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The aim of this study was to optimise conditions for mRNA detection by nonisotopic in situ hybridisation (NISH) using biotinylated and digoxigenin labelled riboprobes. Because lysozyme gene transcripts are present at high concentrations in Paneth and other alimentary cells, archival gut biopsy specimens were chosen as a model system for these experiments. Most of the variables in NISH, from unmasking of mRNA, to its ultimate detection by peroxidase or alkaline phosphatase based detection systems, were examined in detail. The most important findings were that simultaneous heating of tissue targets and riboprobes at 95 degrees C for 15 minutes before hybridisation at 50 degrees C for two hours gave the most intense signal for lysozyme mRNA in Paneth cells, Brunner's glands, and lamina propria macrophages; digoxigenin labelled riboprobes gave a higher signal to noise ratio than their biotinylated counterparts, and probes 600 base pairs long were superior to shorter probes. It is concluded that the mRNA NISH method may be generally useful for detecting gene transcription in archival clinical biopsy specimens. [ABSTRACT FROM PUBLISHER]

Barth Syndrome is a rare X-linked recessive disease, caused by mutations in the G4.5 (TAZ) gene, located at Xq28. The disorder has a variable presentation, but common features include dilated cardiomyopathy, skeletal myopathy, neutropenia, short stature and 3-methylglutaconic aciduria. There is a high rate of mortality during infancy due to congestive cardiomyopathy or overwhelming bacterial infections. However, since both the cardiomyopathy and neutropenia are largely treatable, early diagnosis is key to survival. Over 30 mutations in the G4.5 gene have been reported including missense, splice site, deletions and insertions. Mutational hotspots exist, but mutations are found throughout the gene, with the exception of exon 5. We have designed primers using Primer3 to amplify all 11 exons and intron/exon borders in 7 separate fragments. M13-tagged sequence analysis is undertaken on a LI-COR GeneRead IR 4200 DNA analyser. To date we have detected G4.5 mutations in 5 positive control samples, and identified 2 previously unreported mutations (c446-450delTGT), c437-439delTGT) from a total of 11 referrals. Skewed X-inactivation leading to "allele drop-out" has been reported as a potential problem in the diagnosis of carrier females. We are investigating alternative protocols e.g. Linear-Exponential PCR, dHPLC analysis and buccal samples in female referrals. We are now offering Barth syndrome testing as a routine diagnostic service. [ABSTRACT FROM AUTHOR]

The article presents a correction regarding the claim on the location of the magnetic pole.

An overdose of acetaminophen (APAP) is the leading cause of drug-induced hepatotoxicity and acute liver failure (ALF) in the United States. It is established that the predominant mode of hepatocyte cell death after an APAP overdose is through necrosis, and it is now recognized that this occurs through regulated pathways involving RIP kinases. These kinases, along with the pseudo-kinase MLKL are central players in classical necroptotic cell death. Despite the skepticism regarding the role of necroptosis in APAP-induced liver injury, recent research demonstrating necroptosis-independent roles for MLKL led us to re-examine the role of this pseudo-kinase in APAP pathophysiology. Treatment of Mlkl-/-mice with a moderate (300 mg/kg) overdose of APAP resulted in an exacerbation of liver injury at 6- and 12-hours post-APAP as evidenced by elevated plasma alanine aminotransferase activities, and extensive necrosis accompanied by diminished glutathione levels. Interestingly, these differences between Mlkl-/- and wild type mice were negated at the 24-hour mark, previously scrutinized by others. At 6 and 12 hours post APAP, Mlkl-/- mice exhibited augmented translocation of AIF and Endonuclease G without affecting JNK activation, suggesting enhanced mitochondrial permeability transition in the absence of MLKL. Lack of MLKL also impacted autophagy, the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, with decreased levels of p62 and LC3B and increased expression of CHOP and GRP78 at 6 hours post APAP. In essence, our findings illuminate a noncanonical role for MLKL in the early phases of APAP-induced liver injury, warranting further exploration of its influence on APAP pathophysiology., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Rates of suicide mortality and substance use have increased globally. We updated and extended existing systematic reviews of the association between substance use and suicide., Methods: This systematic review and meta-analysis explored the association between substance use and suicide mortality in peer reviewed, longitudinal cohort studies published from 2003 through 2024. Risk of bias was assessed using the Newcastle-Ottawa Scale. Pooled data were analyzed using a quality effects model. Meta-regression was used to assess the effect of moderation by study quality. Asymmetry in funnel plots and Doi plots were used to detect reporting bias., Findings: The analysis involved 47 studies from 12 countries. Substance misuse (SMR: 5.58, 95 % CI: 3.63-8.57, I 2 : 99 %) was significantly associated with risk for suicide. Alcohol (SMR: 65.39, 95 % CI: 3.02-19.62, I 2 : 99 %), tobacco (SMR: 1.83, 95 % CI: 1.20-2.79, I 2 : 83 %), opioid (SMR: 5.46, 95 % CI: 3.66-8.15, I 2 : 96 %), cannabis (SMR 3.31, 95 % CI: 1.42-7.70, I 2 : 95 %), and amphetamine (SMR 11.97, 95 % CI: 3.13-45.74, I 2 : 99 %) misuse were each linked to higher rates of suicide mortality. The association between substance misuse and suicide was stronger for females (SMR: 12.37, 95 % CI: 7.07-21.63, I 2 : 98 %) than males (SMR: 5.21, 95 % CI: 3.09-8.78, I 2 : 99 %) overall and in analyses of specific substances. Further disaggregated data were not available to sufficiently explore for potential health inequities across social factors., Conclusions: This meta-analysis highlights that substance misuse remains a significant suicide risk factor. It underscores the need for universal and targeted prevention and equitable access to effective interventions., Competing Interests: Nothing Declared., (© 2024 The Authors.)

