Abemaciclib in Combination with Single-Agent Options in Patients with Stage IV Non–Small Cell Lung Cancer: A Phase Ib Study

Purpose: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non–small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC. Patients and Methods: An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules. Results: The three study parts enrolled 86 patients; all received ≥1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1 and 8 ramucirumab (8 mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combination agents did not affect abemaciclib exposure. The disease control rate was 57% for patients treated with abemaciclib–pemetrexed, 25% for abemaciclib–gemcitabine, and 54% for abemaciclib–ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively. Conclusions: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies

1-(2-Hy­droxy-4-meth­oxy­phen­yl)-3-(4-methyl­phen­yl)prop-2-en-1-one

The mol­ecule of the title compound, C17H16O3, exists in the E conformation with respect to the central C=C bond, is almost planar(r.m.s. deviation = 0.003 Å) and has an intra­molecular O—H⋯O hydrogen bond, which generates an S(6) ring. In the crystal, mol­ecules are linked by C—H⋯O inter­actions

Negative phenotypic and genetic associations between copulation duration and longevity in male seed beetles

Reproduction can be costly and is predicted to trade-off against other characters. However, while these trade-offs are well documented for females, there has been less focus on aspects of male reproduction. Furthermore, those studies that have looked at males typically only investigate phenotypic associations, with the underlying genetics often ignored. Here, we report on phenotypic and genetic trade-offs in male reproductive effort in the seed beetle, Callosobruchus maculatus. We find that the duration of a male's first copulation is negatively associated with subsequent male survival, phenotypically and genetically. Our results are consistent with life-history theory and suggest that like females, males trade-off reproductive effort against longevity

Architecture of Androgen Receptor Pathways Amplifying Glucagon-Like Peptide-1 Insulinotropic Action in Male Pancreatic β Cells

Male mice lacking the androgen receptor (AR) in pancreatic β cells exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hyperglycemia. Testosterone activates an extranuclear AR in β cells to amplify glucagon-like peptide-1 (GLP-1) insulinotropic action. Here, we examined the architecture of AR targets that regulate GLP-1 insulinotropic action in male β cells. Testosterone cooperates with GLP-1 to enhance cAMP production at the plasma membrane and endosomes via: (1) increased mitochondrial production of C

Impacts of biomedical hashtag-based Twitter campaign: #DHPSP utilization for promotion of open innovation in digital health, patient safety, and personalized medicine

The open innovation hub Digital Health and Patient Safety Platform (DHPSP) was recently established with the purpose to invigorate collaborative scientific research and the development of new digital products and personalized solutions aiming to improve human health and patient safety. In this study, we evaluated the effectiveness of a Twitter-based campaign centered on using the hashtag #DHPSP to promote the visibility of the DHPSP initiative. Thus, tweets containing #DHPSP were monitored for five weeks for the period 20.10.2020–24.11.2020 and were analyzed with Symplur Signals (social media analytics tool). In the study period, a total of 11,005 tweets containing #DHPSP were posted by 3020 Twitter users, generating 151,984,378 impressions. Analysis of the healthcare stakeholder-identity of the Twitter users who used #DHPSP revealed that the most of participating user accounts belonged to individuals or doctors, with the top three user locations being the United States (501 users), the United Kingdom (155 users), and India (121 users). Analysis of co-occurring hashtags and the full text of the posted tweets further revealed that the major themes of attention in the #DHPSP Twitter-community were related to the coronavirus disease 2019 (COVID-19), medicine and health, digital health technologies, and science communication in general. Overall, these results indicate that the #DHPSP initiative achieved high visibility and engaged a large body of Twitter users interested in the DHPSP focus area. Moreover, the conducted campaign resulted in an increase of DHPSP member enrollments and website visitors, and new scientific collaborations were formed. Thus, Twitter campaigns centered on a dedicated hashtag prove to be a highly efficient tool for visibility-promotion, which could be successfully utilized by healthcare-related open innovation platforms or initiatives

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Antixenosis and antibiosis mechanisms of resistance to pod borer, Helicoverpa armigera in wild relatives of chickpea, Cicer arietinum

The noctuid pod borer, Helicoverpa armigera is one of the most damaging pests of chickpea, Cicer arietinum. The levels of resistance to H. armigera in the cultivated chickpea are low to moderate, but the wild relatives of chickpea have exhibited high levels of resistance to this pest. To develop insect-resistant cultivars with durable resistance, it is important to understand the contribution of different components of resistance, and therefore, we studied antixenosis and antibiosis mechanisms of resistance to H. armigera in a diverse array of wild relatives of chickpea. The genotypes IG 70012, PI 599046, IG 70022, PI 599066, IG 70006, IG 70018 (C. bijugum), ICC 506EB, ICCL 86111 (cultivated chickpea), IG 72933, IG 72953 (C. reticulatum), IG 69979 (C. cuneatum) and IG 599076 (C. chrossanicum) exhibited non preference for oviposition by the females of H. armigera under multi-choice, dual-choice and no-choice cage conditions. Based on detached leaf assay, the genotypes IG 70012, IG 70022, IG 70018, IG 70006, PI 599046, PI 599066 (C. bijugum), IG 69979 (C. cuneatum), PI 568217, PI 599077 (C. judaicum) and ICCW 17148 (C. microphyllum) suffered significantly lower leaf damage, and lower larval weights indicating high levels of antibiosis than on the cultivated chickpea. Glandular and non-glandular trichomes showed negative correlation with oviposition, while the glandular trichomes showed a significant and negative correlation with leaf damage rating. Density of non-glandular trichomes was negatively correlated with larval survival. High performance liquid chromatography (HPLC) fingerprints of leaf surface exudates showed a negative correlation of oxalic acid with oviposition, but positive correlation with malic acid. Both oxalic acid and malic acid showed a significant negative correlation with larval survival. The wild relatives exhibiting low preference for oviposition and high levels of antibiosis can be used as sources of resistance to increase the levels and diversify the basis of resistance to H. armigera in cultivated chickpea

The International Natural Product Sciences Taskforce (INPST) and the power of Twitter networking exemplified through #INPST hashtag analysis

Background: The development of digital technologies and the evolution of open innovation approaches have enabled the creation of diverse virtual organizations and enterprises coordinating their activities primarily online. The open innovation platform titled "International Natural Product Sciences Taskforce" (INPST) was established in 2018, to bring together in collaborative environment individuals and organizations interested in natural product scientific research, and to empower their interactions by using digital communication tools. Methods: In this work, we present a general overview of INPST activities and showcase the specific use of Twitter as a powerful networking tool that was used to host a one-week "2021 INPST Twitter Networking Event" (spanning from 31st May 2021 to 6th June 2021) based on the application of the Twitter hashtag #INPST. Results and Conclusion: The use of this hashtag during the networking event period was analyzed with Symplur Signals (https://www.symplur.com/), revealing a total of 6,036 tweets, shared by 686 users, which generated a total of 65,004,773 impressions (views of the respective tweets). This networking event's achieved high visibility and participation rate showcases a convincing example of how this social media platform can be used as a highly effective tool to host virtual Twitter-based international biomedical research events