Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants that Confer Risk for Breast Cancer.

Breast cancer includes several subtypes with distinct characteristic biological, pathological, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate development of improved prevention and treatment approaches. Here, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case GWAS (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared to luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to 2-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among breast cancer patients. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC.

Lesion-remote astrocytes govern microglia-mediated white matter repair.

Spared regions of the damaged central nervous system undergo dynamic remodeling and exhibit a remarkable potential for therapeutic exploitation. Here, lesion-remote astrocytes (LRAs), which interact with viable neurons, glia and neural circuitry, undergo reactive transformations whose molecular and functional properties are poorly understood. Using multiple transcriptional profiling methods, we interrogated LRAs from spared regions of mouse spinal cord following traumatic spinal cord injury (SCI). We show that LRAs acquire a spectrum of molecularly distinct, neuroanatomically restricted reactivity states that evolve after SCI. We identify transcriptionally unique reactive LRAs in degenerating white matter that direct the specification and function of local microglia that clear lipid-rich myelin debris to promote tissue repair. Fueling this LRA functional adaptation is Ccn1 , which encodes for a secreted matricellular protein. Loss of astrocyte CCN1 leads to excessive, aberrant activation of local microglia with (i) abnormal molecular specification, (ii) dysfunctional myelin debris processing, and (iii) impaired lipid metabolism, culminating in blunted debris clearance and attenuated neurological recovery from SCI. Ccn1 -expressing white matter astrocytes are specifically induced by local myelin damage and generated in diverse demyelinating disorders in mouse and human, pointing to their fundamental, evolutionarily conserved role in white matter repair. Our findings show that LRAs assume regionally divergent reactivity states with functional adaptations that are induced by local context-specific triggers and influence disorder outcome. Astrocytes tile the central nervous system (CNS) where they serve vital roles that uphold healthy nervous system function, including regulation of synapse development, buffering of neurotransmitters and ions, and provision of metabolic substrates 1 . In response to diverse CNS insults, astrocytes exhibit disorder-context specific transformations that are collectively referred to as reactivity 2-5 . The characteristics of regionally and molecularly distinct reactivity states are incompletely understood. The mechanisms through which distinct reactivity states arise, how they evolve or resolve over time, and their consequences for local cell function and CNS disorder progression remain enigmatic. Immediately adjacent to CNS lesions, border-forming astrocytes (BFAs) undergo transcriptional reprogramming and proliferation to form a neuroprotective barrier that restricts inflammation and supports axon regeneration 6-9 . Beyond the lesion, spared but dynamic regions of the injured CNS exhibit varying degrees of synaptic circuit remodeling and progressive cellular responses to secondary damage that have profound consequences for neural repair and recovery 10,11 . Throughout these cytoarchitecturally intact, but injury-reactive regions, lesion-remote astrocytes (LRAs) intermingle with neurons and glia, undergo little to no proliferation, and exhibit varying degrees of cellular hypertrophy 7,12,13 . The molecular and functional properties of LRAs remain grossly undefined. Therapeutically harnessing spared regions of the injured CNS will require a clearer understanding of the accompanying cellular and molecular landscape. Here, we leveraged integrative transcriptional profiling methodologies to identify multiple spatiotemporally resolved, molecularly distinct states of LRA reactivity within the injured spinal cord. Computational modeling of LRA-mediated heterotypic cell interactions, astrocyte-specific conditional gene deletion, and multiple mouse models of acute and chronic CNS white matter degeneration were used to interrogate a newly identified white matter degeneration-reactive astrocyte subtype. We define how this reactivity state is induced and its role in governing the molecular and functional specification of local microglia that clear myelin debris from the degenerating white matter to promote repair.

Dim light at night shifts microglia to a pro-inflammatory state after cerebral ischemia, altering stroke outcome in mice.