There is substantial evidence that children's apparent omission of grammatical morphemes in utterances such as "She play tennis" and "Mummy eating" is in fact errors of commission in which contextually licensed unmarked forms encountered in the input are reproduced in a context-blind fashion. So how do children stop making such errors? In this study, we test the assumption that children's ability to recover from error is related to their developing sensitivity to longer-range dependencies. We use a pre-registered corpus analysis to explore the predictive value of different cues with regards to children's verb-marking errors and observe a developmental pattern consistent with this account. We look at context-independent cues (the identity of the specific verb being used) and at the relative value of context-dependent cues (the identity of the specific subject+verb sequence being used). We find that the only consistent effect across a group of 2- to 3-year-olds and a group of 3- to 4-year-olds is the relative frequency of unmarked forms of specific subject+verb sequences being used. The relative frequency of unmarked forms of the verb alone is predictive only in the younger age group. This is consistent with an account in which children recover from making errors by becoming progressively more sensitive to context, at first the immediately preceding lexical contexts (e.g., the subject that precedes the verb) and eventually more distant grammatical markers (e.g., the fronted auxiliary that precedes the subject in questions). RESEARCH HIGHLIGHTS: We provide a corpus analysis investigating input effects on young children's verb-marking errors (e.g., Mummy go) across development (between 2 and 4 years of age). We find evidence that these apparent errors of omission are in fact input-driven errors of commission that persist into the third year of life. We compare the relative effect on error rates of context-independent (e.g., verb) and context-dependent (e.g., subject+verb sequence) cues across developmental time. Our findings support the proposal that children recover from making verb-marking errors by becoming progressively more sensitive to preceding context., (© 2024 The Author(s). Developmental Science published by John Wiley & Sons Ltd.)

Eating disorders (EDs) are associated with numerous comorbidities and deleterious outcomes (e.g. medical complications, high rates of death by suicide). The complexities of EDs are further compounded by treatment dropout, poor treatment outcomes, and relapse. One way to better understand these complexities is to investigate broad, transdiagnostic risk factors that contribute to the etiology and maintenance of EDs, such as emotion regulation (ER) difficulties. We longitudinally tested the relationship between ER difficulties and ED outcomes in a sample of 101 female ED patients in a southeastern U.S. residential ED treatment facility. Consistent with hypothesis, there were significant improvements in both ER difficulties and eating pathology from admission to discharge. Further, improvement in ER difficulties was associated with improvements in eating pathology. These findings further substantiate the role of ER difficulties in eating disorders and provide further evidence for the relationship between ER difficulties and eating pathology among residential eating disorder patients.

