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The impact of first-generation covalent KRAS G12C inhibitors has been reduced due to the development of drug resistance, tolerability and challenges combining with immunotherapy. We designed olomorasib, a next-generation GDP-binding KRAS G12C inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRAS G12C -mutant cancers, olomorasib reduces RAS activity and pERK levels, leading to substantial and significant tumor growth inhibition. Additionally, olomorasib combined with immune checkpoint inhibitors demonstrates greater anti-tumor activity compared to monotherapy. Furthermore, we demonstrate that olomorasib binds tightly to KRAS G12C even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRAS G12C inhibitors. These findings suggest that olomorasib could be effective for patients with KRAS G12C mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically. The success of KRAS G12C mutation specific inhibitors in patients with KRAS-driven tumours is limited by the emergence of acquired resistance. Here, the authors characterise olomorasib, a next-generation covalent KRAS G12C-mutant inhibitor, demonstrating efficacy in the presence of clinically relevant resistance mutations in preclinical KRAS-driven cancer models.

Parvalbumin (PV) interneurons in the dorsal striatum (DS) are fast-spiking GABAergic cells critical for feedforward inhibition and synaptic integration within basal ganglia circuits. Despite their well-characterized electrophysiological roles, their molecular identity remains incompletely defined. Using the Ribotag approach in Pvalb-Cre mice, we profiled the translatome of DS PV interneurons and identified over 2,700 transcripts significantly enriched (fold-change > 1.5) in this population. Our data validate established PV markers and reveal a distinct molecular signature of DS PV neurons compared to PV interneurons from the nucleus accumbens. Gene ontology analyses highlight prominent expression of genes related to extracellular matrix components, cell adhesion molecules, synaptic organization, ion channels, and neurotransmitter receptors, particularly those mediating glutamatergic and GABAergic signaling. Notably, perineuronal net markers were robustly expressed in DS PV interneurons and confirmed by immunofluorescence. Transcriptomic analysis of DS PV neurons following repeated d-amphetamine exposure identified Gm20683 as the only differentially expressed transcript between treated groups. Furthermore, RNAseq analysis of mice subjected to an operant behavior paradigm with two types of food reward (high-palatable diet or standard chow) identified over 1,000 and 100 genes enriched in DS PV neurons from standard and high-palatable masters, respectively. These findings provide a comprehensive molecular profile of DS PV interneurons, distinguishing them from other striatal PV populations, and reveal specific gene expression changes associated with psychostimulant exposure and reward-driven behaviors. Our findings deepen insight into the molecular mechanisms of PV interneuron activity in striatal circuits and their potential roles in neuropsychiatric, motor and reward-related disorders.

Inadvertent mammalian tissue exposures to low doses of ionizing radiation (IR) after radiation accidents, remediation of radioactive-contaminated areas, space travel or a dirty bomb represent an interesting trauma to an organism. Possible low-dose IR-induced bystander effects could impact our evaluation of human health effects, as cells within tissue are not equally damaged after doses of IR ⩽10 cGy. To understand tissue responses after low IR doses, we generated a reporter system using the human clusterin promoter fused to firefly luciferase (hCLUp-Luc). Secretory clusterin (sCLU), an extracellular molecular chaperone, induced by low doses of cytotoxic agents, clears cell debris. Low-dose IR (⩾2 cGy) exposure induced hCLUp-Luc activity with peak levels at 96 h, consistent with endogenous sCLU levels. As doses increased (⩾1 Gy), sCLU induction amplitudes increased and time-to-peak response decreased. sCLU expression was stimulated by insulin-like growth factor-1, but suppressed by p53. Responses in transgenic hCLUp-Luc reporter mice after low IR doses showed that specific tissues (that is, colon, spleen, mammary, thymus and bone marrow) of female mice induced hCLUp-Luc activity more than male mice after whole body (⩾10 cGy) irradiation. Tissue-specific, non-linear dose- and time-responses of hCLUp-Luc and endogenous sCLU levels were noted. Colon maintained homeostatic balance after 10 cGy. Bone marrow responded with delayed, but prolonged and elevated expression. Intraperitoneal administration of α-transforming growth factor (TGF)β1 (1D11), but not control (13C4) antibodies, immediately following IR exposure abrogated CLU induction responses. Induction in vivo also correlated with Smad signaling by activated TGFβ1 after IR. Mechanistically, media with elevated sCLU levels suppressed signaling, blocked apoptosis and increased survival of TGFβ1-exposed tumor or normal cells. Thus, sCLU is a pro-survival bystander factor that abrogates TGFβ1 signaling and most likely promotes wound healing.

