Eli Lilly (Singapore)

Abstract Cell free DNA (cfDNA) analysis has a large potential for cancer patient diagnosis. Given the evidence that cfDNA partially preserves chromatin architecture of tumor cells, it potentially allows the detection of tumor responses after therapeutic treatment. In this study, we aimed to detect the responses of abemaciclib, a potent cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6 inhibitor), in metastatic recurrent breast cancer patients through cfDNA analysis. Our results suggest that cfDNA can be used as a valuable marker to monitor cancer burden, cancer responses to drug treatment, and sensitivity against therapeutic reagents. CfDNA concentrations purified from serum are significantly higher in cancer patients compared to healthy donors, suggesting that a significant portion of the cfDNA originates from tumors in our samples. The cfDNA concentrations are also significantly decreased after abemaciclib treatment. The sequencing analysis of cfDNAs revealed a higher enrichment of cfDNAs at open chromatin regions and differentiated the cfDNA enrichment patterns between abemaciclib treated and non-treated samples. Altered cfDNA signals are frequently associated with the genes that are involved in apoptosis and CDK4/6 related pathways. Finally, the differentially enriched region analysis also detected the differences in abemaciclib cases that could be treated long-term and cases that had an exacerbation after short-term treatment. In conclusion, this research enhances our understanding of the biology of abemaciclib and provides new insights into CDK4/6 inhibitor’s action in metastatic breast cancer.

Type2 diabetes mellitus (T2DM) is a complex metabolic disease with several treatment options. Some glucagon-like peptide1 receptor agonists (GLP-1 RAs) approved by the European Medicines Agency include dulaglutide, subcutaneous (s.c.) semaglutide, and oral semaglutide. This study examines dulaglutide and semaglutide dosing patterns for T2DM in France and Italy. IQVIA Longitudinal Prescription Data identified adults with T2DM prescribed dulaglutide or semaglutide between August 1, 2020 and December 31, 2022. Cohort1 (incident) and cohort2 (prevalent) users were followed for 12months. In France and Italy, 255,571 and 350,853 patients, respectively, received at least one study GLP-1 RA. Most dulaglutide-naïve patients in France (62%) and approximately half in Italy (49%) started on 1.5mg and remained on this dose for up to 12months (France: 66% cohort1, 88% cohort2; Italy: 73% cohort1, 87% cohort2). In cohort1, s.c. semaglutide users mostly started on 0.25mg (France, 78%; Italy, 61%). At 12months, s.c. semaglutide 1.0mg was most prescribed (France: 58% cohort1, 75% cohort2; Italy: 59% cohort2), with cohort1 in Italy mostly receiving 0.5mg (57%). Most oral semaglutide users in Italy started on 3.0mg (78% cohort1; 68% cohort2), which was increased to 7.0mg (62% cohort1) and 14.0mg (48% cohort2) at 12months. GLP-1 RA dosing patterns, although similar between France and Italy, were heterogeneous over time. As oral semaglutide and higher dulaglutide doses are recent to the market, additional real-world evidence is required to evaluate utilization patterns. Graphical abstract available for this article.

Introduction:Disparities in the recruitment of minority populations in research are well-documented. However, the degree of participation and retention of minorities following enrollment is less known, particularly in decentralized studies. Although decentralized clinical research methods may allow researchers to engage broader study populations with less participation burden, they may present different retention challenges. To evaluate racial and ethnic differences in the degree of participation after enrollment in a decentralized study, we analyzed data from a cohort of patients with inflammatory bowel diseases following COVID-19 immunization.Methods:We compared by race and ethnicity the following post-enrollment participation metrics: response to > 50% of follow-up surveys, donation of a blood sample for antibody testing, consent to use of bio samples for future research, and withdrawal prior to study completion.Results:Overall, we observed higher levels of post-enrollment study participation among non-Hispanic White (NHW) participants as compared to Black or Hispanic participants: 95% of NHW participants completed follow-up versus 87% of Black participants and 91% of Hispanic participants, 73% of NHW participants provided bio samples versus 64% Black participants and 67% Hispanic participants, and 65% of NHW participants provided consent for future research versus 62% of Black participants and 52% of Hispanic participants.Conclusions:Our findings demonstrate that the degree of study participation after enrollment in this decentralized study differed by race and ethnicity, indicating that attention to diversity, equity, and inclusion is needed not only in clinical research recruitment but also throughout study administration.