Background: Long-standing theoretical perspectives on suicidal ideation (SI) have posited that SI arises, in part, as a way to obtain relief from intense emotional pain. Yet, little research has examined whether SI is linked with other relief-driven behaviors. The present study sought to provide preliminary support for the link between SI and relief-driven safety behavior usage, a commonly used strategy for managing distress among trauma-exposed individuals., Methods: Trauma-exposed participants (n = 95) recruited for a larger study assessing mechanisms of posttraumatic stress disorder symptomology and completed a battery of self-report measures, including SI and their use of safety behaviors. Zero-inflated negative binomial regressions were utilized to examine the association of safety behavior usage with the presence/absence of SI (i.e., zero-inflation) and SI severity., Results: In bivariate models, safety behaviors were associated with a greater likelihood of experiencing any SI and reporting more severe SI. When covariates were added to the model, safety behavior usage remained significantly and positively associated with SI severity., Limitations: The present study employed cross-sectional analyses of self-report data. Future research should use neurobehavioral tasks and intensive longitudinal data to test whether an underlying sensitivity to, or propensity to engage in, relief-driven behaviors contributes to SI., Discussion: Among trauma-exposed individuals, those who more frequently engage in negatively reinforced safety behaviors also report more severe SI. These findings dovetail with theoretical foundations of suicide linking SI with relief-driven motivations and provide further support that a propensity to engage in relief-driven behaviors is associated with SI., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: The multicenter, open-label, randomized phase 2 NCI-9944 study (NCT02595892) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank P = .044, which met the one-sided significance level of 0.1 used for sample size calculation)., Methods: We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib., Results: At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P = .18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P = .06)., Conclusion: The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials.

Growing evidence supports the hypothesis that temperate herbivores surf the green wave of emerging plants during spring migration. Despite the importance of autumn migration, few studies have conceptualized resource tracking of temperate herbivores during this critical season. We adapted the frost wave hypothesis (FWH), which posits that animals pace their autumn migration to reduce exposure to snow but increase acquisition of forage. We tested the FWH in a population of mule deer in Wyoming, USA by tracking the autumn migrations of n = 163 mule deer that moved 15-288 km from summer to winter range. Migrating deer experienced similar amounts of snow but 1.4-2.1 times more residual forage than if they had naïve knowledge of when or how fast to migrate. Importantly, deer balanced exposure to snow and forage in a spatial manner. At the fine scale, deer avoided snow near their mountainous summer ranges and became more risk prone to snow near winter range. Aligning with their higher tolerance of snow and lingering behavior to acquire residual forage, deer increased stopover use by 1 ± 1 day (95% CI) day for every 10% of their migration completed. Our findings support the prediction that mule deer pace their autumn migration with the onset of snow and residual forage, but refine the FWH to include movement behavior en route that is spatially dynamic., (© 2024 The Ecological Society of America.)

Several lines of preclinical evidence indicate that combining PI3K and CDK4/6 inhibitors may further enhance the efficacy of hormonal therapy by overcoming de novo and acquired resistance to PI3K and CDK4/6 blockade. We evaluated the combination of abemaciclib, letrozole and LY3023414 (an orally available, selective inhibitor of the class I PI3K isoforms and mTORC1/2) in recurrent endometrial cancer (EC). This study was terminated prematurely after 5 patients initiated protocol therapy due to discontinuation of further development of LY3023414. We report our findings from these patients, including one with recurrent endometrioid EC with AKT1, CTNNB1 and ESR1 hotspot mutations who had previously progressed through letrozole/everolimus and achieved a partial response to letrozole/abemaciclib/LY3023414., Competing Interests: Niya Xiong, Carolyn Krasner, Hannah Sawyer, Madeline Polak, Hope Needham, Megan Geddes, Lani Koppermann and Su-Chun Cheng have nothing to disclose. Megan Shea reports participation on a Data Safety Monitoring Board or Advisory Board from GSK and Eisai, and support for attending meetings and/or travel from Massachusetts Society of Clinical Oncology. Joyce Liu reports funding to Dana-Farber Cancer Institute for Trials on which she is the PI from 2X Oncology, Aravive, Arch Oncology, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, GlaxoSmithKline, Impact Therapeutics, Regeneron, Seagen, Vigeo Therapeutics, and Zentalis Pharmaceuticals; she also reports consulting and/or advisory board participation from AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Daiichi Sankyo, Eisai, Genentech, GlaxoSmithKline, Regeneron Therapeutics and Zentalis Pharmaceuticals; she also reports being Co-chair of the NRG Oncology Ovarian Subcommittee and Co-chair of Tina’s Wish Scientific Advisory Board. Panagiotis Konstantinopoulos reports funding to Dana-Farber Cancer Institute from AstraZeneca, Pfizer, Eli Lilly, Bayer, Merck, GSK, Tesaro, Merck KGaA on trials which he is the PI; he also reports consulting and/or advisory board participation from Immunogen, GSK, Novartis, Alkermes, AstraZeneca, Bayer, Merck, Pfizer, Tesaro, Vertex, EMD Serono, Kadmon, BMS, IMV, Repare, Artios, Mersana. Ursula Matulonis reports consulting fees from Merck, GSK, AstraZeneca, Pfizer; payment on a CME lecture and slides on endometrial cancer from Med Learning Group; travel support from Immunogen to travel to an FDA launch meeting; she also reports fees from participation in advisory boards from Allarity, NextCure, Trillium, Agenus, Profound Bio, Novartis, Boerhinger Ingelheim, Rivkin Foundation, Ovarian Cancer Research Alliance, Clearity Foundation, Morphosy, CureLab, Eisai and fees from participation in Data Safety Monitoring Boards from Alkermes and Symphogen. Cesar Castro reports consulting fees from Qiagen, Teladoc and Advanced Medical. Elizabeth Lee reports funding to Dana-Farber Cancer Institute for a clinical Trial on which she is the PI from Merck; she also reports consulting fees from Aadi Biosciences and a GOG New Investigator Award for travel support to attend NRG Oncology conferences.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

