Due to compromised homologous recombination (HR) repair, BRCA1‐ and BRCA2‐mutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that ...target specifically BRCA2‐deficient cells, we screened a chemical library containing compounds in clinical use. The top hit was chlorambucil, a bifunctional alkylating agent used for the treatment of chronic lymphocytic leukaemia (CLL). We establish that chlorambucil is specifically toxic to BRCA1/2‐deficient cells, including olaparib‐resistant and cisplatin‐resistant ones, suggesting the potential clinical use of chlorambucil against disease which has become resistant to these drugs. Additionally, chlorambucil eradicates BRCA2‐deficient xenografts and inhibits growth of olaparib‐resistant patient‐derived tumour xenografts (PDTXs). We demonstrate that chlorambucil inflicts replication‐associated DNA double‐strand breaks (DSBs), similarly to cisplatin, and we identify ATR, FANCD2 and the SNM1A nuclease as determinants of sensitivity to both drugs. Importantly, chlorambucil is substantially less toxic to normal cells and tissues in vitro and in vivo relative to cisplatin. Because chlorambucil and cisplatin are equally effective inhibitors of BRCA2‐compromised tumours, our results indicate that chlorambucil has a higher therapeutic index than cisplatin in targeting BRCA‐deficient tumours.
Synopsis
BRCA1/2‐deficient tumours accumulate DNA damage and genomic rearrangements conducive for tumour progression, which is exploited in the clinic by targeted therapies against the BRCA1/2‐mutated tumour subset. Chlorambucil is identified as the most effective drug in eliminating BRCA2‐deficient cells.
The bi‐functional alkylator chlorambucil was specifically toxic to BRCA1/2‐deficient cells and tumours, but not to wild type controls.
Chlorambucil effectively eliminated cisplatin‐resistant and olaparib‐resistant BRCA1/2‐deficient cells and tumours.
Mechanistically, chlorambucil toxicity is mediated by accumulation of replication‐associated DNA damage, similarly to cisplatin.
ATR, FANCD2 and SNM1A nuclease are determinants of cellular sensitivity to both drugs.
Chlorambucil is substantially less toxic to normal cells and tissues than cisplatin.
BRCA1/2‐deficient tumours accumulate DNA damage and genomic rearrangements conducive for tumour progression, which is exploited in the clinic by targeted therapies against the BRCA1/2‐mutated tumour subset. Chlorambucil is identified as the most effective drug in eliminating BRCA2‐deficient cells.
Due to compromised homologous recombination (HR) repair, BRCA1‐ and BRCA2‐mutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that ...target specifically BRCA2‐deficient cells, we screened a chemical library containing compounds in clinical use. The top hit was chlorambucil, a bifunctional alkylating agent used for the treatment of chronic lymphocytic leukaemia (CLL). We establish that chlorambucil is specifically toxic to BRCA1/2‐deficient cells, including olaparib‐resistant and cisplatin‐resistant ones, suggesting the potential clinical use of chlorambucil against disease which has become resistant to these drugs. Additionally, chlorambucil eradicates BRCA2‐deficient xenografts and inhibits growth of olaparib‐resistant patient‐derived tumour xenografts (PDTXs). We demonstrate that chlorambucil inflicts replication‐associated DNA double‐strand breaks (DSBs), similarly to cisplatin, and we identify ATR, FANCD2 and the SNM1A nuclease as determinants of sensitivity to both drugs. Importantly, chlorambucil is substantially less toxic to normal cells and tissues in vitro and in vivo relative to cisplatin. Because chlorambucil and cisplatin are equally effective inhibitors of BRCA2‐compromised tumours, our results indicate that chlorambucil has a higher therapeutic index than cisplatin in targeting BRCA‐deficient tumours.
Due to compromised homologous recombination (HR) repair,
and
mutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that target ...specifically BRCA2-deficient cells, we screened a chemical library containing compounds in clinical use. The top hit was chlorambucil, a bifunctional alkylating agent used for the treatment of chronic lymphocytic leukaemia (CLL). We establish that chlorambucil is specifically toxic to BRCA1/2-deficient cells, including olaparib-resistant and cisplatin-resistant ones, suggesting the potential clinical use of chlorambucil against disease which has become resistant to these drugs. Additionally, chlorambucil eradicates BRCA2-deficient xenografts and inhibits growth of olaparib-resistant patient-derived tumour xenografts (PDTXs). We demonstrate that chlorambucil inflicts replication-associated DNA double-strand breaks (DSBs), similarly to cisplatin, and we identify ATR, FANCD2 and the SNM1A nuclease as determinants of sensitivity to both drugs. Importantly, chlorambucil is substantially less toxic to normal cells and tissues
and
relative to cisplatin. Because chlorambucil and cisplatin are equally effective inhibitors of BRCA2-compromised tumours, our results indicate that chlorambucil has a higher therapeutic index than cisplatin in targeting BRCA-deficient tumours.
