The Role of Tumor Stromal Discoidin Domain Receptor 2 (DDR2) in Breast Cancer Metastasis.

Characteristics of breast tumor stroma, including altered collagen architecture and increased stiffness, are known to contribute to tumor invasion and metastasis. However, the cellular and molecular mechanisms by which these changes occur are not fully understood. To address this question, we used a mouse genetic model to delete Discoidin Domain Receptor 2 (DDR2) from mouse tumor stromal cells and interrogated breast cancer associated fibroblasts (CAFs) to determine the molecular events downstream of DDR2 action that may lead to changes in the tumor extracellular matrix (ECM). Our work revealed that the action of DDR2 in breast stromal cells is required for tumor lung metastasis but does not affect tumor growth or latency. Interestingly, stromal DDR2 action led to lengthened, thickened, and straightened collagen fibers while also stiffening the tumor. Tumor stiffness was found to be greatest at the invasive front of the tumor, closest to the tumor/stromal boundary; this finding was obliterated in tumor stromas without DDR2. Selectively studying CAFs ex vivo, we found that DDR2 promotes increased cellular contraction and traction force. Super-resolution microscopy analysis of focal adhesion complexes in CAFs revealed that DDR2 collagen binding facilitates focal adhesion maturation and enhances integrin Ã1 activation through recruitment of Talin11. We also find that DDR2 regulates Rap1 activation, suggesting a mechanism by which Talin11 is activated downstream of DDR2 collagen binding. Taken together, these results identify DDR2 as a novel mechanosensing/mechanotransducing cell surface receptor that promotes tumor invasion and metastasis by acting in tumor stromal CAFs to control ECM remodeling, in part through regulation of integrin Ã1 activity via inside-out signaling

DDR2 controls breast tumor stiffness and metastasis by regulating integrin mediated mechanotransduction in CAFs

Biomechanical changes in the tumor microenvironment influence tumor progression and metastases. Collagen content and fiber organization within the tumor stroma are major contributors to biomechanical changes (e., tumor stiffness) and correlated with tumor aggressiveness and outcome. What signals and in what cells control collagen organization within the tumors, and how, is not fully understood. We show in mouse breast tumors that the action of the collagen receptor DDR2 in CAFs controls tumor stiffness by reorganizing collagen fibers specifically at the tumor-stromal boundary. These changes were associated with lung metastases. The action of DDR2 in mouse and human CAFs, and tumors in vivo, was found to influence mechanotransduction by controlling full collagen-binding integrin activation via Rap1-mediated Talin1 and Kindlin2 recruitment. The action of DDR2 in tumor CAFs is thus critical for remodeling collagen fibers at the tumor-stromal boundary to generate a physically permissive tumor microenvironment for tumor cell invasion and metastases

Neural circuits for the adaptive regulation of fear and extinction memory

The regulation of fear memories is critical for adaptive behaviors and dysregulation of these processes is implicated in trauma- and stress-related disorders. Treatments for these disorders include pharmacological interventions as well as exposure-based therapies, which rely upon extinction learning. Considerable attention has been directed toward elucidating the neural mechanisms underlying fear and extinction learning. In this review, we will discuss historic discoveries and emerging evidence on the neural mechanisms of the adaptive regulation of fear and extinction memories. We will focus on neural circuits regulating the acquisition and extinction of Pavlovian fear conditioning in rodent models, particularly the role of the medial prefrontal cortex and hippocampus in the contextual control of extinguished fear memories. We will also consider new work revealing an important role for the thalamic nucleus reuniens in the modulation of prefrontal-hippocampal interactions in extinction learning and memory. Finally, we will explore the effects of stress on this circuit and the clinical implications of these findings

A multicenter international prospective study of the validity and reliability of a COVID-19-specific health-related quality of life questionnaire