For many, the COVID-19 pandemic felt overwhelming and stressful due to longer work hours and caring for self and others. More people experienced anxiety, fear, anger, sadness, and helplessness. Self-care is important. It enables anyone to maintain their physical, emotional, mental, spiritual, and social health. Practicing mindfulness when implementing self-care can include a holistic approach that focuses on five areas: Physical, Emotional, Mental, Spiritual and Social (PEMSS). The mindfulness approach helps with properly implementing applicable, direct self-care from any of these areas. Approaching self-care from any of these five areas can be helpful in eradicating the challenges of identifying self-care behaviors that are effective for maintaining personal and professional well-being in the face of the unique demands of work. Mindfulness self-care can help identify untargeted self-care patterns and blocks to implementing targeted self-care as well as how to develop intentional, targeted self-care., (© 2023 Elsevier Inc. All rights reserved.)

Fences have recently been recognized as one of the most prominent linear infrastructures on earth. As animals traverse fenced landscapes, they adjust movement behaviours to optimize resource access while minimizing energetic costs of coping with fences. Examining individual responses is key for connecting localized fence effects with population dynamics. We investigated the multi-scale effects of fencing on animal movements, space use and survival of 61 pronghorn and 96 mule deer on a gradient of fence density in Wyoming, USA. Taking advantage of the recently developed Barrier Behaviour Analysis, we classified individual movement responses upon encountering fences (i.e. barrier behaviours). We adopted the reaction norm framework to jointly quantify individual plasticity and behavioural types of barrier behaviours, as well as behaviour syndromes between barrier behaviours and animal space use. We also assessed whether barrier behaviours affect individual survival. Our results highlighted a high-level individual plasticity encompassing differences in the degree and direction of barrier behaviours for both pronghorn and mule deer. Additionally, these individual differences were greater at higher fence densities. For mule deer, fence density determined the correlation between barrier behaviours and space use and was negatively associated with individual survival. However, these relationships were not statistically significant for pronghorn. By integrating approaches from movement ecology and behavioural ecology with the emerging field of fence ecology, this study provides new evidence that an extraordinarily widespread linear infrastructure uniquely impacts animals at the individual level. Managing landscape for lower fence densities may help prevent irreversible behavioural shifts for wide-ranging animals in fenced landscapes., (© 2023 The Authors. Journal of Animal Ecology © 2023 British Ecological Society.)

Objective: To investigate whether fear of failure (FOF) influences a clinician's perception of how confident and comfortable they are in their delivery of end-of-life (EOL) care., Methods: Cross-sectional questionnaire study with recruitment of physicians and nurses across two large NHS hospital trusts in the UK and national UK professional networks. A total of 104 physicians and 101 specialist nurses across 20 hospital specialities provided data that were analysed using a two-step hierarchical regression., Results: The study validated the PFAI measure for use in medical contexts. Number of EOL conversations, gender, and role were shown to impact confidence and comfortableness with EOL care. Four FOF subscales did show a significant relationship with perceived delivery of EOL care., Conclusion: Aspects of FOF can be shown to negatively impact the clinician experience of delivering EOL care., Clinical Implications: Further study should explore how FOF develops, populations that are more susceptible, sustaining factors, and its impact on clinical care. Techniques developed to manage FOF in other populations can now be investigated in a medical population.

