Changes in epithelial proportions and transcriptional state underlie major premenopausal breast cancer risks

The human breast undergoes lifelong remodeling in response to estrogen and progesterone, but hormone exposure also increases breast cancer risk. Here, we use single-cell analysis to identify distinct mechanisms through which breast composition and cell state affect hormone signaling. We show that prior pregnancy reduces the transcriptional response of hormone-responsive (HR+) epithelial cells, whereas high body mass index (BMI) reduces overall HR+ cell proportions. These distinct changes both impact neighboring cells by effectively reducing the magnitude of paracrine signals originating from HR+ cells. Because pregnancy and high BMI are known to protect against hormone-dependent breast cancer in premenopausal women, our findings directly link breast cancer risk with person-to-person heterogeneity in hormone responsiveness. More broadly, our findings illustrate how cell proportions and cell state can collectively impact cell communities through the action of cell-to-cell signaling networks

Impact of Patient Demographic Factors on Preoperative Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function, Pain Interference, and Depression Computer Adaptive Testing Scores in Patients Undergoing Shoulder and Elbow Surgery

Background: There has been a growing emphasis in orthopaedics on providing patient-centered care. The US National Institutes of Health launched the Patient-Reported Outcomes Measurement Information System (PROMIS) initiative that incorporates patient-reported outcome measures across a number of medical domains. The relationship between PROMIS domains and the impact of patient demographic factors in those undergoing upper extremity surgery remains unclear. Purpose/Hypothesis: The goal of this study was to investigate the correlation between physical function, pain interference, and depression in patients undergoing shoulder and elbow surgery as measured by PROMIS computer adaptive testing (CAT) forms and to determine the impact of patient demographic factors. We hypothesized that there would be a significant negative correlation between physical function and both pain interference and depression in this patient population. Study Design: Cross-sectional study; Level of evidence, 3. Methods: All patients who underwent elective shoulder or elbow surgery by 3 shoulder, elbow, and/or sports medicine fellowship–trained orthopaedic surgeons were included in the study. Preoperative PROMIS–Upper Extremity (PROMIS-UE), PROMIS–Pain Interference (PROMIS-PI), and PROMIS-Depression (PROMIS-D) CAT scores were analyzed. Pearson correlations were calculated between PROMIS domains as well as between PROMIS outcomes with patient demographic factors. Results: Preoperative PROMIS CAT scores for all 3 domains were collected and analyzed from 172 unique patients (516 individual CAT forms) with shoulder and elbow injuries. A negative correlation of moderate strength was found between the PROMIS-UE and PROMIS-PI (R = –0.61; P \u3c.001), and a negligible correlation was found between the PROMIS-UE and PROMIS-D (R = –0.28; P \u3c.001). When stratified by patient demographic factors, the correlation between the PROMIS-UE and PROMIS-PI was stronger in female patients compared with male patients (R = –0.77 vs –0.46, respectively; P \u3c.001 for both), stronger in black patients compared with white patients (R = –0.72 vs –0.56, respectively; P \u3c.001 for both), and highest in current tobacco users (R = –0.80; P \u3c.001). Conclusion: Before shoulder and elbow surgery, patients demonstrated impairments in physical function and pain interference as measured by CAT forms, with a moderate negative correlation between baseline upper extremity physical function and pain interference scores. In certain subpopulations, such as female patients, black patients, and current tobacco users, the correlations between these tested domains were stronger than in other groups

The Effects of Momentary Visual Disruption on Hazard Anticipation in Driving

Driver distraction is known to increase crashes, especially when the driver glances for especially long periods of time inside the vehicle. While it is clear that such glances increase risk for the driver when looking inside the vehicle, it is less clear how these glances disrupt the ongoing processing of information outside the vehicle once the eyes return to the road. The present study was aimed at exploring the effect of visual disruptions on the top-down processes that guide the detection and monitoring of hazards on the forward roadway. Using a driving simulator, twelve participants were monitored with an eye tracking system while they navigated various hazardous scenarios. Six participants were momentarily interrupted by a visual secondary task (simulating a glance inside the vehicle) prior to the hazard occurrence and six were not. Eye movement analyses show that interrupted drivers often failed to continue scanning for a hazard when their forward view reappeared. Implications of this study are discussed

Satb1 overexpression drives tumor-promoting activities in cancer-associated dendritic cells

Special AT-rich sequence-binding protein 1 (Satb1) governs genome-wide transcriptional programs. Using a conditional knockout mouse, we find that Satb1 is required for normal differentiation of conventional dendritic cells (DCs). Furthermore, Satb1 governs the differentiation of inflammatory DCs by regulating major histocompatibility complex class II (MHC II) expression through Notch1 signaling. Mechanistically, Satb1 binds to the Notch1 promoter, activating Notch expression and driving RBPJ occupancy of the H2-Ab1 promoter, which activates MHC II transcription. However, tumor-driven, unremitting expression of Satb1 in activated Zbtb46(+) inflammatory DCs that infiltrate ovarian tumors results in an immunosuppressive phenotype characterized by increased secretion of tumor-promoting Galectin-1 and IL-6. In vivo silencing of Satb1 in tumor-associated DCs reverses their tumorigenic activity and boosts protective immunity. Therefore, dynamic fluctuations in Satb1 expression govern the generation and immunostimulatory activity of steady-state and inflammatory DCs, but continuous Satb1 overexpression in differentiated DCs converts them into tolerogenic/pro-inflammatory cells that contribute to malignant progression.Fil: Tesone, Amelia J.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Rutkowski, Melanie R.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Brencicova, Eva. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Svoronos, Nikolaos. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Perales Puchal, Alfredo. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Stephen, Tom L.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Allegrezza, Michael J.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Payne, Kyle K.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Nguyen, Jenny M.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Wickramasinghe, Jayamanna. The Wistar Institute. Center for Systems and Computational Biology; Estados UnidosFil: Tchou, Julia. University of Pennsylvania; Estados UnidosFil: Borowsky, Mark E.. Christiana Care Health System. Helen F. Graham Cancer Center; Estados UnidosFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Kossenkov, Andrew V.. The Wistar Institute. Center for Systems and Computational Biology; Estados UnidosFil: Conejo Garcia, José R.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados Unido

Cryptic Variation in Morphological Evolution: HSP90 as a Capacitor for Loss of Eyes in Cavefish

In the process of morphological evolution, the extent to which cryptic, preexisting variation provides a substrate for natural selection has been controversial. We provide evidence that heat shock protein 90 (HSP90) phenotypically masks standing eye-size variation in surface populations of the cavefish Astyanax mexicanus. This variation is exposed by HSP90 inhibition and can be selected for, ultimately yielding a reduced-eye phenotype even in the presence of full HSP90 activity. Raising surface fish under conditions found in caves taxes the HSP90 system, unmasking the same phenotypic variation as does direct inhibition of HSP90. These results suggest that cryptic variation played a role in the evolution of eye loss in cavefish and provide the first evidence for HSP90 as a capacitor for morphological evolution in a natural setting