Novel mammogram-based measures improve breast cancer risk prediction beyond an established mammographic density measure. Nguyen Tuong L,Schmidt Daniel F,Makalic Enes,Maskarinec Gertraud,Li Shuai,Dite Gillian S,Aung Ye K,Evans Christopher F,Trinh Ho N,Baglietto Laura,Stone Jennifer,Song Yun-Mi,Sung Joohon,MacInnis Robert J,Dugué Pierre-Antoine,Dowty James G,Jenkins Mark A,Milne Roger L,Southey Melissa C,Giles Graham G,Hopper John L International journal of cancer Mammograms contain information that predicts breast cancer risk. We developed two novel mammogram-based breast cancer risk measures based on image brightness (Cirrocumulus) and texture (Cirrus). Their risk prediction when fitted together, and with an established measure of conventional mammographic density (Cumulus), is not known. We used three studies consisting of: 168 interval cases and 498 matched controls; 422 screen-detected cases and 1197 matched controls; and 354 younger-diagnosis cases and 944 controls frequency-matched for age at mammogram. We conducted conditional and unconditional logistic regression analyses of individually- and frequency-matched studies, respectively. We estimated measure-specific risk gradients as the change in odds per standard deviation of controls after adjusting for age and body mass index (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). For interval, screen-detected and younger-diagnosis cancer risks, the best fitting models (OPERAs [95% confidence intervals]) involved: Cumulus (1.81 [1.41-2.31]) and Cirrus (1.72 [1.38-2.14]); Cirrus (1.49 [1.32-1.67]) and Cirrocumulus (1.16 [1.03 to 1.31]); and Cirrus (1.70 [1.48 to 1.94]) and Cirrocumulus (1.46 [1.27-1.68]), respectively. The AUCs were: 0.73 [0.68-0.77], 0.63 [0.60-0.66], and 0.72 [0.69-0.75], respectively. Combined, our new mammogram-based measures have twice the risk gradient for screen-detected and younger-diagnosis breast cancer (P ≤ 10 ), have at least the same discriminatory power as the current polygenic risk score, and are more correlated with causal factors than conventional mammographic density. Discovering more information about breast cancer risk from mammograms could help enable risk-based personalised breast screening. 10.1002/ijc.33396
    Similarities in Risk for COVID-19 and Cancer Disparities. Newman Lisa A,Winn Robert A,Carethers John M Clinical cancer research : an official journal of the American Association for Cancer Research Coronavirus disease 2019 (COVID-19) is a novel infectious disease that has spread worldwide. In the United States, COVID-19 disproportionately affects racial and ethnic minorities, particularly African Americans, with an observed 2-fold higher rate for hospitalization and greater than 2-fold higher rate for death as compared with White Americans. The disparity seen with COVID-19 is consistent with patterns of disparities observed for cancer; it is well documented that 5-year survival rates for multiple cancers are lower in African Americans compared with White Americans. Root cause contributions for the disparity overlap between COVID-19 and cancer. While cancer is a genetic disease that is influenced by tissue microenvironment, COVID-19 is an infectious disease that is enabled by cellular expression of angiotensin-converting enzyme 2 receptors. However, socioeconomic disadvantages, level of education, lifestyle factors, health comorbidities, and limited access to medical care appear to fuel underlying risk for both cancer and COVID-19 disparities. In addition to African Americans demonstrating higher risk of acquiring and dying from either disease, they are underrepresented in clinical trials involving cancer or COVID-19. Long-term disparities are present with survivorship from cancer and may be likely with survivorship from COVID-19; both have revealed untoward effects on postdiagnosis economic viability for African Americans. Collaborative strategies that include community engagement, diverse participation in cancer and COVID-19 clinical trials, providing insurance for affected persons who lost employment due to either disease, and supporting safety-net and public hospitals for health care access will be critical to stem these disparities. 10.1158/1078-0432.CCR-20-3421