Purpose: Estrogen receptor (ER)-positive endometrial cancers (ECs) are characterized by phosphatidylinositol 3-kinase (PI3K) and receptor tyrosine kinase (RTK)/RAS/β-catenin (CTNNB1) pathway alterations in approximately 90% and 80% of cases, respectively. Extensive cross-talk between ER, PI3K, and RTK/RAS/CTNNB1 pathways leads to both ligand-dependent and ligand-independent ER transcriptional activity as well as upregulation of cyclin D1 which, in complex with cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), is a critical regulator of cell cycle progression and a key mediator of resistance to hormonal therapy. We hypothesized that the combination of the aromatase inhibitor letrozole and CDK4/6 inhibitor abemaciclib would demonstrate promising activity in this setting., Methods: We conducted a phase II, two-stage study of letrozole/abemaciclib in recurrent ER-positive EC. Eligibility criteria included measurable disease, no limit on prior therapies, and all EC histologies; prior hormonal therapy was allowed. Primary end points were objective response rate by RECIST 1.1 and progression-free survival (PFS) rate at 6 months., Results: At the data cutoff date (December 03, 2021), 30 patients (28 with endometrioid EC) initiated protocol therapy; 15 (50%) patients had prior hormonal therapy. There were nine total responses (eight confirmed), for an objective response rate of 30% (95% CI, 14.7 to 49.4), all in endometrioid adenocarcinomas. Median PFS was 9.1 months, PFS at 6 months was 55.6% (95% CI, 35.1 to 72), and median duration of response was 7.4 months. Most common ≥ grade 3 treatment-related adverse events were neutropenia (20%) and anemia (17%). Responses were observed regardless of grade, prior hormonal therapy, mismatch repair, and progesterone receptor status. Exploratory tumor profiling revealed several mechanistically relevant candidate predictors of response ( CTNNB1 , KRAS , and CDKN2A mutations) or absence of response ( TP53 mutations), which require independent validation., Conclusion: Letrozole/abemaciclib demonstrated encouraging and durable evidence of activity in recurrent ER positive endometrioid EC.

The ability to freely move across the landscape to track the emergence of nutritious spring green-up (termed 'green-wave surfing') is key to the foraging strategy of migratory ungulates. Across the vast landscapes traversed by many migratory herds, habitats are being altered by development with unknown consequences for surfing. Using a unique long-term tracking dataset, we found that when energy development occurs within mule deer (Odocoileus hemionus) migration corridors, migrating animals become decoupled from the green wave. During the early phases of a coalbed natural gas development, deer synchronized their movements with peak green-up. But faced with increasing disturbance as development expanded, deer altered their movements by holding up at the edge of the gas field and letting the green wave pass them by. Development often modified only a small portion of the migration corridor but had far-reaching effects on behaviour before and after migrating deer encountered it, thus reducing surfing along the entire route by 38.65% over the 14-year study period. Our study suggests that industrial development within migratory corridors can change the behaviour of migrating ungulates and diminish the benefits of migration. Such disruptions to migratory behaviour present a common mechanism whereby corridors become unprofitable and could ultimately be lost on highly developed landscapes., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