Circadian rhythms are endogenous biological cycles that regulate physiology and behavior and are set to precisely 24-h by light exposure. Light at night (LAN) dysregulates physiology and function including immune response; a critical component that contributes to stroke pathophysiological progression of neuronal injury and may impair recovery from injury. The goal of this study is to explore the effects of dim LAN (dLAN) in a murine model of ischemic stroke to assess how nighttime lighting from hospital settings can affect stroke outcome. Further, this study sought to identify mechanisms underlying pathophysiological changes to immune response after circadian disruption. Male and female adult Swiss Webster (CFW) mice were subjected to transient or permanent focal cerebral ischemia, then were subsequently placed into either dark night conditions (LD) or one night of dLAN (5 lx). 24 h post-stroke, sensorimotor impairments and infarct sizes were quantified. A single night of dLAN following MCAO increased infarct size and sensorimotor deficits across both sexes and reduced survival in males after 24 h. Flow cytometry was performed to assess microglial phenotypes after MCAO, and revealed that dLAN altered the percentage of microglia that express pro-inflammatory markers (MHC II+ and IL-6) and microglia that express CD206 and IL-10 that likely contributed to poor ischemic outcomes. Following these results, microglia were reduced in the brain using Plexxikon 5622 (PLX 5622) a CSFR1 inhibitor, then the mice received an MCAO and were exposed to LD or dLAN conditions for 24 h. Microglial depletion by PLX5622 resulted in infarct sizes that were comparable between lighting conditions. This study provides supporting evidence that environmental lighting exacerbates ischemic injury and post-stroke mortality by a biological mechanism that exposure to dLAN causes a fundamental shift of activated microglial phenotypes from beneficial to detrimental at an early time point after stroke, resulting in irreversible neuronal death.

Association of breast cancer with quantitative mammographic density measures for women receiving contrast-enhanced mammography.

Women with high mammographic density have an increased risk of breast cancer. They may be offered contrast-enhanced mammography to improve breast cancer screening performance. Using a cohort of women receiving contrast-enhanced mammography, we evaluated whether conventional and modified mammographic density measures were associated with breast cancer. Sixty-six patients with newly diagnosed unilateral breast cancer were frequency matched on the basis of age to 133 cancer-free control individuals. On low-energy craniocaudal contrast-enhanced mammograms (equivalent to standard mammograms), we measured quantitative mammographic density using CUMULUS software at the conventional intensity threshold ("Cumulus") and higher-than-conventional thresholds ("Altocumulus," "Cirrocumulus"). The measures were standardized to enable estimation of odds ratio per adjusted standard deviation (OPERA). In multivariable logistic regression of case-control status, only the highest-intensity measure (Cirrocumulus) was statistically significantly associated with breast cancer (OPERA = 1.40, 95% confidence interval = 1.04 to 1.89). Conventional Cumulus did not contribute to model fit. For women receiving contrast-enhanced mammography, Cirrocumulus mammographic density may better predict breast cancer than conventional quantitative mammographic density.

Plant-pollinator network architecture does not impact intraspecific microbiome variability.

Variation in how individuals interact with food resources can directly impact, and be affected by, their microbial interactions due to the potential for transmission. The degree to which this transmission occurs, however, may depend on the structure of forager networks, which determine the community-scale transmission opportunities. In particular, how the community-scale opportunity for transfer balances individual-scale barriers to transmission is unclear. Examining the bee-flower and bee-microbial interactions of over 1000 individual bees, we tested (1) the degree to which individual floral visits predicted microbiome composition and (2) whether plant-bee networks with increased opportunity for microbial transmission homogenized the microbiomes of bees within that network. The pollen community composition carried by bees was associated with microbiome composition at some sites, suggesting that microbial transmission at flowers occurred. Contrary to our predictions, however, microbiome variability did not differ based on transfer opportunity: bee microbiomes in asymmetric networks with high opportunity for microbial transfer were similarly variable compared to microbiomes in networks with more evenly distributed links. These findings suggest that microbial transmission at flowers is frequent enough to be observed at the community level, but that community network structure did not substantially change the dynamics of this transmission, perhaps due to filtering processes in host guts.

In masks we trust: explicit and implicit reactions to masked faces vary by political orientation.

Previous studies in the context of the COVID-19 pandemic indicated that wearing a medical-style mask affects whether a stranger's face is judged as more trustworthy, socially desirable, or likely to be ill. However, given political controversies around mask use, these effects might vary by political orientation. In a pre-registered online experiment, we measured evaluations of trustworthiness, social desirability and perceived illness in masked and unmasked faces by 1241 British and US participants. We included questions on political orientation, along with the implicit online-VAAST approach/avoid task to test reaction times to masked/unmasked faces. There was a medium-sized effect of masks on trustworthiness and a significant interaction with political orientation, in that conservatives found masked faces less trustworthy than did liberals. Participants were quicker to approach masked than unmasked faces, but conservatives were relatively slower than liberals. The effects on trustworthiness suggest that differential moralization of novel social norms can affect how their adherents are evaluated in terms of their suitability for social interactions. Furthermore, the congruence between implicit and explicit methods implies that such differences can have deep-seated effects on reactions.

