Modulation of TRPV4 protects against degeneration induced by sustained loading and promotes matrix synthesis in the intervertebral disc.

While it is well known that mechanical signals can either promote or disrupt intervertebral disc (IVD) homeostasis, the molecular mechanisms for transducing mechanical stimuli are not fully understood. The transient receptor potential vanilloid 4 (TRPV4) ion channel activated in isolated IVD cells initiates extracellular matrix (ECM) gene expression, while TRPV4 ablation reduces cytokine production in response to circumferential stretching. However, the role of TRPV4 on ECM maintenance during tissue-level mechanical loading remains unknown. Using an organ culture model, we modulated TRPV4 function over both short- (hours) and long-term (days) and evaluated the IVDs' response. Activating TRPV4 with the agonist GSK101 resulted in a Ca2+ flux propagating across the cells within the IVD. Nuclear factor (NF)-κB signaling in the IVD peaked at 6 h following TRPV4 activation that subsequently resulted in higher interleukin (IL)-6 production at 7 days. These cellular responses were concomitant with the accumulation of glycosaminoglycans and increased hydration in the nucleus pulposus that culminated in higher stiffness of the IVD. Sustained compressive loading of the IVD resulted in elevated NF-κB activity, IL-6 and vascular endothelial growth factor A (VEGFA) production, and degenerative changes to the ECM. TRPV4 inhibition using GSK205 during loading mitigated the changes in inflammatory cytokines, protected against IVD degeneration, but could not prevent ECM disorganization due to mechanical damage in the annulus fibrosus. These results indicate TRPV4 plays an important role in both short- and long-term adaptations of the IVD to mechanical loading. The modulation of TRPV4 may be a possible therapeutic for preventing load-induced IVD degeneration.

Modifiable risk factors in women at high risk of breast cancer: a systematic review.

BACKGROUND: Modifiable risk factors (alcohol, smoking, obesity, hormone use, and physical activity) affect a woman's breast cancer (BC) risk. Whether these factors affect BC risk in women with inherited risk (family history, BRCA1/2 mutations, or familial cancer syndrome) remains unclear. METHODS: This review included studies on modifiable risk factors for BC in women with inherited risk. Pre-determined eligibility criteria were used and relevant data were extracted. RESULTS: The literature search resulted in 93 eligible studies. For women with family history, most studies indicated that modifiable risk factors had no association with BC and some indicated decreased (physical activity) or increased risk (hormonal contraception (HC)/menopausal hormone therapy (MHT), smoking, alcohol). For women with BRCA mutations, most studies reported no association between modifiable risk factors and BC; however, some observed increased (smoking, MHT/HC, body mass index (BMI)/weight) and decreased risk (alcohol, smoking, MHT/HC, BMI/weight, physical activity). However, measurements varied widely among studies, sample sizes were often small, and a limited number of studies existed. CONCLUSIONS: An increasing number of women will recognize their underlying inherited BC risk and seek to modify that risk. Due to heterogeneity and limited power of existing studies, further studies are needed to better understand how modifiable risk factors influence BC risk in women with inherited risk.

Repeated measures of mammographic density and texture to evaluate prediction and risk of breast cancer: a systematic review of the methods used in the literature.

PURPOSE: It may be important for women to have mammograms at different points in time to track changes in breast density, as fluctuations in breast density can affect breast cancer risk. This systematic review aimed to assess methods used to relate repeated mammographic images to breast cancer risk. METHODS: The databases including Medline (Ovid) 1946-, Embase.com 1947-, CINAHL Plus 1937-, Scopus 1823-, Cochrane Library (including CENTRAL), and Clinicaltrials.gov were searched through October 2021. Eligibility criteria included published articles in English describing the relationship of change in mammographic features with risk of breast cancer. Risk of bias was assessed using the Quality in Prognostic Studies tool. RESULTS: Twenty articles were included. The Breast Imaging Reporting and Data System and Cumulus were most commonly used for classifying mammographic density and automated assessment was used on more recent digital mammograms. Time between mammograms varied from 1 year to a median of 4.1, and only nine of the studies used more than two mammograms. Several studies showed that adding change of density or mammographic features improved model performance. Variation in risk of bias of studies was highest in prognostic factor measurement and study confounding. CONCLUSION: This review provided an updated overview and revealed research gaps in assessment of the use of texture features, risk prediction, and AUC. We provide recommendations for future studies using repeated measure methods for mammogram images to improve risk classification and risk prediction for women to tailor screening and prevention strategies to level of risk.