While migrating, animals make directionally persistent movements and may only respond to human-induced rapid environmental change (HIREC), such as climate and land-use change, once a threshold of HIREC is surpassed. In contrast, animals on other seasonal ranges (e.g., winter range) make more localized and tortuous movements while foraging and may have the flexibility to adjust the location of their range and the intensity of use within it to minimize interactions with HIREC. Because of these seasonal differences in movement, animals on seasonal ranges should avoid areas that contain any level of HIREC, however, during migration, animals should use areas that contain low levels of HIREC, avoiding it only once a threshold of HIREC has been surpassed. We tested this hypothesis using a decade of GPS collar data collected from migratory mule deer (Odocoileus hemionus; n = 56 migration, 143 winter) and pronghorn (Antilocapra americana; n = 70 migration, 89 winter) that winter on and migrate through a natural gas field in western Wyoming. Using surface disturbance caused by well pads and roads as an index of HIREC, we evaluated behavioral responses across three spatial scales during winter and migration seasons. During migration, both species tolerated low levels of disturbance. Once a disturbance threshold was surpassed, however, they avoided HIREC. For mule deer, thresholds were consistently ~3%, whereas thresholds for pronghorn ranged from 1% to 9.25% surface disturbance. In contrast to migration, both species generally avoided all levels of HIREC while on winter range. Our study suggests that animal responses to HIREC are mediated by season-specific movement patterns. Our results provide further evidence of ungulates avoiding human disturbance on winter range and reveal disturbance thresholds that trigger mule deer and pronghorn responses during migration: information that managers can use to maintain the ecological function of migration routes and winter ranges., (© 2022 The Ecological Society of America.)

Importance: Although the activity of pembrolizumab and lenvatinib (the only US Food and Drug Administration-approved immunotherapy for mismatch repair proficient endometrial cancer [MMRP EC]) is compelling, there are no biomarkers of response and most patients do not tolerate, do not respond to, or develop resistance to this regimen, highlighting the need for additional, potentially biomarker-driven therapeutic approaches for patients with recurrent MMRP EC., Objective: To assess the potential positive outcomes and safety of the combination of the polyadenosine diphosphate-ribose polymerase inhibitor talazoparib and the programmed cell death ligand 1 (PD-L1) inhibitor avelumab in recurrent MMRP EC., Design, Settings, and Participants: This investigator-initiated, open-label, single-arm, 2-stage, phase 2 study nonrandomized controlled trial patients at 4 institutions in the US. Key eligibility criteria included measurable disease, unlimited prior therapies, and all endometrial cancer histologies., Interventions: Talazoparib, 1 mg, orally, daily, and avelumab, 10 mg/kg, intravenously, every 2 weeks, were administered until disease progression or unacceptable toxic effects., Main Outcomes and Measures: Statistical considerations were developed for 2 coprimary objectives of objective response rate and rate of progression-free survival at 6 months, with a 2-stage design that allowed for early discontinuation for futility. Prespecified exploratory objectives included the association of immunogenomic features (determined by targeted-panel next-generation sequencing and immunohistochemistry) with activity., Results: Thirty-five female patients (mean [SD] age, 67.9 [8.41] years) received protocol therapy; 9 (25.7%) derived clinical benefit after meeting at least 1 of the 2 coprimary end points. Four patients (11.4%) exhibited confirmed objective response rates (4 partial responses), and 8 (22.9%) survived progression free at 6 months. The most common grade 3 and 4 treatment-related toxic effects were anemia (16 [46%]), thrombocytopenia (10 [29%]), and neutropenia (4 [11%]); no patient discontinued receipt of therapy because of toxic effects. Tumors with homologous recombination repair alterations were associated with clinical benefit from treatment with avelumab and talazoparib. Tumor mutational burden, tumor-infiltrating lymphocytes, and PD-L1 status were not associated with clinical benefit., Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that treatment with avelumab and talazoparib demonstrated a favorable toxic effect profile and met the predetermined criteria to be considered worthy of further evaluation in MMRP EC. Immunogenomic profiling provided insights that may inform ongoing and future studies of polyadenosine diphosphate-ribose polymerase and PD-L1 inhibitor combinations in endometrial cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT02912572.

Aim: Macroecological studies that require habitat suitability data for many species often derive this information from expert opinion. However, expert-based information is inherently subjective and thus prone to errors. The increasing availability of GPS tracking data offers opportunities to evaluate and supplement expert-based information with detailed empirical evidence. Here, we compared expert-based habitat suitability information from the International Union for Conservation of Nature (IUCN) with habitat suitability information derived from GPS-tracking data of 1,498 individuals from 49 mammal species., Location: Worldwide., Time Period: 1998-2021., Major Taxa Studied: Forty-nine terrestrial mammal species., Methods: Using GPS data, we estimated two measures of habitat suitability for each individual animal: proportional habitat use (proportion of GPS locations within a habitat type), and selection ratio (habitat use relative to its availability). For each individual we then evaluated whether the GPS-based habitat suitability measures were in agreement with the IUCN data. To that end, we calculated the probability that the ranking of empirical habitat suitability measures was in agreement with IUCN's classification into suitable, marginal and unsuitable habitat types., Results: IUCN habitat suitability data were in accordance with the GPS data (> 95% probability of agreement) for 33 out of 49 species based on proportional habitat use estimates and for 25 out of 49 species based on selection ratios. In addition, 37 and 34 species had a > 50% probability of agreement based on proportional habitat use and selection ratios, respectively., Main Conclusions: We show how GPS-tracking data can be used to evaluate IUCN habitat suitability data. Our findings indicate that for the majority of species included in this study, it is appropriate to use IUCN habitat suitability data in macroecological studies. Furthermore, we show that GPS-tracking data can be used to identify and prioritize species and habitat types for re-evaluation of IUCN habitat suitability data., Competing Interests: The authors have no conflict of interest to declare., (© 2022 The Authors. Global Ecology and Biogeography published by John Wiley & Sons Ltd.)

