Purpose: Tumor progression has been linked to stiffening of the extracellular matrix caused by fibrosis. Cancer cells can be mechanically conditioned by stiff extracellular matrix, exhibiting a 1,004-gene signature [mechanical conditioning (MeCo) score]. Nintedanib has demonstrated antifibrotic activity in idiopathic pulmonary fibrosis. This study explores nintedanib’s antifibrotic effect on breast cancer outcomes. Experimental Design: We present long-term follow-up and analysis of a neoadjuvant randomized phase II trial in early HER2-negative breast cancer. Patients (N = 130) underwent a baseline biopsy and received 12 paclitaxel courses alone (control arm) or in combination with nintedanib (experimental arm). The tumor MeCo score was determined by RNA sequencing. The primary aim was to assess nintedanib’s impact on event-free survival based on MeCo scores. Results: Follow-up data were retrieved from 111 patients; 75 baseline and 24 post-run-in phase samples were sequenced. After median follow-up of 9.67 years, median event-free survival was not statistically different between arms (P = 0.37). However, in the control arm, high- versus low-MeCo patients had a statistically higher relapse risk: HR = 0.21; P = 0.0075. This risk was corrected by nintedanib in the experimental arm: HR = 0.37; P = 0.16. Nintedanib demonstrated pharmacodynamic engagement, reducing the MeCo score by 25% during the run-in phase (P < 0.01). Patients with low MeCo after run-in had the best long-term prognosis (HR = 0.087; P = 0.03). Conclusions: High MeCo is predictive of poor outcomes in HER2-negative early breast cancer, although this risk can be mitigated by nintedanib, which is able to specifically reduce MeCo.

Purpose: Endometrial cancer is highly prevalent and lacking noninvasive diagnostic techniques. Diagnosis depends on histological investigation of biopsy samples. Serum biomarkers for endometrial cancer have lacked sensitivity and specificity. The objective of this study was to investigate the cervicovaginal environment to improve the understanding of metabolic reprogramming related to endometrial cancer and identify potential biomarker candidates for noninvasive diagnostic and prognostic tests. Experimental Design: Cervicovaginal lavages were collected from 192 participants with endometrial cancer (n = 66) and non-malignant conditions (n = 108), and global untargeted metabolomics was performed. Using the metabolite data (n = 920), we completed a multivariate biomarker discovery analysis. Results: We analyzed grade 1/2 endometrioid carcinoma (n = 53) and other endometrial cancer subtypes (n = 13) to identify shared and unique metabolic signatures between the subtypes. When compared to non-malignant conditions, downregulation of proline (P < 0.0001), tryptophan (P < 0.0001), and glutamate (P < 0.0001) was found among both endometrial cancer groups, relating to key hallmarks of cancer including immune suppression and redox balance. Upregulation (q < 0.05) of sphingolipids, fatty acids, and glycerophospholipids was observed in endometrial cancer in a type-specific manner. Furthermore, cervicovaginal metabolites related to tumor characteristics, including tumor size and myometrial invasion. Conclusions: Our findings provide insights into understanding the endometrial cancer metabolic landscape and improvement in diagnosis. The metabolic dysregulation described in this article linked specific metabolites and pathophysiological mechanisms including cellular proliferation, energy supply, and invasion of neighboring tissues. Furthermore, cervicovaginal metabolite levels related to tumor characteristics, which are used for risk stratification. Overall, development of noninvasive diagnostics can improve both the acceptability and accessibility of diagnosis.

The National Diabetes Prevention Program (DPP) promotes lifestyle changes to prevent diabetes. However, only one‐third of DPP participants achieve weight loss goals, and changes in diet are limited. Continuous glucose monitoring (CGM) has shown potential to raise awareness about the effects of diet and activity on glucose among people with diabetes, yet the feasibility of including CGM in behavioral interventions for people with prediabetes has not been explored. This study assessed the feasibility of adding a brief CGM intervention to the Arizona Cooperative Extension National DPP. Extension DPP participants were invited to participate in a single CGM‐based education session and subsequent 10‐day CGM wear period, during which participants reflected on diet and physical activity behaviors occurring prior to and after hyperglycemic events. Following the intervention, participants completed a CGM acceptability survey and participated in a focus group reflecting on facilitators and barriers to CGM use and its utility as a behavior change tool. A priori feasibility benchmarks included opt‐in participation rates ≥ 50%, education session attendance ≥ 80%, acceptability scores ≥ 80%, and greater advantages than disadvantages of CGM emerging from focus groups, as analyzed using the Key Point Summary (KPS) method. Thirty‐five DPP members were invited to participate; 27 (77%) consented, and 24 of 27 (89%) attended the brief CGM education session. Median survey scores indicated high acceptability of CGM (median = 5, range = 1–5), with nearly all (n = 23/24, 96%) participants believing that CGM should be offered as part of the DPP. In focus groups, participants described how CGM helped them make behavior changes to improve their glucose (e.g., reduced portion sizes, increased activity around eating events, and meditation). In conclusion, adding a single CGM‐based education session and 10‐day CGM wear to the DPP was feasible and acceptable. Future research will establish the efficacy of adding CGM to the DPP on participant health outcomes and behaviors.

