Effectiveness of Community Education for Breast Cancer Screening.

OBJECTIVE: Screening based on individual risk factors results in detection of earlier, more curable breast cancer. There is expectation that improved public education about the importance of personalized screening will result in earlier diagnoses and reduced breast cancer mortality. The purpose of this study is to evaluate the effectiveness of community education on patient perceptions about risk-based screening. METHODS: This study is Health Insurance Portability and Accountability Act-compliant and institutional review board exempt. A standardized curriculum was used by radiologists and experts to conduct nine 1-hour patient education sessions between October 2018 and January 2019 about breast cancer risk factors and screening options. Patient participants completed voluntary, anonymous pre-event and post event surveys to determine if the presented educational program led to attitude changes. Survey results were summarized using statistical analysis including mean, median, range, and percentage of participants responding and comparison of pre- and post event fear and anxiety. RESULTS: Of 336 education session participants, 59.5% (200/336) completed the pre-event and 44.3% (149/336) completed the post event surveys, Respondents reported decreased anxiety and fear regarding breast cancer screening following educational sessions, with 36.1% (64/178) reporting anxiety pre-event compared to 23.3% (31/133) post event, although the difference was not statistically significant (P = .96). Additionally, 64.7% (55/85) of participants stated they were more likely to schedule breast cancer screening based on individual risk factors, and 98.0% (145/148) of participants reported increased knowledge on post event surveys. CONCLUSION: This study demonstrates the importance and effectiveness of community-based educational programs in increasing knowledge of risk-based screening and potentially reducing anxiety related to screening.

OXR1 maintains the retromer to delay brain aging under dietary restriction.

Dietary restriction (DR) delays aging, but the mechanism remains unclear. We identified polymorphisms in mtd, the fly homolog of OXR1, which influenced lifespan and mtd expression in response to DR. Knockdown in adulthood inhibited DR-mediated lifespan extension in female flies. We found that mtd/OXR1 expression declines with age and it interacts with the retromer, which regulates trafficking of proteins and lipids. Loss of mtd/OXR1 destabilized the retromer, causing improper protein trafficking and endolysosomal defects. Overexpression of retromer genes or pharmacological restabilization with R55 rescued lifespan and neurodegeneration in mtd-deficient flies and endolysosomal defects in fibroblasts from patients with lethal loss-of-function of OXR1 variants. Multi-omic analyses in flies and humans showed that decreased Mtd/OXR1 is associated with aging and neurological diseases. mtd/OXR1 overexpression rescued age-related visual decline and tauopathy in a fly model. Hence, OXR1 plays a conserved role in preserving retromer function and is critical for neuronal health and longevity.

Natural trait variation across Saccharomycotina species.

Among molecular biologists, the group of fungi called Saccharomycotina is famous for its yeasts. These yeasts in turn are famous for what they have in common-genetic, biochemical, and cell-biological characteristics that serve as models for plants and animals. But behind the apparent homogeneity of Saccharomycotina species lie a wealth of differences. In this review, we discuss traits that vary across the Saccharomycotina subphylum. We describe cases of bright pigmentation; a zoo of cell shapes; metabolic specialties; and species with unique rules of gene regulation. We discuss the genetics of this diversity and why it matters, including insights into basic evolutionary principles with relevance across Eukarya.

Stem cell transcriptional profiles from mouse subspecies reveal cis-regulatory evolution at translation genes.

A key goal of evolutionary genomics is to harness molecular data to draw inferences about selective forces that have acted on genomes. The field progresses in large part through the development of advanced molecular-evolution analysis methods. Here we explored the intersection between classical sequence-based tests for selection and an empirical expression-based approach, using stem cells from Mus musculus subspecies as a model. Using a test of directional, cis-regulatory evolution across genes in pathways, we discovered a unique program of induction of translation genes in stem cells of the Southeast Asian mouse M. m. castaneus relative to its sister taxa. As a complement, we used sequence analyses to find population-genomic signatures of selection in M. m. castaneus, at the upstream regions of the translation genes, including at transcription factor binding sites. We interpret our data under a model of changes in lineage-specific pressures across Mus musculus in stem cells with high translational capacity. Together, our findings underscore the rigor of integrating expression and sequence-based methods to generate hypotheses about evolutionary events from long ago.

Optimizing the Patient Experience in Breast Imaging Facilities: AJR Expert Panel Narrative Review.