Studies of parenchymal texture added to mammographic breast density and risk of breast cancer: a systematic review of the methods used in the literature.

This systematic review aimed to assess the methods used to classify mammographic breast parenchymal features in relation to the prediction of future breast cancer. The databases including Medline (Ovid) 1946-, Embase.com 1947-, CINAHL Plus 1937-, Scopus 1823-, Cochrane Library (including CENTRAL), and Clinicaltrials.gov were searched through October 2021 to extract published articles in English describing the relationship of parenchymal texture features with the risk of breast cancer. Twenty-eight articles published since 2016 were included in the final review. The identification of parenchymal texture features varied from using a predefined list to machine-driven identification. A reduction in the number of features chosen for subsequent analysis in relation to cancer incidence then varied across statistical approaches and machine learning methods. The variation in approach and number of features identified for inclusion in analysis precluded generating a quantitative summary or meta-analysis of the value of these features to improve predicting risk of future breast cancers. This updated overview of the state of the art revealed research gaps; based on these, we provide recommendations for future studies using parenchymal features for mammogram images to make use of accumulating image data, and external validation of prediction models that extend to 5 and 10 years to guide clinical risk management. Following these recommendations could enhance the applicability of models, helping improve risk classification and risk prediction for women to tailor screening and prevention strategies to the level of risk.

The association of caregiver attitudes, information sources, and trust with HPV vaccine initiation among adolescents.

This study described caregiver attitudes and the information sources they access about HPV vaccination for adolescents and determined their influence on human papillomavirus (HPV) vaccination initiation. An online survey was administered to 1,016 adults in July 2021. Participants were eligible if they were the caregiver of a child aged 9-17 residing in Mississippi, Arkansas, Tennessee, Missouri, and select counties in Southern Illinois. Multivariate logistic regression was used to estimate the association of caregiver attitudes and information sources with HPV vaccination. Information from doctors or healthcare providers (87.4%) and internet sources other than social media (31.0%) were the most used sources for HPV vaccine information. The highest proportion of caregivers trusted their doctor or healthcare providers (92.4%) and family or friends (68.5%) as sources of information. The HPV vaccine series was more likely to be initiated in children whose caregivers agreed that the vaccine is beneficial (AOR = 4.39, 95% CI = 2.05, 9.39), but less likely with caregivers who were concerned about side effects (AOR = 0.61, 95% CI = 0.42, 0.88) and who received HPV vaccination information from family or friends (AOR = 0.57, 95% CI = 0.35, 0.93). This study found that caregivers' attitudes, information sources, and trust in those sources were associated with their adolescent's HPV vaccination status. These findings highlight the need to address attitudes and information sources and suggest that tailored interventions considering these factors could increase HPV vaccination rates.

Strategies to Achieve Breast Health Equity in the St. Louis Region and Beyond over 15+ Years.

Community-based participatory strategies are a promising approach to addressing disparities in community health outcomes. This paper details the efforts of Siteman Cancer Center to achieve breast health equity over the past 15+ years. We begin by describing the activities and successes arising from our breast health community partnerships including identifying priorities, developing recommendations, and implementing patient navigation services to advance breast health. This system-wide coordinated navigation approach that includes primary and specialty care providers helped to increase potential impact on reducing breast health disparities by expediting care, increasing care efficiency, and standardizing referral procedures across systems for all women including those who are uninsured and underinsured. We also discuss a mobile mammography unit that has been deployed to serve women living in both urban and rural regions. The van reached a particularly vulnerable population that was mostly poor, uninsured, and with limited educational backgrounds regardless of their zip code of service. This work shows that collaborations between academic and community partners have resulted in decreased late stage at diagnosis and improved access to mammography. Furthermore, we offer lessons learned and recommendations that may be applicable to other communities.