Dendritic spines are the postsynaptic compartment of a neuronal synapse and are critical for synaptic connectivity and plasticity. A developmental precursor to dendritic spines, dendritic filopodia (DF), facilitate synapse formation by sampling the environment for suitable axon partners during neurodevelopment and learning. Despite the significance of the actin cytoskeleton in driving these dynamic protrusions, the actin elongation factors involved are not well characterized. We identified the Ena/VASP protein EVL as uniquely required for the morphogenesis and dynamics of DF. Using a combination of genetic and optogenetic manipulations, we demonstrated that EVL promotes protrusive motility through membrane-direct actin polymerization at DF tips. EVL forms a complex at nascent protrusions and DF tips with MIM/MTSS1, an I-BAR protein important for the initiation of DF. We proposed a model in which EVL cooperates with MIM to coalesce and elongate branched actin filaments, establishing the dynamic lamellipodia-like architecture of DF.

Vaginal dysbiosis is implicated in persistent human papillomavirus (HPV) infection and cervical cancer. Yet, there is a paucity of data on the vaginal microbiome in Native American communities. Here, we aimed to elucidate the relationships between microbiome, HPV, sociodemographic, and behavioral risk factors to better understand an increased cervical cancer risk in Native American women. In this pilot study, we recruited 31 participants (16 Native American and 15 non-Native women) in Northern Arizona and examined vaginal microbiota composition, HPV status, and immune mediators. We also assessed individuals’ sociodemographic information and physical, mental, sexual, and reproductive health. Overall, microbiota profiles were dominated by common Lactobacillus species (associated with vaginal health) or a mixture of bacterial vaginosis–associated bacteria. Only 44% of Native women exhibited Lactobacillus dominance, compared with 58% of non-Native women. Women with vaginal dysbiosis also had elevated vaginal pH and were more frequently infected with high-risk HPV. Furthermore, we observed associations of multiple people in a household, lower level of education, and high parity with vaginal dysbiosis and abundance of specific bacterial species. Finally, women with dysbiotic microbiota presented with elevated vaginal levels of proinflammatory cytokines. Altogether, these findings indicate an interplay between HPV, vaginal microbiota, and host defense, which may play a role in the cervical cancer disparity among Native American women. Future longitudinal studies are needed to determine the mechanistic role of vaginal microbiota in HPV persistence in the context of social determinants of health toward the long-term goal of reducing health disparities between non-Hispanic White and Native American populations. Prevention Relevance: Cervical cancer disproportionally affects Native American women. Sociodemographic and behavioral factors might contribute to this disparity via alteration of vaginal microbiota. Here, we show the association between these factors and vaginal dysbiosis and immune activation, which can be implicated in high-risk HPV infection among Native American and other racial/ethnic populations.

Intermittent sun exposure is the major environmental risk factor for cutaneous melanoma (CM). Cumulative sun exposure and other environmental agents, such as environmental arsenic exposure, have not shown consistent associations. Ambient ultraviolet radiation (UVR) was used to measure individual total sun exposure as this is thought to be less prone to misclassification and recall bias. Data were analyzed from 1096 CM cases and 1033 controls in the Iowa Study of Skin Cancer and Its Causes, a population-based, case-control study. Self-reported residential histories were linked to satellite-derived ambient UVR, spatially derived environmental soil arsenic concentration, and drinking water arsenic concentrations. In men and women, ambient UVR during childhood and adolescence was not associated with CM but was positively associated during adulthood. Lifetime ambient UVR was positively associated with CM in men (OR for highest vs. lowest quartile: 6.09, 95% confidence interval (CI) 2.21–16.8), but this association was not as strong among women (OR for highest vs. lowest quartile: 2.15, 95% CI 0.84–5.54). No association was detected for environmental soil or drinking water arsenic concentrations and CM. Our findings suggest that lifetime and adulthood sun exposures may be important risk factors for CM.