Breast imaging studies are complex examinations for patients and providers. Breast imaging providers and organizations invest significant resources in educating patients and referring providers to address variability in changing breast cancer screening recommendations, cultural biases, and socioeconomic barriers for patients. The breast imaging examination frequently involves multiple imaging modalities including interventional procedures, thus requiring multiple room types. Practices need to consider variables that affect workflow efficiency throughout the process of scheduling, examination performance, interpretation, and results delivery, as well as options in facilities design to create inviting yet functional environments for patients. Breast imaging appointments provide opportunity to capture individual breast cancer risk and to engage patients in health education and breast screening awareness. This AJR Expert Panel Narrative Review discusses ways in which breast imaging facilities can optimize patient experience throughout the complex process of a breast imaging examination, based on the authors' observations and opinions that include private and academic breast imaging experience.

Systems biology and machine learning approaches identify metabolites that influence dietary lifespan and healthspan responses across flies and humans.

Dietary restriction (DR) is a potent method to enhance lifespan and healthspan, but individual responses are influenced by genetic variations. Understanding how metabolism-related genetic differences impact longevity and healthspan are unclear. To investigate this, we used metabolites as markers to reveal how different genotypes respond to diet to influence longevity and healthspan traits. We analyzed data from Drosophila Genetic Reference Panel strains raised under AL and DR conditions, combining metabolomic, phenotypic, and genome-wide information. Employing two computational methods across species-random forest modeling within the DGRP and Mendelian randomization in the UK Biobank-we pinpointed key traits with cross-species relevance that influence lifespan and healthspan. Notably, orotate was linked to parental age at death in humans and counteracted DR effects in flies, while threonine extended lifespan, in a strain- and sex-specific manner. Thus, utilizing natural genetic variation data from flies and humans, we employed a systems biology approach to elucidate potential therapeutic pathways and metabolomic targets for diet-dependent changes in lifespan and healthspan.

A natural variation-based screen in mouse cells reveals USF2 as a regulator of the DNA damage response and cellular senescence.

Cellular senescence is a program of cell cycle arrest, apoptosis resistance, and cytokine release induced by stress exposure in metazoan cells. Landmark studies in laboratory mice have characterized a number of master senescence regulators, including p16INK4a, p21, NF-κB, p53, and C/EBPß. To discover other molecular players in senescence, we developed a screening approach to harness the evolutionary divergence between mouse species. We found that primary cells from the Mediterranean mouse Mus spretus, when treated with DNA damage to induce senescence, produced less cytokine and had less-active lysosomes than cells from laboratory Mus musculus. We used allele-specific expression profiling to catalog senescence-dependent cis-regulatory variation between the species at thousands of genes. We then tested for correlation between these expression changes and interspecies sequence variants in the binding sites of transcription factors. Among the emergent candidate senescence regulators, we chose a little-studied cell cycle factor, upstream stimulatory factor 2 (USF2), for molecular validation. In acute irradiation experiments, cells lacking USF2 had compromised DNA damage repair and response. Longer-term senescent cultures without USF2 mounted an exaggerated senescence regulatory program-shutting down cell cycle and DNA repair pathways, and turning up cytokine expression, more avidly than wild-type. We interpret these findings under a model of pro-repair, anti-senescence regulatory function by USF2. Our study affords new insights into the mechanisms by which cells commit to senescence, and serves as a validated proof of concept for natural variation-based regulator screens.

Body composition and chemotherapy toxicity among women treated for breast cancer: a systematic review.

PURPOSE: Toxicity is a significant problem among women receiving systemic chemotherapy for breast cancer, with up to 60% experiencing hematologic and 14% experiencing non-hematologic toxicity. Chemotherapy is dosed using body surface area, which does not account for heterogeneity in lean body mass (LBM) and adipose tissue (AT). This systematic review, registered with the PROSPERO International Prospective Register of Systematic Reviews (#CRD42021279874), evaluates associations between body composition and chemotherapy-related toxicity during breast cancer treatment. METHODS: Scientific literature databases (PubMed, Scopus, CINAHL, and CENTRAL) were systematically searched in November 2021 for studies evaluating associations between body composition (assessed using computed tomography or dual x-ray absorptiometry) and chemotherapy-related toxicity among women receiving breast cancer treatment. Eligibility was not limited by year or country of publication. Article screening and data abstraction was conducted using the Covidence Systematic Review Management System. Predetermined criteria were used to evaluate rigor of participant recruitment, representativeness of the population, and use of validated measures of body composition and toxicity. RESULTS: An inverse association between LBM and toxicity was reported in seven of the eight included studies, although definitions of low LBM differed across studies. Three studies evaluated the association between AT and chemotherapy toxicity with inconsistent findings. Heterogeneity in body composition measures/definitions and treatment regimens precluded the ability to perform meta-analyses. CONCLUSION: Low LBM appears to be a risk factor for chemotherapy toxicity, but the role of AT is unclear. IMPLICATIONS FOR CANCER SURVIVORS: Further research that accounts for guideline concordance in chemotherapy prescriptions and the use of supportive care medications is needed.