Purpose: To develop and validate a health-related quality of life (HRQoL) questionnaire for patients with current or previous coronavirus disease (COVID-19) in an international setting. Methods: This multicenter international methodology study followed standardized guidelines for a four-phase questionnaire development. Here, we report on the pretesting and validation of our international questionnaire. Adults with current or previous COVID-19, in institutions or at home were eligible. In the pretesting, 54 participants completed the questionnaire followed by interviews to identify administration problems and evaluate content validity. Thereafter, 371 participants completed the revised questionnaire and a debriefing form to allow preliminary psychometric analysis. Validity and reliability were assessed (correlation-based methods, Cronbach’s α, and intra-class correlation coefficient). Results: Eleven countries within and outside Europe enrolled patients. From the pretesting, 71 of the 80 original items fulfilled the criteria for item-retention. Most participants (80%) completed the revised 71-item questionnaire within 15 min, on paper (n = 175) or digitally (n = 196). The final questionnaire included 61 items that fulfilled criteria for item retention or were important to subgroups. Item-scale correlations were > 0.7 for all but nine items. Internal consistency (range 0.68–0.92) and test–retest results (all but one scale > 0.7) were acceptable. The instrument consists of 15 multi-item scales and six single items. Conclusion: The Oslo COVID-19 QLQ-W61© is an international, stand-alone, multidimensional HRQoL questionnaire that can assess the symptoms, functioning, and overall quality of life in COVID-19 patients. It is available for use in research and clinical practice. Further psychometric validation in larger patient samples will be performed.publishedVersio

The Effects of Hydraulic Fracturing on Childhood Cancer

Background/Objective: Cancer is the leading cause of death by disease among children, yet little is known about its risk factors. Exposure to hydraulic fracturing has been implicated in many health conditions, including childhood cancer. However, little is known about the relationship between hydraulic fracturing and childhood cancer in states with significant hydraulic fracturing activity. The objective of this study is to determine whether rates of childhood cancer are elevated in counties with hydraulic fracturing activity in Texas. Methods: Childhood cancer case data for individuals ages 0-19 diagnosed with CNS tumors, acute myeloid leukemia, acute lymphocytic leukemia, Ewing’s tumors, Hodgkin’s Lymphoma, or non-Hodgkin’s Lymphoma between 2010-2018 were obtained from the Texas Cancer Registry. County-level hydraulic fracturing data for 2010 were obtained from the Texas Railroad Commission. Average age-specific cancer rates were calculated for each of the cancer types of interest by five-year age group for 2010-2018. Standardized Incidence Ratios and 95% confidence intervals were calculated for each of these cancer types from 2014 to 2018 in relation to 2010 hydraulic fracturing activity. Results: Average age-specific cancer rates according to hydraulic fracturing exposure varied by cancer type. Cases of CNS tumors, Ewing’s tumors, leukemias, and lymphomas were higher than expected in counties without drilling activity (SIR=1.12, 95% CI: 0.99-1.26; SIR=1.31, 95% CI: 0.77-2.11; SIR=1.14, 95% CI: 1.00-1.30; SIR=1.07, 95% CI: 0.90-1.27; respectively). Cases of CNS tumors were higher than expected in counties with horizontal drilling activity (SIR=1.02, 95% CI: 0.95-1.09). In counties with other drilling activity, cases of leukemias and lymphomas were slightly but not statistically significantly elevated (SIR=1.01, 95% CI: 0.96-1.06; SIR=1.00, 95% CI: 0.94-1.07; respectively). Conclusion: This study did not find evidence of a relationship between elevated childhood cancer rates and hydraulic fracturing activity. Future research using individual-level data is needed to evaluate risk factors for childhood cancer. By gaining an understanding of the role that hydraulic fracturing exposure plays in childhood cancer development, evidence will be gathered that can inform future evaluations about the risks of childhood cancer, the leading cause of death by disease in children

Data from: Selection on parental performance opposes selection for larger body mass in a wild population of blue tits

There is abundant evidence in many taxa for positive directional selection on body size, and yet little evidence for microevolutionary change. In many species, variation in body size is partly determined by the actions of parents, so a proposed explanation for stasis is the presence of a negative genetic correlation between direct and parental effects. Consequently, selecting genes for increased body size would result in a correlated decline in parental effects, reducing body size in the following generation. We show that these arguments implicitly assume that parental care is cost free, and that including a cost alters the predicted genetic architectures needed to explain stasis. Using a large cross-fostered population of blue tits, we estimate direct selection on parental effects for body mass, and show it is negative. Negative selection is consistent with a cost to parental care, mainly acting through a reduction in current fecundity rather than survival. Under these conditions, evolutionary stasis is possible for moderately negative genetic correlations between direct and parental effects. This is in contrast to the implausibly extreme correlations needed when care is assumed to be cost free. Thus, we highlight the importance of accounting correctly for complete selection acting on traits across generations

