macronutrient with maternal carbohydrates intake, antenatal steroids, smoking, and postnatal age. Improvement in milk composition could be achieved by modification of these related factors.

Abstract New, multigram routes to suitably protected L‐iduronyl monosaccharide donors 4 and 5 and 2‐azidoglucose acceptors 6 and 7 are described. The L‐iduronyl and D‐glucuronyl disaccharides 1−3 were then prepared from these compounds, by means of efficient and regioselective protective group manipulations. These disaccharides form the basis of a combinatorial approach toward the synthesis of heparan sulfate fragments representative of the heterogeneous regions of this polysaccharide. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)Introduction