A genome-wide association study of contralateral breast cancer in the Women's Environmental Cancer and Radiation Epidemiology Study.

BACKGROUND: Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common variants, remains incomplete. This study aimed to investigate the genetic basis of CBC to better understand this malignancy. FINDINGS: We performed a genome-wide association analysis in the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age < 55 years including 1161 with CBC who served as cases and 1668 with unilateral breast cancer (UBC) who served as controls. We observed two loci (rs59657211, 9q32, SLC31A2/FAM225A and rs3815096, 6p22.1, TRIM31) with suggestive genome-wide significant associations (P < 1 × 10-6). We also found an increased risk of CBC associated with a breast cancer-specific polygenic risk score (PRS) comprised of 239 known breast cancer susceptibility single nucleotide polymorphisms (SNPs) (rate ratio per 1-SD change: 1.25; 95% confidence interval 1.14-1.36, P < 0.0001). The protective effect of chemotherapy on CBC risk was statistically significant only among patients with an elevated PRS (Pheterogeneity = 0.04). The AUC that included the PRS and known breast cancer risk factors was significantly elevated. CONCLUSIONS: The present GWAS identified two previously unreported loci with suggestive genome-wide significance. We also confirm that an elevated risk of CBC is associated with a comprehensive breast cancer susceptibility PRS that is independent of known breast cancer risk factors. These findings advance our understanding of genetic risk factors involved in CBC etiology.

How school policies, strategies, and relational factors contribute to teacher victimization and school safety.

In this study, we examined how school policies and strategies (i.e., positive discipline, hardening strategies, and positive behavioral strategies) affect teacher relational factors and teacher reports of victimization and safety. Specifically, we examined the mediational roles of teacher support of student learning, maltreatment of students by teachers, and teachers' differential treatment of students in schools. Using a sample of 6643 pre-K-12th-grade teachers, path analysis results revealed that positive behavior strategies, hardening strategies, and positive discipline were indirectly associated with teacher victimization and sense of safety. Additionally, teachers' perceptions of other teachers maltreating students had the greatest contributions to their sense of safety and victimization by students. Positive discipline was directly and indirectly associated with teacher victimization and safety. Implications and directions for future studies are discussed.

Association of Breast Cancer Odds with Background Parenchymal Enhancement Quantified Using a Fully Automated Method at MRI: The IMAGINE Study.

Background Background parenchymal enhancement (BPE) at breast MRI has been associated with increased breast cancer risk in several independent studies. However, variability of subjective BPE assessments have precluded its use in clinical practice. Purpose To examine the association between fully objective measures of BPE at MRI and odds of breast cancer. Materials and Methods This prospective case-control study included patients who underwent a bilateral breast MRI examination and were receiving care at one of three centers in the United States from November 2010 to July 2017. Breast volume, fibroglandular tissue (FGT) volume, and BPE were quantified using fully automated software. Fat volume was defined as breast volume minus FGT volume. BPE extent was defined as the proportion of FGT voxels with enhancement of 20% or more. Spearman rank correlation between quantitative BPE extent and Breast Imaging Reporting and Data System (BI-RADS) BPE categories assigned by an experienced board-certified breast radiologist was estimated. With use of multivariable logistic regression, breast cancer case-control status was regressed on tertiles (low, moderate, and high) of BPE, FGT volume, and fat volume, with adjustment for covariates. Results In total, 536 case participants with breast cancer (median age, 48 years [IQR, 43-55 years]) and 940 cancer-free controls (median age, 46 years [IQR, 38-55 years]) were included. BPE extent was positively associated with BI-RADS BPE (rs = 0.54; P < .001). Compared with low BPE extent (range, 2.9%-34.2%), high BPE extent (range, 50.7%-97.3%) was associated with increased odds of breast cancer (odds ratio [OR], 1.74 [95% CI: 1.23, 2.46]; P for trend = .002) in a multivariable model also including FGT volume (OR, 1.39 [95% CI: 0.97, 1.98]) and fat volume (OR, 1.46 [95% CI: 1.04, 2.06]). The association of high BPE extent with increased odds of breast cancer was similar for premenopausal and postmenopausal women (ORs, 1.75 and 1.83, respectively; interaction P = .73). Conclusion Objectively measured BPE at breast MRI is associated with increased breast cancer odds for both premenopausal and postmenopausal women. Clinical trial registration no. NCT02301767 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Bokacheva in this issue.