The impact of first-generation covalent KRAS inhibitors has been reduced due to the development of drug resistance, tolerability and challenges combining with immunotherapy. We designed olomorasib, a next-generation GDP-binding KRAS inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRAS -mutant cancers, olomorasib reduces RAS activity and pERK levels, leading to substantial and significant tumor growth inhibition. Additionally, olomorasib combined with immune checkpoint inhibitors demonstrates greater anti-tumor activity compared to monotherapy. Furthermore, we demonstrate that olomorasib binds tightly to KRAS even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRAS inhibitors. These findings suggest that olomorasib could be effective for patients with KRAS mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically.

PurposeAbemaciclib in combination with endocrine therapy (ET) has demonstrated significant efficacy benefits in HR+ , HER2− advanced breast cancer patients in the Phase 3 studies MONARCH 2 (fulvestrant as ET) and MONARCH 3 (letrozole or anastrozole as ET). Here, we report age-specific safety and efficacy outcomes.MethodsExploratory analyses of MONARCH 2 and 3 were performed for 3 age groups (<65, 65–74, and ≥75 years). For safety, data were pooled from both studies; for efficacy, a subgroup analysis of PFS was performed for each trial independently.ResultsPooled safety data were available for 1152 patients. Clinically relevant diarrhea (Grade 2/3) was higher in older patients receiving abemaciclib + ET (<65, 39.5%; 65–74, 45.2%; ≥75, 55.4%) versus placebo + ET (<65, 6.8%; 65–74, 4.5%; ≥75, 16.0%). Nausea, decreased appetite, and venous thromboembolic events were all moderately higher in older patients. Neutropenia (Grade ≥ 3) did not differ as a function of age in the abemaciclib + ET arm (<65, 25.8%; 65–74, 27.4%; ≥75, 18.1%). Dose adjustments and discontinuation rates were slightly higher in older patients. Abemaciclib + ET improved PFS compared with placebo + ET independent of patient age, with no significant difference in abemaciclib treatment effect between the 3 age groups (MONARCH 2: interaction p-value, 0.695; MONARCH 3: interaction p-value, 0.634). Estimated hazard ratios ranged from 0.523–0.633 (MONARCH 2) and 0.480–0.635 (MONARCH 3).ConclusionsWhile higher rates of adverse events were reported in older patients, they were manageable with dose adjustments and concomitant medication. Importantly, a consistent efficacy benefit was observed across all age groups.Clinical trial registrationClinicalTrials.gov: NCT02107703 (first posted April 8, 2014) and NCT02246621 (first posted September 23, 2014).

Extracellular vesicles (EVs) are nano-sized lipid bilayer vesicles released by virtually every cell type. EVs have diverse biological activities, ranging from roles in development and homeostasis to cancer progression, which has spurred the development of EVs as disease biomarkers and drug nanovehicles. Owing to the small size of EVs, however, most studies have relied on isolation and biochemical analysis of bulk EVs separated from biofluids. Although informative, these approaches do not capture the dynamics of EV release, biodistribution, and other contributions to pathophysiology. Recent advances in live and high-resolution microscopy techniques, combined with innovative EV labeling strategies and reporter systems, provide new tools to study EVs in vivo in their physiological environment and at the single-vesicle level. Here we critically review the latest advances and challenges in EV imaging, and identify urgent, outstanding questions in our quest to unravel EV biology and therapeutic applications.This Review describes the state of the art in imaging extracellular vesicles in animals to study their release, biodistribution and uptake, and covers labeling strategies, microscopy methods and discoveries made in model organisms.