Potassium-chelating drug sodium polystyrene sulfonate enhances lysosomal function and suppresses proteotoxicity.

Lysosomes are crucial for degradation and recycling of damaged proteins and cellular components. Therapeutic strategies enhancing lysosomal function are a promising approach for aging and age-related neurodegenerative diseases. Here, we show that an FDA approved drug sodium polystyrene sulfonate (SPS), used to reduce high blood potassium in humans, enhances lysosomal function both in C. elegans and in human neuronal cells. Enhanced lysosomal function following SPS treatment is accompanied by the suppression of proteotoxicity caused by expression of the neurotoxic peptides Aß and TAU. Additionally, treatment with SPS imparts health benefits as it significantly increases lifespan in C. elegans. Overall our work supports the potential use of SPS as a prospective geroprotective intervention.

Dissecting an ancient stress resistance trait syndrome in the compost yeast Kluyveromyces marxianus.

In the search to understand how evolution builds new traits, ancient events are often the hardest to dissect. Species-unique traits pose a particular challenge for geneticists-cases in which a character arose long ago and, in the modern day, is conserved within a species, distinguishing it from reproductively isolated relatives. In this work, we have developed the budding yeast genus Kluyveromyces as a model for mechanistic dissection of trait variation across species boundaries. Phenotypic profiling revealed robust heat and chemical-stress tolerance phenotypes that distinguished the compost yeast K. marxianus from the rest of the clade. We used culture-based, transcriptomic, and genetic approaches to characterize the metabolic requirements of the K. marxianus trait syndrome. We then generated a population-genomic resource for K. marxianus and harnessed it in molecular-evolution analyses, which found hundreds of housekeeping genes with evidence for adaptive protein variation unique to this species. Our data support a model in which, in the distant past, K. marxianus underwent a vastly complex remodeling of its proteome to achieve stress resistance. Such a polygenic architecture, involving nucleotide-level allelic variation on a massive scale, is consistent with theoretical models of the mechanisms of long-term adaptation, and suggests principles of broad relevance for interspecies trait genetics.

Genome Organization and Copy-Number Variation Reveal Clues to Virulence Evolution in Coccidioides posadasii.

The human fungal pathogen Coccidioides spp. causes valley fever, a treatment-refractory and sometimes deadly disease prevalent in arid regions of the western hemisphere. Fungal virulence in the mammalian host hinges on a switch between growth as hyphae and as large spherules containing infectious spores. How these virulence programs are encoded in the genome remains poorly understood. Drawing on Coccidioides genomic resources, we first discovered a new facet of genome organization in this system: spherule-gene islands, clusters of genes physically linked in the genome that exhibited specific mRNA induction in the spherule phase. Next, we surveyed copy-number variation genome-wide among strains of C. posadasii. Emerging from this catalog were spherule-gene islands with striking presence-absence differentiation between C. posadasii populations, a pattern expected from virulence factors subjected to different selective pressures across habitats. Finally, analyzing single-nucleotide differences across C. posadasii strains, we identified signatures of natural selection in spherule-expressed genes. Together, our data establish spherule-gene islands as candidate determinants of virulence and targets of selection in Coccidioides.

A role for worm cutl-24 in background- and parent-of-origin-dependent ER stress resistance.

BACKGROUND: Organisms in the wild can acquire disease- and stress-resistance traits that outstrip the programs endogenous to humans. Finding the molecular basis of such natural resistance characters is a key goal of evolutionary genetics. Standard statistical-genetic methods toward this end can perform poorly in organismal systems that lack high rates of meiotic recombination, like Caenorhabditis worms. RESULTS: Here we discovered unique ER stress resistance in a wild Kenyan C. elegans isolate, which in inter-strain crosses was passed by hermaphrodite mothers to hybrid offspring. We developed an unbiased version of the reciprocal hemizygosity test, RH-seq, to explore the genetics of this parent-of-origin-dependent phenotype. Among top-scoring gene candidates from a partial-coverage RH-seq screen, we focused on the neuronally-expressed, cuticlin-like gene cutl-24 for validation. In gene-disruption and controlled crossing experiments, we found that cutl-24 was required in Kenyan hermaphrodite mothers for ER stress tolerance in their inter-strain hybrid offspring; cutl-24 was also a contributor to the trait in purebred backgrounds. CONCLUSIONS: These data establish the Kenyan strain allele of cutl-24 as a determinant of a natural stress-resistant state, and they set a precedent for the dissection of natural trait diversity in invertebrate animals without the need for a panel of meiotic recombinants.