Trends in Radiation Dose to the Contralateral Breast During Breast Cancer Radiation Therapy.

Over 4 million survivors of breast cancer live in the United States, 35% of whom were treated before 2009. Approximately half of patients with breast cancer receive radiation therapy, which exposes the untreated contralateral breast to radiation and increases the risk of a subsequent contralateral breast cancer (CBC). Radiation oncology has strived to reduce unwanted radiation dose, but it is unknown whether a corresponding decline in actual dose received to the untreated contralateral breast has occurred. The purpose of this study was to evaluate trends in unwanted contralateral breast radiation dose to inform risk assessment of second primary cancer in the contralateral breast for long-term survivors of breast cancer. Individually estimated radiation absorbed doses to the four quadrants and areola central area of the contralateral breast were estimated for 2,132 women treated with radiation therapy for local/regional breast cancers at age <55 years diagnosed between 1985 and 2008. The two inner quadrant doses and two outer quadrant doses were averaged. Trends in dose to each of the three areas of the contralateral breast were evaluated in multivariable models. The population impact of reducing contralateral breast dose on the incidence of radiation-associated CBC was assessed by estimating population attributable risk fraction (PAR) in a multivariable model. The median dose to the inner quadrants of the contralateral breast was 1.70 Gy; to the areola, 1.20 Gy; and to the outer quadrants, 0.72 Gy. Ninety-two percent of patients received ≥1 Gy to the inner quadrants. For each calendar year of diagnosis, dose declined significantly for each location, most rapidly for the inner quadrants (0.04 Gy/year). Declines in dose were similar across subgroups defined by age at diagnosis and body mass index. The PAR for CBC due to radiation exposure >1 Gy for women <40 years of age was 17%. Radiation dose-reduction measures have reduced dose to the contralateral breast during breast radiation therapy. Reducing the dose to the contralateral breast to <1 Gy could prevent an estimated 17% of subsequent radiation-associated CBCs for women treated under 40 years of age. These dose estimates inform CBC surveillance for the growing number of breast cancer survivors who received radiation therapy as young women in recent decades. Continued reductions in dose to the contralateral breast could further reduce the incidence of radiation-associated CBC.

Astrocytic deletion of protein kinase R-like ER kinase (PERK) does not affect learning and memory in aged mice but worsens outcome from experimental stroke.

Aging is associated with cognitive decline and is the main risk factor for a myriad of conditions including neurodegeneration and stroke. Concomitant with aging is the progressive accumulation of misfolded proteins and loss of proteostasis. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress and activation of the unfolded protein response (UPR). The UPR is mediated, in part, by the eukaryotic initiation factor 2α (eIF2α) kinase protein kinase R-like ER kinase (PERK). Phosphorylation of eIF2α reduces protein translation as an adaptive mechanism but this also opposes synaptic plasticity. PERK, and other eIF2α kinases, have been widely studied in neurons where they modulate both cognitive function and response to injury. The impact of astrocytic PERK signaling in cognitive processes was previously unknown. To examine this, we deleted PERK from astrocytes (AstroPERKKO ) and examined the impact on cognitive functions in middle-aged and old mice of both sexes. Additionally, we tested the outcome following experimental stroke using the transient middle cerebral artery occlusion (MCAO) model. Tests of short-term and long-term learning and memory as well as of cognitive flexibility in middle-aged and old mice revealed that astrocytic PERK does not regulate these processes. Following MCAO, AstroPERKKO had increased morbidity and mortality. Collectively, our data demonstrate that astrocytic PERK has limited impact on cognitive function and has a more prominent role in the response to neural injury.

Children endorse deterrence motivations for third-party punishment but derive higher enjoyment from compensating victims.