    Cannabis vapor self-administration elicits sex- and dose-specific alterations in stress reactivity in rats. Glodosky Nicholas C,Cuttler Carrie,Freels Timothy G,Wright Hayden R,Rojas Manuel J,Baglot Samantha L,Hill Matthew N,McLaughlin Ryan J Neurobiology of stress Rationale:Cannabis users frequently report stress relief as their primary reason for use. Recent studies indicate that human cannabis users exhibit blunted stress reactivity; however, it is unknown whether this is a cause or a consequence of chronic cannabis use. Objectives:To determine whether chronic cannabis vapor self-administration elicits sex- and/or dose-dependent alterations in stress reactivity and basal corticosterone (CORT) concentrations, or whether pre-vapor exposure stress reactivity predicts rates of cannabis vapor self-administration. Methods:Male and female rats were subjected to 30 min acute restraint stress to assess stress reactivity prior to vapor self-administration. Rats were then trained to self-administer cannabis extract vapor containing 69.9% Δ-tetrahydrocannabinol (THC) at one of four extract concentrations (0, 75, 150, or 300 mg/ml) daily for 30 days. Half of the rats were then subjected to a second restraint stress challenge 24 h after the final self-administration session, while the other half served as no-stress controls. Plasma CORT concentrations were measured prior to stress and immediately post-stress offset. Results:Female rats earned significantly more vapor deliveries than male rats. Pre-vapor stress reactivity was not a predictor of self-administration rates in either sex. Basal CORT concentrations were increased following vapor self-administration relative to pre-vapor assessment, irrespective of treatment condition. Importantly, cannabis self-administration dose-dependently reduced stress reactivity in female, but not male, rats. Conclusions:These data indicate that chronic cannabis use can significantly dampen stress reactivity in female rats and further support the use of the cannabis vapor self-administration model in rats of both sexes. 10.1016/j.ynstr.2020.100260
    Neonatal AAV gene therapy rescues hearing in a mouse model of SYNE4 deafness. Taiber Shahar,Cohen Roie,Yizhar-Barnea Ofer,Sprinzak David,Holt Jeffrey R,Avraham Karen B EMBO molecular medicine Genetic variants account for approximately half the cases of congenital and early-onset deafness. Methods and technologies for viral delivery of genes into the inner ear have evolved over the past decade to render gene therapy a viable and attractive approach for treatment. Variants in SYNE4, encoding the protein nesprin-4, a member of the linker of nucleoskeleton and cytoskeleton (LINC), lead to DFNB76 human deafness. Syne4 mice have severe-to-profound progressive hearing loss and exhibit mislocalization of hair cell nuclei and hair cell degeneration. We used AAV9-PHP.B, a recently developed synthetic adeno-associated virus, to deliver the coding sequence of Syne4 into the inner ears of neonatal Syne4 mice. Here we report rescue of hair cell morphology and survival, nearly complete recovery of auditory function, and restoration of auditory-associated behaviors, without observed adverse effects. Uncertainties remain regarding the durability of the treatment and the time window for intervention in humans, but our results suggest that gene therapy has the potential to prevent hearing loss in humans with SYNE4 mutations. 10.15252/emmm.202013259
    Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis. Pastushenko Ievgenia,Mauri Federico,Song Yura,de Cock Florian,Meeusen Bob,Swedlund Benjamin,Impens Francis,Van Haver Delphi,Opitz Matthieu,Thery Manuel,Bareche Yacine,Lapouge Gaelle,Vermeersch Marjorie,Van Eycke Yves-Rémi,Balsat Cédric,Decaestecker Christine,Sokolow Youri,Hassid Sergio,Perez-Bustillo Alicia,Agreda-Moreno Beatriz,Rios-Buceta Luis,Jaen Pedro,Redondo Pedro,Sieira-Gil Ramon,Millan-Cayetano Jose F,Sanmatrtin Onofre,D'Haene Nicky,Moers Virginie,Rozzi Milena,Blondeau Jeremy,Lemaire Sophie,Scozzaro Samuel,Janssens Veerle,De Troya Magdalena,Dubois Christine,Pérez-Morga David,Salmon Isabelle,Sotiriou Christos,Helmbacher Francoise,Blanpain Cédric Nature FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers. However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation and progression are poorly understood. Here, using mouse models of skin squamous cell carcinoma and lung tumours, we found that deletion of Fat1 accelerates tumour initiation and malignant progression and promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype. We also found this hybrid EMT state in FAT1-mutated human squamous cell carcinomas. Skin squamous cell carcinomas in which Fat1 was deleted presented increased tumour stemness and spontaneous metastasis. We performed transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies, which revealed that loss of function of FAT1 activates a CAMK2-CD44-SRC axis that promotes YAP1 nuclear translocation and ZEB1 expression that stimulates the mesenchymal state. This loss of function also inactivates EZH2, promoting SOX2 expression, which sustains the epithelial state. Our comprehensive analysis identified drug resistance and vulnerabilities in FAT1-deficient tumours, which have important implications for cancer therapy. Our studies reveal that, in mouse and human squamous cell carcinoma, loss of function of FAT1 promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state. 10.1038/s41586-020-03046-1