The interplay between corticotropin-releasing hormone (CRH) and the dopaminergic system has predominantly been studied in addiction and reward, while CRH-dopamine interactions in anxiety are scarcely ...understood. We describe a new population of CRH-expressing, GABAergic, long-range-projecting neurons in the extended amygdala that innervate the ventral tegmental area and alter anxiety following chronic CRH depletion. These neurons are part of a distinct CRH circuit that acts anxiolytically by positively modulating dopamine release.
The serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described ...targeting the active form of the enzyme, FXIa. Herein, we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement factor D inhibitor and exhibited submicromolar FXIa activity and an encouraging absorption, distribution, metabolism, and excretion (ADME) profile while being devoid of a peptidomimetic architecture. Optimization of interactions in the S1, S1β, and S1′ pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with subnanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a preclinical pharmacokinetics (PK) profile consistent with bid dosing in patients.
To address continually decreasing enrollment and rising attrition in post-secondary STEM degree (science, technology, engineering, and mathematics) programs, particularly for women, the present study ...examines the utility of motivation and emotion variables to account for persistence and achievement in science in male and female students transitioning from high school to junior college. Consistent with self-determination theory (Deci & Ryan, 2012) and achievement-goal theory (Senko, Hulleman, & Harackiewicz, 2011), structural equation modelling based on data from 1,309 students from four English-language CEGEPs showed students' achievement goals, self-efficacy, and perceived autonomy support to impact intrinsic motivation, emotions, and achievement that, in turn, predicted persistence in the science domain.
Significant changes to daily life and educational routines due to the COVID-19 pandemic resulted in changes in social interactions and might have contributed to an increase in screen-based ...activities, loneliness, and mental health issues among adolescents. Two years after the pandemic outbreak, the present study examined the relationships between time spent using digital technology (DT), loneliness and well-being among three cohorts of adolescents in Croatia. A moderated mediation model of relationship between time spent using DT and well-being was tested, with loneliness as a potential mediator and gender as a moderator. A nationally representative sample included 3706 11-year-olds, 3866 13-year-olds and 8815 17-year-olds. The study was conducted in lower and upper secondary schools in the spring of 2022. The questionnaire contained a single item self-report measure of time spent using DT and loneliness, while the adapted WHO-5 was used for measuring adolescents’ well-being. Results indicated that time spent using DT was positively associated with loneliness and negatively associated with well-being. Loneliness mediated the relationship between time spent using DT and well-being in all cohorts. This mediation was moderated by gender in the group of 11-year-olds only. Gender moderated the direct effect on well-being among 11- and 13-year-olds. Effects were stronger among girls and younger participants. The results are discussed in light of the displacement hypothesis, which posits that negative effects on well-being are a consequence of the replacement of in-person activities with screen-based activities.
Significant changes to daily life and educational routines due to the COVID-19 pandemic resulted in changes in social interactions and might have contributed to an increase in screen-based ...activities, loneliness, and mental health issues among adolescents. Two years after the pandemic outbreak, the present study examined the relationships between time spent using digital technology (DT), loneliness and well-being among three cohorts of adolescents in Croatia. A moderated mediation model of relationship between time spent using DT and well-being was tested, with loneliness as a potential mediator and gender as a moderator. A nationally representative sample included 3706 11-year-olds, 3866 13-year-olds and 8815 17-year-olds. The study was conducted in lower and upper secondary schools in the spring of 2022. The questionnaire contained a single item self-report measure of time spent using DT and loneliness, while the adapted WHO-5 was used for measuring adolescents’ well-being. Results indicated that time spent using DT was positively associated with loneliness and negatively associated with well-being. Loneliness mediated the relationship between time spent using DT and well-being in all cohorts. This mediation was moderated by gender in the group of 11-year-olds only. Gender moderated the direct effect on well-being among 11- and 13-year-olds. Effects were stronger among girls and younger participants. The results are discussed in light of the displacement hypothesis, which posits that negative effects on well-being are a consequence of the replacement of in-person activities with screen-based activities.
To better understand how student and faculty perceptions of the learning
climate in science/mathematics classes influence success and persistence, we
followed a cohort of 1425 academically able ...students who entered CEGEP in the
fall of 2003. Students completed surveys in their first, second and fourth
semesters. In the second semester 84 faculty members completed a similar
survey. Faculty conceptions of teaching were identified using a framework
developed by Scardamalia and Bereiter (1989). No significant gender differences
in achievement were found. Self-efficacy declined over students first semester
as did affect towards science. Classes that students perceived as fostering
their development had a positive impact on persistence and success while
classes characterized as transmitting had a negative impact. Females were more
likely than males to characterize a class as transmitting and to abandon
science. Faculty members who had pedagogical training were more likely to
create a fostering atmosphere in their classes.
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