Children's punishment behavior may be driven by both retribution and deterrence, but the potential primacy of either motive is unknown. Moreover, children's punishment enjoyment and compensation enjoyment have never been directly contrasted. Here, British, Colombian, and Italian 7- to 11-year-old children (N = 123) operated a Justice System in which they viewed different moral transgressions in Minecraft, a globally popular video game, either face-to-face with an experimenter or over the internet. Children could respond to transgressions by punishing transgressors and compensating victims. The purpose of the system was framed in terms of retribution, deterrence, or compensation between participants. Children's performance, endorsement, and enjoyment of punishment and compensation were measured, along with their endorsement of retribution versus deterrence as punishment justifications, during and/or after justice administration. Children overwhelmingly endorsed deterrence over retribution as their punishment justification irrespective of age. When asked to reproduce the presented frame in their own words, children more reliably reproduced the deterrence frame rather than the retribution frame. Punishment enjoyment decreased while compensation enjoyment increased over time. Despite enjoying compensation more, children preferentially endorsed punishment over compensation, especially with increasing age and transgression severity. Reported deterrent justifications, superior reproduction of deterrence framing, lower enjoyment of punishment than of compensation, and higher endorsement of punishment over compensation together suggest that children felt that they ought to mete out punishment as a means to deter future transgressions. Face-to-face and internet-mediated responses were not distinguishable, supporting a route to social psychology research with primary school-aged children unable to physically visit labs.

Opioid Use Among Medicare Beneficiaries With Knee Osteoarthritis: Prevalence and Correlates of Chronic Use.

OBJECTIVE: To determine the prevalence of chronic and occasional opioid use and identify risk factors of opioid use among persons with knee osteoarthritis (OA). METHODS: We used the Medicare Current Beneficiary Survey to select a knee OA cohort. We obtained data on demographics characteristics, marital status, comorbidities, insurance, and prescription medication coverage from survey data and linked Medicare claims. We included all prescribed medication records classified as opioid under the First Databank therapeutic antiarthritics or analgesics categories. We stratified individuals with knee OA into 3 opioid use groups: 1) nonusers (0 prescriptions/year), 2) occasional users (1-5 prescriptions/year), and 3) chronic users (6+ prescriptions/year). We built multivariable logistic regression models using a generalized estimating equation to determine correlates of chronic opioid use. RESULTS: Among 3,549 Medicare beneficiaries with knee OA and a mean ± SD age of 78 ± 7 years, 68% were female, 9% were chronic users, and 21% used opioids occasionally. Multivariable analysis showed that non-Hispanic ethnicity (odds ratio [OR] 4.8, 95% confidence interval [95% CI] 2.2-10.2), divorced status (vs. married; OR 2.3, 95% CI 1.5-3.5), Medicaid eligibility (OR 1.9, 95% CI 1.3-2.7), depression (OR 1.9, 95% CI 1.5-2.5), chronic obstructive pulmonary disease (OR 1.9, 95% CI 1.4-2.5), and inability to walk without assistive devices (vs. no difficulty walking; OR 2.4, 95% CI 1.5-3.7) were independently associated with chronic opioid use. CONCLUSION: A total of 9% of persons with knee OA use opioids chronically. Efforts to find nonopioid regimens for treating knee OA pain should be tailored to patients at high risk for chronic use.

Integrating science, technology, engineering, and math (STEM) and music: Putting the arts in science, technology, engineering, arts, and math (STEAM) through acoustics.

Music is an important part of education and most students are ardent fans. However, the students are not necessarily aware of the artistic and technical details it takes to create what they hear. These details are what necessitate music and technology coming together. Part of science, technology, engineering, and math (STEM) education should be to help students appreciate the practical applications that come from each of the entities in STEM, namely, science, technology, engineering, and math. Music provides the connection of these elements with a topic that interests the students and motivates their learning. This paper outlines ways for educators to integrate music with STEM topics and put the "A" in "STEAM" (science, technology, engineering, arts, and math).

Mid-Infrared Imaging Characterization to Differentiate Lung Cancer Subtypes.