Fetal heart rate variability (fHRV) of normal-to-normal (NN) beat intervals provides high-temporal resolution access to assess the functioning of the autonomic nervous system (ANS). To determine critical periods of fetal autonomic maturation. The developmental pace is hypothesized to change with gestational age (GA). Prospective longitudinal observational study. 60 healthy singleton fetuses were followed up by fetal magnetocardiographic heart rate monitoring 4-11 times (median 6) during the second half of gestation. FHRV parameters, accounting for differential aspects of the ANS, were studied applying linear mixed models over four predefined pregnancy segments of interest (SoI: <27; 27+0-31+0; 31+1-35+0; >35+1 weeks GA). Periods of fetal active sleep and quiescence were accounted for separately. Skewness of the NN interval distribution VLF/LF band power ratio and complexity describe a saturation function throughout the period of interest. A decreasing LF/HF ratio and an increase in pNN5 indicate a concurrent shift in sympathovagal balance. Fluctuation amplitude and parameters of short-term variability (RMSSD, HF band) mark a second acceleration towards term. In contrast, fetal quiescence is characterized by sequential, but low-margin transformations; ascending overall variability followed by an increase of complexity and superseded by fluctuation amplitude. An increase in sympathetic activation, connected with by a higher ability of parasympathetic modulation and baseline stabilization, is reached during the transition from the late 2nd into the early 3rd trimester. Pattern characteristics indicating fetal well-being saturate at 35 weeks GA. Pronounced fetal breathing efforts near-term mirror in fHRV as respiratory sinus arrhythmia.

Motivational interactions during multiple language learning have been largely neglected in language motivation research. To fill this gap, we investigate longitudinal relations between Swiss German students' value beliefs in English, French, and German in upper secondary schools and whether there are differences in motivational development between multilingual and monolingual students. Multivariate latent growth modeling was used to analyze data from 850 students (Mage = 15.61 years, SD = .62; 54% female) gathered yearly from Grades 9 to 11. Results suggest an interference between students' value beliefs in English and the other 2 languages. Students who reported higher value beliefs in English in Grade 9 showed steeper decreases in their value beliefs for French and German from Grades 9 to 11. However, stronger increases in English value beliefs over time were associated with stronger increases in French and German value beliefs. Moreover, while multilingual students reported higher initial value beliefs in French and English, they also showed steeper decreases in French and English value beliefs over time compared to their monolingual peers. Findings are discussed in relation to their implications for teaching practice and future research directions.

At 8 years of follow-up, premenopausal women with breast cancer had higher rates of disease-free and overall survival with the addition of ovarian suppression to antiestrogen therapy and a higher rate of hormonal side effects than with tamoxifen alone.

Following from previous research on intensity bias and the accessibility model of emotional self-report, the present study examined the role of emotional exhaustion in explaining the discrepancy in teachers' reports of their trait (habitual) versus state (momentary, \"real\") emotions. Trait reports (habitual emotions, exhaustion) were assessed via trait questionnaires, and state reports (momentary emotions) were assessed in real time via the experience sampling method by using personal digital assistants (N = 69 high school teachers; 1,089 measures within teachers). In line with our assumptions, multi-level analyses showed that, as compared to the state assessment, teachers reported higher levels of habitual teaching-related emotions of anger, anxiety, shame, boredom, enjoyment, and pride. Additionally, the state-trait discrepancy in self-reports of negative emotions was accounted for by teachers' emotional exhaustion, with high exhaustion levels corresponding with a greater state-trait discrepancy. Exhaustion levels did not moderate the state-trait discrepancy in positive emotions indicating that perceived emotional exhaustion may reflect identity-related cognitions specific to the negative belief system. Implications for research and educational practice are discussed.