Cancer-associated fibroblasts support vascular growth through mechanical force

Abstract The role of cancer-associated fibroblasts (CAFs) as regulators of tumor progression, specifically vascular growth, has only recently been described. CAFs are thought to be more mechanically active but how this trait may alter the tumor microenvironment is poorly understood. We hypothesized that enhanced mechanical activity of CAFs, as regulated by the Rho/ROCK pathway, contributes to increased blood vessel growth. Using a 3D in vitro tissue model of vasculogenesis, we observed increased vascularization in the presence of breast cancer CAFs compared to normal breast fibroblasts. Further studies indicated this phenomenon was not simply a result of enhanced soluble signaling factors, including vascular endothelial growth factor (VEGF), and that CAFs generated significantly larger deformations in 3D gels compared to normal fibroblasts. Inhibition of the mechanotransductive pathways abrogated the ability of CAFs to deform the matrix and suppressed vascularization. Finally, utilizing magnetic microbeads to mechanically stimulate mechanically-inhibited CAFs showed partial rescue of vascularization. Our studies demonstrate enhanced mechanical activity of CAFs may play a crucial and previously unappreciated role in the formation of tumor-associated vasculature which could possibly offer potential novel targets in future anti-cancer therapies

Cancer-associated fibroblasts support vascular growth through mechanical force.

The role of cancer-associated fibroblasts (CAFs) as regulators of tumor progression, specifically vascular growth, has only recently been described. CAFs are thought to be more mechanically active but how this trait may alter the tumor microenvironment is poorly understood. We hypothesized that enhanced mechanical activity of CAFs, as regulated by the Rho/ROCK pathway, contributes to increased blood vessel growth. Using a 3D in vitro tissue model of vasculogenesis, we observed increased vascularization in the presence of breast cancer CAFs compared to normal breast fibroblasts. Further studies indicated this phenomenon was not simply a result of enhanced soluble signaling factors, including vascular endothelial growth factor (VEGF), and that CAFs generated significantly larger deformations in 3D gels compared to normal fibroblasts. Inhibition of the mechanotransductive pathways abrogated the ability of CAFs to deform the matrix and suppressed vascularization. Finally, utilizing magnetic microbeads to mechanically stimulate mechanically-inhibited CAFs showed partial rescue of vascularization. Our studies demonstrate enhanced mechanical activity of CAFs may play a crucial and previously unappreciated role in the formation of tumor-associated vasculature which could possibly offer potential novel targets in future anti-cancer therapies

A Quasi-Experiment to Assess the Impact of a Scalable, Community-Based Weight Loss Program: Combining Reach, Effectiveness, and Cost

BACKGROUND: Primary care addresses obesity through physician oversight of intensive lifestyle interventions or referral to external programs with demonstrated efficacy. However, limited information exists on community program reach, effectiveness, and costs across different groups of participants. OBJECTIVE: To evaluate a scalable, community weight loss program using reach, effectiveness, and cost metrics. DESIGN: Longitudinal pre-post quasi-experiment without control. PARTICIPANTS: Enrolled participants in Weigh and Win (WAW), a community-based weight loss program. INTERVENTION: A 12-month program with daily social cognitive theory-based email and/or text support, online access to health coaches, objective weight assessment through 83 community-based kiosks, and modest financial incentives to increase program reach. MAIN MEASURES: Number of participants, representativeness, weight loss achievement (3%, 5% of initial weight lost), and cost of implementation. KEY RESULTS: A total of 40,308 adults (79% women; 73% white; BMI = 32.3 +/- 7.44, age = 43.9 +/- 13.1 years) enrolled in WAW. Women were more likely than men to enroll in the program and continue engagement beyond an initial weigh-in (57% vs. 53%). Based on census data, African Americans were over-represented in the sample. Among participants who engaged in the program beyond an initial weigh-in (n = 19,029), 47% and 34% of participants lost 3% and 5% of their initial body weight, respectively. The average duration for those who achieved 5% weight loss was 1.7 +/- 1.3 years. African American participants were more likely to achieve 5% weight loss and remain enrolled in the program longer compared to non-African American participants (2.0 +/- 1.3 vs. 1.6 +/- 1.2 years). Implementation costs were $2,822,698. Cost per clinically meaningful weight loss for African Americans ($257.97/3% loss; $335.96/5$318.62; $431.10) and Caucasians ($313.65; $441.87), due to the higher success rate of that subgroup of participants. CONCLUSIONS: Weigh and Win is a scalable technology-supported and community-based weight loss program that reaches a large number of participants and may contribute to reducing health disparities