The aims of this study were to test a noninvasive self-management intervention supported by specialist nurses versus intervention alone in patients with inflammatory bowel disease (IBD) experiencing fecal incontinence and to conduct a qualitative evaluation of the trial. Multicenter, parallel-group, open-label, mixed-methods randomized controlled trial (RCT). The sample comprised patients from a preceding case-finding study who reported fecal incontinence and met study requirements; the RCT was delivered via IBD outpatient clinics in 6 hospitals (5 in major UK cities, 1 rural) between September 2015 and August 2017. Sixteen participants and 11 staff members were interviewed for qualitative evaluation. Adults with IBD completed the study activities over a 3-month period following randomization. Each participant received either four 30-minute structured sessions with an IBD clinical nurse specialist and a self-management booklet or the booklet alone. Low retention numbers precluded statistical analysis; individual face-to-face or telephone interviews, recorded digitally and transcribed professionally, were conducted to evaluate the RCT. Transcripts were analyzed thematically using an inductive method. Sixty-seven participants (36%) of the targeted 186 participants were recruited. The groups comprised 32 participants (17% of targeted participants) allocated to the nurse + booklet intervention and 35 (18.8% of targeted participants) allocated to the booklet alone. Less than one-third (n = 21, 31.3%) completed the study. Given the low recruitment and high attrition, statistical analysis of quantitative data was considered futile. Participant interviews were conducted concerning study participation and 4 themes emerged that described experiences of patients and staff. These data provided insights into reasons for low recruitment and high attrition, as well as challenges of delivering resource-heavy studies in busy health service environments. Alternative approaches to trials of nurse-led interventions in hospital settings are needed as many interfering factors may prevent successful completion.

Abstract The potential for miRNAs to regulate gene expression remains controversial. DROSHA initiates the biogenesis of miRNAs while Argonaute (AGO) and TNRC6 proteins form complexes with miRNAs that recognize RNA. Here we investigate the fate of miRNAs in the absence of critical RNAi protein factors. Knockout ofDROSHAexpression reduced levels of some miRNAs, but not others. Knocking out AGO proteins, which directly contact the mature miRNA, decreased expression of miRNAs. Quantitative analysis indicates compensation to maintain the overall pool of AGO after knockout of AGO variants. Evaluation of miRNA binding to AGO proteins revealed that association between AGO and miRNAs was similar for AGO1 - 4. Contrary to the assumptions underlying many peer-reviewed reports, not all annotated miRNAs have equal potential as biological regulators. Cellular abundance, DROSHA dependence, and physical association with AGO must be considered when forming hypotheses related to their function. Our data prioritize sixty miRNAs – under two percent of the overall annotated miRNA repertoire – as being most likely to function as robust gene regulators. Our approach will facilitate identifying biologically active miRNAs.

The pharmaceutical industry needs design tools to identify greener and more resource-efficient process routes. Current model-based solvent selection methodologies often focus on the choice of solvent in a single unit operation, with fixed operating conditions. In particular, the two key stages of synthesis and separation are usually treated independently. This often results in the use of different solvents for each processing task, which typically requires energy-intensive solvent swap operations. In the current paper, we present a novel computer-aided approach based on computer-aided mixture/blend design (CAM^<em>b</em>D) that couples property prediction with simple process models and optimisation to simultaneously identify optimal solvents and anti-solvents, compositions and process conditions for integrated synthesis and crystallisation. Solvents are chosen using key performance indicators (KPIs) that quantify mass efficiency and product quality. The proposed methodology is illustrated by identifying promising reaction and crystallisation solvents for the synthesis of mefenamic acid from 2,3-dimethylaniline and 2-chlorobenzoic acid. Furthermore, multi-objective optimisation is deployed to highlight the trade-offs between the solvent or process E-factor and safety indicators, and between the solvent E-factor and crystal yield. The inclusion of mass-based KPIs and safety specifications ensures that only high-performance solvents are chosen. The findings of our approach are expected to guide the rational selection of solvents for greener pharmaceutical manufacturing during early-stage process development.

Abstract Background: Aim of this multicenter, observational, cross-sectional study was to evaluate health-related quality of life (HRQoL) and treatment satisfaction of current medications in Chinese knee OA patients. Methods: Brief Pain Inventory (BPI), Treatment Satisfaction Questionnaire (TSQM-1.4), and HRQoL (EQ-5D-5L) were assessed in total of 601 OA of knee patients. Results: Mean score of EQ-5D-5L of patients with BPI-Severity ≥4 was significantly lower than those with BPI-Severity &lt;4. All the scores of TSQM in 4 dimensions were lower in patients with BPI-Severity ≥4 than in those with BPI-Severity &lt;4. Both HRQoL scores and TSQM scores showed a statistically significant decreasing trend with increasing BPI-Severity pain score.Conclusion: Chronic knee OA pain has a significant impact on patients’ HRQoL. More severe patients with OA were less satisfied with current treatments. Trial registration (Clinical Trials identifier): Not applicable