Introduction: Lung cancer is the most common malignancy worldwide. Squamous cell carcinoma (SQ) and adenocarcinoma (LUAD) are the two most frequent histological subtypes. Small cell carcinoma (SCLC) subtype has the worst prognosis. Differential diagnosis is essential for proper oncological treatment. Life science associated mid- and near-infrared based microscopic techniques have been developed exponentially, especially in the past decade. Vibrational spectroscopy is a potential non-destructive approach to investigate malignancies. Aims: Our goal was to differentiate lung cancer subtypes by their label-free mid-infrared spectra using supervised multivariate analyses. Material and Methods: Formalin-fixed paraffin-embedded (FFPE) samples were selected from the archives. Three subtypes were selected for each group: 10-10 cases SQ, LUAD and SCLC. 2 µm thick sections were cut and laid on aluminium coated glass slides. Transflection optical setup was applied on Perkin-Elmer infrared microscope. 250 × 600 µm areas were imaged and the so-called mid-infrared fingerprint region (1800-648cm-1) was further analysed with linear discriminant analysis (LDA) and support vector machine (SVM) methods. Results: Both "patient-based" and "pixel-based" approaches were examined. Patient-based analysis by using 3 LDA models and 2 SVM models resulted in different separations. The higher the cut-off value the lower is the accuracy. The linear C-support vector classification (C-SVC) SVM resulted in the best (100%) accuracy for the three subtypes using a 50% cut-off value. The pixel-based analysis gave, similarly, the linear C-SVC SVM model to be the most efficient in the statistical indicators (SQ sensitivity 81.65%, LUAD sensitivity 82.89% and SCLC sensitivity 88.89%). The spectra cut-off, the kernel function and the algorithm function influence the accuracy. Conclusion: Mid-Infrared imaging could be used to differentiate FFPE lung cancer subtypes. Supervised multivariate tools are promising to accurately separate lung tumor subtypes. The long-term perspective is to develop a spectroscopy-based diagnostic tool, revolutionizing medical differential diagnostics, especially cancer identification.

Association of contralateral breast cancer risk with mammographic density defined at higher-than-conventional intensity thresholds.

Mammographic dense area (MDA) is an established predictor of future breast cancer risk. Recent studies have found that risk prediction might be improved by redefining MDA in effect at higher-than-conventional intensity thresholds. We assessed whether such higher-intensity MDA measures gave stronger prediction of subsequent contralateral breast cancer (CBC) risk using the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study, a population-based CBC case-control study of ≥1 year survivors of unilateral breast cancer diagnosed between 1990 and 2008. Three measures of MDA for the unaffected contralateral breast were made at the conventional intensity threshold ("Cumulus") and at two sequentially higher-intensity thresholds ("Altocumulus" and "Cirrocumulus") using the CUMULUS software and mammograms taken up to 3 years prior to the first breast cancer diagnosis. The measures were fitted separately and together in multivariable-adjusted logistic regression models of CBC (252 CBC cases and 271 unilateral breast cancer controls). The strongest association with CBC was MDA defined using the highest intensity threshold, Cirrocumulus (odds ratio per adjusted SD [OPERA] 1.40, 95% CI 1.13-1.73); and the weakest association was MDA defined at the conventional threshold, Cumulus (1.32, 95% CI 1.05-1.66). In a model fitting the three measures together, the association of CBC with Cirrocumulus was unchanged (1.40, 95% CI 0.97-2.05), and the lower brightness measures did not contribute to the CBC model fit. These results suggest that MDA defined at a high-intensity threshold is a better predictor of CBC risk and has the potential to improve CBC risk stratification beyond conventional MDA measures.

Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans.

Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.

Sex differences in the foraging behavior of a generalist hawkmoth.

Within-species variation in pollinator behavior is widely observed, but its causes have been minimally investigated. Pollinator sex is associated with large differences in behavior that may lead to predictable differences in flower foraging, but this expectation has not been explicitly tested. We investigate sex-associated differences in nectar-foraging behavior of the hawkmoth Hyles lineata, using pollen on the proboscis as a proxy for flower visitation. We tested two predictions emerging from the literature: (1) the sexes differ in the flower species they visit, (2) females are more specialized in flower choice. We also examined potential drivers underlying these predictions by performing field and laboratory experiments to test whether males (3) switch among flower species more frequently, or (4) fly farther and therefore encounter more species than females. Consistent with prediction (1), pollen load composition differed between the sexes, indicative of visitation differences. Contrary to prediction (2), females consistently carried more species-rich pollen loads than males. (3) Both sexes switched between flower species at similar rates, suggesting that differences in floral fidelity are unlikely to explain why females are less specialized than males. (4) Males flew longer distances than females; coupled with larger between-site differences in pollen composition for females, this result suggests that sex differences in mobility influence foraging, and that females may forage more frequently and in smaller areas than males. Together, our results demonstrate that sex-associated foraging differences can be large and consistent over time, and highlight the importance of sex as a driver of variation in pollinator behavior.