Correction: Genetic and metabolomic architecture of variation in diet restriction-mediated lifespan extension in Drosophila.

[This corrects the article DOI: 10.1371/journal.pgen.1008835.].

A fly GWAS for purine metabolites identifies human FAM214 homolog medusa, which acts in a conserved manner to enhance hyperuricemia-driven pathologies by modulating purine metabolism and the inflammatory response.

Elevated serum urate (hyperuricemia) promotes crystalline monosodium urate tissue deposits and gout, with associated inflammation and increased mortality. To identify modifiers of uric acid pathologies, we performed a fly Genome-Wide Association Study (GWAS) on purine metabolites using the Drosophila Genetic Reference Panel strains. We tested the candidate genes using the Drosophila melanogaster model of hyperuricemia and uric acid crystallization ("concretion formation") in the kidney-like Malpighian tubule. Medusa (mda) activity increased urate levels and inflammatory response programming. Conversely, whole-body mda knockdown decreased purine synthesis precursor phosphoribosyl pyrophosphate, uric acid, and guanosine levels; limited formation of aggregated uric acid concretions; and was sufficient to rescue lifespan reduction in the fly hyperuricemia and gout model. Levels of mda homolog FAM214A were elevated in inflammatory M1- and reduced in anti-inflammatory M2-differentiated mouse bone marrow macrophages, and influenced intracellular uric acid levels in human HepG2 transformed hepatocytes. In conclusion, mda/FAM214A acts in a conserved manner to regulate purine metabolism, promotes disease driven by hyperuricemia and associated tissue inflammation, and provides a potential novel target for uric acid-driven pathologies.

A chromosomal-level reference genome of the widely utilized Coccidioides posadasii laboratory strain "Silveira".

Coccidioidomycosis is a common fungal disease that is endemic to arid and semi-arid regions of both American continents. Coccidioides immitis and Coccidioides posadasii are the etiological agents of the disease, also known as Valley Fever. For several decades, the C. posadasii strain Silveira has been used widely in vaccine studies, is the source strain for production of diagnostic antigens, and is a widely used experimental strain for functional studies. In 2009, the genome was sequenced using Sanger sequencing technology, and a draft assembly and annotation were made available. In this study, the genome of the Silveira strain was sequenced using single molecule real-time sequencing PacBio technology, assembled into chromosomal-level contigs, genotyped, and the genome was reannotated using sophisticated and curated in silico tools. This high-quality genome sequencing effort has improved our understanding of chromosomal structure, gene set annotation, and lays the groundwork for identification of structural variants (e.g. transversions, translocations, and copy number variants), assessment of gene gain and loss, and comparison of transposable elements in future phylogenetic and population genomics studies.

Temperature-dependent genetics of thermotolerance between yeast species.

Many traits of industrial and basic biological interest arose long ago, and manifest now as fixed differences between a focal species and its reproductively isolated relatives. In these systems, extant individuals can hold clues to the mechanisms by which phenotypes evolved in their ancestors. We harnessed yeast thermotolerance as a test case for such molecular-genetic inferences. In viability experiments, we showed that extant Saccharomyces cerevisiae survived at temperatures where cultures of its sister species S. paradoxus died out. Then, focusing on loci that contribute to this difference, we found that the genetic mechanisms of high-temperature growth changed with temperature. We also uncovered an enrichment of low-frequency variants at thermotolerance loci in S. cerevisiae population sequences, suggestive of a history of non-neutral selective forces acting at these genes. We interpret these results in light of models of the evolutionary mechanisms by which the thermotolerance trait arose in the S. cerevisiae lineage. Together, our results and interpretation underscore the power of genetic approaches to explore how an ancient trait came to be.

Barcoded reciprocal hemizygosity analysis via sequencing illuminates the complex genetic basis of yeast thermotolerance.

Decades of successes in statistical genetics have revealed the molecular underpinnings of traits as they vary across individuals of a given species. But standard methods in the field cannot be applied to divergences between reproductively isolated taxa. Genome-wide reciprocal hemizygosity mapping (RH-seq), a mutagenesis screen in an interspecies hybrid background, holds promise as a method to accelerate the progress of interspecies genetics research. Here, we describe an improvement to RH-seq in which mutants harbor barcodes for cheap and straightforward sequencing after selection in a condition of interest. As a proof of concept for the new tool, we carried out genetic dissection of the difference in thermotolerance between two reproductively isolated budding yeast species. Experimental screening identified dozens of candidate loci at which variation between the species contributed to the thermotolerance trait. Hits were enriched for mitosis genes and other housekeeping factors, and among them were multiple loci with robust sequence signatures of positive selection. Together, these results shed new light on the mechanisms by which evolution solved the problems of cell survival and division at high temperature in the yeast clade, and they illustrate the power of the barcoded RH-seq approach.