Purpose: PARP inhibitor resistance may be overcome by combinatorial strategies with agents that disrupt homologous recombination repair (HRR). Multiple HRR pathway components are HSP90 clients, so that HSP90 inhibition leads to abrogation of HRR and sensitisation to PARP inhibition. We performed in vivo preclinical studies of the HSP90 inhibitor onalespib with olaparib and conducted a Phase 1 combination study., Patients and Methods: Tolerability and efficacy studies were performed in patient-derived xenograft(PDX) models of ovarian cancer. Clinical safety, tolerability, steady-state pharmacokinetics and preliminary efficacy of olaparib and onalespib were evaluated using a standard 3 + 3 dose-escalation design., Results: Olaparib/onalespib exhibited anti-tumour activity against BRCA1-mutated PDX models with acquired PARPi resistance and PDX models with RB-pathway alterations(CDKN2A loss and CCNE1 overexpression). Phase 1 evaluation revealed that dose levels up to olaparib 300 mg/onalespib 40 mg and olaparib 200 mg/onalespib 80 mg were safe without dose-limiting toxicities. Coadministration of olaparib and onalespib did not appear to affect the steady-state pharmacokinetics of either agent. There were no objective responses, but disease stabilisation ≥24 weeks was observed in 7/22 (32%) evaluable patients including patients with BRCA-mutated ovarian cancers and acquired PARPi resistance and patients with tumours harbouring RB-pathway alterations., Conclusions: Combining onalespib and olaparib was feasible and demonstrated preliminary evidence of anti-tumour activity., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

While the tendency to return to previously visited locations-termed 'site fidelity'-is common in animals, the cause of this behaviour is not well understood. One hypothesis is that site fidelity is shaped by an animal's environment, such that animals living in landscapes with predictable resources have stronger site fidelity. Site fidelity may also be conditional on the success of animals' recent visits to that location, and it may become stronger with age as the animal accumulates experience in their landscape. Finally, differences between species, such as the way memory shapes site attractiveness, may interact with environmental drivers to modulate the strength of site fidelity. We compared inter-year site fidelity in 669 individuals across eight ungulate species fitted with GPS collars and occupying a range of environmental conditions in North America and Africa. We used a distance-based index of site fidelity and tested hypothesized drivers of site fidelity using linear mixed effects models, while accounting for variation in annual range size. Mule deer Odocoileus hemionus and moose Alces alces exhibited relatively strong site fidelity, while wildebeest Connochaetes taurinus and barren-ground caribou Rangifer tarandus granti had relatively weak fidelity. Site fidelity was strongest in predictable landscapes where vegetative greening occurred at regular intervals over time (i.e. high temporal contingency). Species differed in their response to spatial heterogeneity in greenness (i.e. spatial constancy). Site fidelity varied seasonally in some species, but remained constant over time in others. Elk employed a 'win-stay, lose-switch' strategy, in which successful resource tracking in the springtime resulted in strong site fidelity the following spring. Site fidelity did not vary with age in any species tested. Our results provide support for the environmental hypothesis, particularly that regularity in vegetative phenology shapes the strength of site fidelity at the inter-annual scale. Large unexplained differences in site fidelity suggest that other factors, possibly species-specific differences in attraction to known sites, contribute to variation in the expression of this behaviour. Understanding drivers of variation in site fidelity across groups of organisms living in different environments provides important behavioural context for predicting how animals will respond to environmental change., (© 2021 The Authors. Journal of Animal Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Society.)