Metastasis is the leading cause of cancer-related death and drives patient morbidity as well as healthcare costs. Bone is the primary site of metastasis for several cancers—breast and prostate cancers in particular. Efforts to treat bone metastases have been stymied by a lack of models to study the progression, cellular players, and signaling pathways driving bone metastasis. In this review, we examine newly described and classic models of bone metastasis. Through the use of current in vivo, microfluidic, and in silico computational bone metastasis models we may eventually understand how cells escape the primary tumor and how these circulating tumor cells then home to and colonize the bone marrow. Further, future models may uncover how cells enter and then escape dormancy to develop into overt metastases. Recreating the metastatic process will lead to the discovery of therapeutic targets for disrupting and treating bone metastasis.

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Metastasis is the leading cause of cancer-related death and drives patient morbidity as well as 13 healthcare costs. For several cancers, breast and prostate in particular, bone is the primary site of 14 metastasis. Efforts to treat bone metastases have been stymied by a lack of models to study the 15 progression and cellular players and signaling pathways driving bone metastasis. In this review, we 16 examine the newly described and classic models of bone metastasis. Through the use of current in vivo, 17 microfluidic and in silico computational models bone metastasis models we may eventually understand 18 how cells escape the primary tumor and how these circulating tumor cells then home to and colonize 19 the bone marrow. Further, future models may uncover how cell enter and escape dormancy to develop 20 into overt metastases. Recreating the metastatic process will lead to the discovery of therapeutic targets 21 for disrupting and treating bone metastasis. 22Keywords: bone metastasis, tissue engineering, mesenchymal stem cells, osteoclast, osteoblast, 23 dormancy, mouse models, circulating tumor cell 24 25 Introduction 26Bone is a common site of metastatic cancer, with an estimated 280,000 adults in the United States 27 suffering from metastatic bone disease.[1] The cancers that most commonly metastasize to bone are 28 prostate and breast cancer, which are also two of the most common cancers in the United States. [2][3][4] 29 Additionally, lung, thyroid, and kidney primary tumors are reported to metastasize to bone, albeit less 30 frequently.[2] These bone lesions cause serious skeletal complications, including spinal cord or nerve root 31 compression, hypercalcemia of malignancy, pathologic fractures, and debilitating bone pain.[1] 32 Furthermore, the median survival after a diagnosis of overt skeletal metastases is approximately 2-3 33 years.[4,5] These aforementioned facts illustrate the clinical importance of preventing or curing bone 34 metastasis. Despite this, current treatment options for patients with bone metastases are seldom curative, 35 and are instead mostly palliative.[2] Further, metastatic bone disease poses a significant burden on the 36 healthcare economy. Accordingly, Schulman et al. [6] estimated care for patients with bone metastases 37 cost the United States thirteen billion dollars in 2005 alone. With the current emphasis on decreasing 38 healthcare expenditure, a significant step towards a curative and/or preventive treatment for bone 39 metastases would undoubtedly address a clinical and economic problem in one fell swoop.40The largest barrier to clinical translation in bone metastasis research is the lack of an appropriate in 41 vivo animal model. [7][8][9] This lack is due to several factors, the most glaring being our incomplete 42 Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 23understanding of the complex pathophysiological mechanisms at play during bone metastasis. [2,8] 43Increased knowledge of cancer cell osteotropism would be the foundation for the developmen...

National rates of obesity and severe obesity continue to increase among children, with over 35% of children being overweight or obese in 2016 (1). Currently, one in three children in the United States is obese or overweight; this predisposes them to obesity-related comorbidities that often persist into adulthood (2), in addition to comorbidities during childhood such as hypertension or diabetes (3). Cardiovascular disease risk factors include abnormal levels of triglycerides, LDL, HDL, fasting insulin, and elevated systolic or diastolic blood pressure (4). Although only 5% of children with body mass index (BMI) <25 percentile for age have two or more risk factors, that proportion increases to 59% for children with BMI >99 percentile (4). Although some programs have demonstrated varying levels of success treating obesity in children ( 5), it is a difficult task to accomplish. There are many underlying factors associated with childhood obesity that are difficult to address in a clinical setting: income level, lack of access to healthy foods, and genetic predisposition ( 6).Among all age-groups, the majority of individuals with obesity identify as ethnic or racial minority and/or low socioeconomic status (7). Racial and ethnic minority groups are defined as people who differ in race or cultural origin from the majority population, which is Caucasian in the United States. Children of ethnic and racial minority backgrounds have obesity at a disproportionate rate compared with their White counterparts (8). Disparities can be linked to lower parental education, increased stress, and lack of accessibility to healthy foods as well as safe locations for activities (9). One study analyzing the effect of structural racism on food availability states that non-Latinx/Hispanic Blacks and Latinx/Hispanics were at least twice as likely to be food insecure compared with non-Latinx/Hispanic Whites (10). Associations have also been made between having food insecurity and obesity (10). Addressing disparities in clinical settings is difficult but should be accounted; interventions that aim to modify lifestyle factors such as physical activity (PA) should account for these factors.Only one-third of children meet the recommended moderate to vigorous PA goal of 60 min•d −1 . PA is defined as movements or activities requiring physical effort, which leads to improved health and fitness. Addressing the childhood obesity epidemic necessitates intervention to improve PA levels (11), which may be difficult in racial and ethnic minority populations because of disparities in social determinants of health, such as unsafe neighborhoods, built environment, and income, resulting in less potential for PA near a child's home (12). Parental