Virtual Interviews for Breast Imaging Fellowship During the COVID-19 Pandemic: Perspectives of Program Directors and Applicants.

OBJECTIVE: To compare in-person and virtual breast fellowship interview experiences from the perspective of fellowship program directors (PDs) and applicants. METHODS: Three separate voluntary, anonymous, e-mail delivered surveys were developed for PDs, in-person interview applicants in 2019-2020, and virtual interview applicants in 2020-2021. PD and applicant survey responses regarding the two interview cycles were compared. RESULTS: The response rate was 56% (53/95) for PDs, 19% (23/123) for in-person applicants, and 38% (49/129) for virtual applicants. PDs reported significantly lower cost for virtual compared to in-person interviews (P < 0.001). They reported no significant difference in number of applications received, number of applicants interviewed, applicant pool geographic regions, number of interview days offered, or format of interviews. Most PDs (31/53, 58%) felt the virtual format still allowed them to get to know the applicants well. Cost was significantly higher for in-person compared to virtual applicants (P < 0.001). More in-person applicants (11/23, 48%) listed cost as a barrier compared to virtual applicants (7/49, 14%) (P = 0.002). Virtual and in-person applicants reported a similar number of program applications, but virtual applicants completed more interviews (P = 0.012). Both groups preferred scheduled time to speak with the current fellows and a one-on-one interview format with two to four faculty members. Most applicants (36/49, 73%) felt the virtual format still allowed them to get to know each program well. CONCLUSION: Virtual interviews provide a reasonable alternative to in-person interviews for breast imaging fellowship applicants, with decreased cost being the main advantage.

Multicenter Study of Whole Breast Stiffness Imaging by Ultrasound Tomography (SoftVue) for Characterization of Breast Tissues and Masses.

We evaluated whole breast stiffness imaging by SoftVue ultrasound tomography (UST), extracted from the bulk modulus, to volumetrically map differences in breast tissues and masses. A total 206 women with either palpable or mammographically/sonographically visible masses underwent UST scanning prior to biopsy as part of a prospective, HIPAA-compliant multicenter cohort study. The volumetric data sets comprised 298 masses (78 cancers, 105 fibroadenomas, 91 cysts and 24 other benign) in 239 breasts. All breast tissues were segmented into six categories, using sound speed to separate fat from fibroglandular tissues, and then subgrouped by stiffness into soft, intermediate and hard components. Ninety percent of women had mammographically dense breasts but only 11.2% of their total breast volume showed hard components while 69% of fibroglandular tissues were softer. All smaller masses (<1.5 cm) showed a greater percentage of hard components than their corresponding larger masses (p < 0.001). Cancers had significantly greater mean stiffness indices and lower mean homogeneity of stiffness than benign masses (p < 0.05). SoftVue stiffness imaging demonstrated small stiff masses, mainly due to cancers, amongst predominantly soft breast tissues. Quantitative stiffness mapping of the whole breast and underlying masses may have implications for screening of women with dense breasts, cancer risk evaluations, chemoprevention and treatment monitoring.

Current and Future Directions of Breast MRI.

Magnetic resonance imaging (MRI) is the most sensitive exam for detecting breast cancer. The American College of Radiology recommends women with 20% or greater lifetime risk of developing breast cancer be screened annually with MRI. However, other high-risk populations would also benefit. Hartmann et al. reported women with atypical hyperplasia have nearly a 30% incidence of breast cancer at 25-year follow-up. Women with dense breast tissue have up to a 4-fold increased risk of breast cancer when compared to average-risk women; their cancers are more likely to be mammographically occult. Because multiple cohorts of women are at high risk for developing breast cancer, there has been a movement to develop an abbreviated MRI (abMRI) protocol to expand the availability of MRI screening. Studies on abMRI effectiveness have been promising, with Weinstein et al. demonstrating a cancer detection rate of 27.4/1000 in women with dense breasts after a negative digital breast tomosynthesis. Breast MRI is also used to evaluate the extent of disease as part of preoperative assessment in women with newly diagnosed breast cancer, and to assess a patient's response to neoadjuvant chemotherapy. This paper aims to explore the current uses of MRI and propose future indications and directions.