ABSTRACT
Background: CDK4/6 inhibitors showed a favorable progression-free survival (PFS) in DD LPS, a sarcoma bearing 12q 13-15 amplicon that implies CDK4 amplification. The median PFS was 4 and 7 months (m) for palbociclib and abemaciclib, respectively. Preclinical experiments in 10 sarcoma cell lines and 6 PDX models, including only one DD LPS, showed higher efficacy of anti-CDK4 in cases with high expression of CDK4 and low expression of p16. This rationale supported the design of a phase II trial exploring palbociclib in a wide range of sarcomas, excluding DD LPS. Methods: Progressing pretreated advanced soft tissue sarcoma, excluding DD LPS, or osteosarcoma adult patients (pts), whose tumors overexpressed CDK4 and underexpressed CDKN2A mRNA in a baseline mandatory biopsy, were enrolled. CDK4 and CDKN2A expression were assessed by qRT-PCR, using an external control as reference (Universal human reference RNA;Agilent Technologies). The primary endpoint was 6-m PFS rate. Minimax Simon's two-stage with type 1 and 2 errors of 10%, and null and alternative hypothesis of H0 15%, H1 40%, 6-month PFS rates were specified. The study will warrant further investigation if 6 or more pts had a PFS > 6 m from 21 evaluable pts. Palbociclib was administered orally at 125 mg/ day 21 out of 28 days. Pre-screening intended to increase the probability of positive profile in the baseline biopsy. Results: A total of 214 pts with 236 CDK4/ CDKN2A determinations were assessed for enrolment;141 for prescreening, in archive tumor sample, and 95 for screening, in a baseline biopsy. There were 38/141 (27%) and 28/95 (29%) pts with favorable mRNA profile from pre and screening, respectively. Twenty-two pts were enrolled with a median of previous systemic lines of 3 (1- 5). There were 9 different sarcoma subtypes, including 2 osteosarcomas. With a median FU of 10 m (0.4-23.3), the median PFS was 4.2 m (95% CI 0.9-7.4), while the 6- and 12-m PFS rates were 30% (95% CI 9-51) and 18% (95% CI 12-48) respectively. From 19 evaluable pts (1 early death by COVID, 1 withdrew consent and for 1 it was too early to be assessed) 11 had stable disease (58%) and 8 progressed (42%) as the best response. Patients with CDK4 expression above the median value had significantly longer mPFS in the univariate analysis: 5.9 m (95% CI 1.4-10.4) vs 1.9 m (95% CI 0.6- 3.2), p = 0.046;and longer OS: 15.5 m (95% CI 6.8-24.3) vs 10.6 m (95% CI 0-23.2), p = 0.047, respectively. The probability to find a positive profile in the screening was 29%, but this proportion increased up to 41% if in pre-screening had been positive. Conclusions: Palbociclib showed to be effective in a wide variety of sarcoma subtypes, other than DD LPS, selected by CDK4/CDKN2A biomarkers.
ABSTRACT
The University of California Center for Laboratory Safety held its fifth biennial Workshop on Laboratory Safety in May of 2021. The Workshops on Laboratory Safety provide a unique forum for researchers and safety professionals to exchange perspectives and ideas. The theme of this year's workshop was Advancing Safety in Teaching and Research Laboratories. Speakers emphasized the importance of an enlightened leadership style, the significance of integrating risk assessments into the science curriculum, and the impact of human factors on risk minimization. Furthermore, speakers discussed innovative programs to engage Principal Investigators in organizational safety culture and computational approaches for defining the toxicity of chemical compounds. Panels discussed two topics: student-led safety initiatives and the long-term impact of COVID-19 on academic life, research, and lab safety. Finally, 11 workgroups examined current safety topics over the 3 day course of the workshop culminating in final presentations on their recommendations. This paper summarizes all presentations and lists key resources from each discussion.
ABSTRACT
Although Cultural Heritage is a recognized source of well-being, its touristic overexploitation generates strong negative impacts, aggravated in large cities due to the concentration of effects in space. This work addresses the case of Madrid, a city that has first-rate heritage assets in its metropolitan periphery, whose better touristic use would help to mitigate the negative impact on the capital, while contributing to the economic and social development of the periphery. In the research, a dynamic methodological approach was applied with four complementary analysis planes: documentary and networks, qualitative, quantitative and participatory processes. The results show the need to adopt cultural management and tourism planning strategies aimed at rebalancing visitor flows. The activation of the neighbors themselves is revealed as an especially valuable resource to strengthen proximity, experiential and more sustainable tourism. The The impact of Covid-19, on the one hand, and the declaration of Paseo del Prado and El Retiro as World Heritage Sites, on the other, have made this situation even more topical.
ABSTRACT
SARS-CoV-2 has highlighted the requirement for a drastic change in pandemic response. While cases continue to rise, there is an urgent need to deploy sensitive and rapid testing in order to identify potential outbreaks before there is an opportunity for further community spread. Currently, reverse transcription quantitative polymerase chain reaction (RT-qPCR) is considered the gold standard for diagnosing an active infection, using a nasopharyngeal swab;however, it can take days after symptoms develop to properly identify and trace the infection. While many civilian jobs can be performed remotely, the Department of Defense (DOD) is by nature a very fluid organization which requires in-person interaction and a physical presence to maintain effectiveness. In this commentary, we examine several current and emergent technologies and their ability to identify both active and previous SARS-CoV-2 infection, possibly in those without symptoms. Further, we will explore an ongoing study at the Air Force Research Laboratory, utilizing Reverse Transcription Loop-mediated isothermal amplification (RT-LAMP), next-generation sequencing, and the presence of SARS-CoV-2 antibodies through Lateral Flow Immunoassays. The ability to identify SARS-CoV-2 through volatile organic compound biomarker identification will also be explored. By exploring and validating multiple testing strategies, and contributing to Operation Warp Speed, the DOD is postured to respond to SARS-CoV-2, and future pandemics.