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Background Little is known about the pathways linking parent feeding practices with appetitive traits and BMIz throughout infancy. This study examined bidirectional associations between parental feeding practices, infant appetitive traits, and infant BMIz. Methods Parents (n = 380) of infants aged less than 6 months at baseline reported their feeding practices (using the Feeding Practices and Structure Questionnaire (FPSQ) for infants and toddlers), infant appetitive traits (using the Baby Eating Behaviour Questionnaire) and infant BMIz (parent-reported) at three timepoints ( Results There was strong continuity across the three timepoints for maternal feeding practices, infant appetitive traits, and infant BMIz. Infant food avoidance was prospectively associated with higher parental persuasive feeding. Infant BMIz was prospectively associated with higher parent-led feeding. Parent use of food to calm was prospectively associated with lower infant BMIz, and infant BMIz was prospectively associated with higher infant food approach. Feeding on demand was prospectively associated with lower infant food approach. Conclusion This study highlights the complex associations between parental feeding practices, infant appetitive traits and infant BMIz. The study demonstrated that both child and parent effects are important, suggesting a need for tailored programs beginning in infancy to promote and support infant appetitive traits and parent feeding practices that support healthy development.

OBJECTIVE: To examine the sources and timing of advice formula feeding parents receive and how this and other factors influence the choice of formula product and formula preparation. DESIGN: Components of a cross-sectional survey. SETTING: A child and family health service in New South Wales, Australia. PARTICIPANTS: Parents (n = 153) who were fully or partially formula feeding infants aged 0-6 months and who visited the service's facilities or its social media site. VARIABLES MEASURED: Type of formula, preparation of formula, and use and sources of formula feeding advice. ANALYSIS: Descriptive statistics, Mann-Whitney U or Pearson's chi-square tests, and inductive content analysis. RESULTS: The most common source of formula feeding advice was the formula tin/packet (96.6%). Although 79.2% received advice from a health professional, only 18.9% reported receiving this advice before using formula. Approximately half (48.0%) of the parents chose a standard cow's milk-based formula. The most common reason for their choice of formula type/brand was a personal recommendation (53.0%). Parents' responses indicated that nearly half (46.3%) incorrectly prepared the formula. CONCLUSION AND IMPLICATIONS: Although health professional advice was widely received, this was rarely before starting formula. Despite the current national infant feeding regulations, parents who were not exclusively breastfeeding their infants did not always receive timely, health professional advice about formula feeding.

Background: Examining appetitive traits with person-centered analytical approaches can advance the understanding of appetitive phenotype trajectories across infancy, their origins, and influences upon them. The objective of the present study was to empirically describe appetitive phenotype trajectories in infancy and examine the associations with infant and parent factors.Materials and Methods: In this longitudinal cohort study of Australian infants, parents completed three online surveys ~3 months apart, beginning when the infant was z-score. Group-based trajectory modeling identified appetitive phenotype trajectories using the BEBQ. Multilevel modeling examined change in feeding practices and child BMI z-score over time by appetitive phenotype trajectories.Results: At time 1, 380 participants completed the survey (mean infant age 98 days), 178 at time 2 (mean infant age 198 days), and 154 at time 3 (mean infant age 303 days). Three multi-trajectory appetitive phenotype groups were identified and labeled as (Phenotype 1) food avoidant trending toward low food approach (21.32% of infants), (Phenotype 2) persistently balanced (50.53% of infants), and (Phenotype 3) high and continuing food approach (28.16% of infants). Formula feeding was more common in Phenotype 1 (p = 0.016). Parents of infants in Phenotype 1 were more likely to rate them as being more difficult than average, compared to infants with phenotypes 2 or 3. Phenotype 2 had the greatest increase in persuasive feeding over time [0.30; 95% CI (0.12, −0.47)].Conclusions: Distinct multi-trajectory appetitive phenotype groups emerge early in infancy. These trajectories appear to have origins in both infant and parent characteristics as well as parent behaviors and cognitions. The infant multi-trajectory appetitive phenotype groups suggest that for some infants, difficulties in self-regulating appetite emerge early in life. Investigation of infant multi-trajectory appetitive phenotype groups that utilize a range of measures, examine relationships to key covariates and outcomes, and extend from infancy into childhood are needed.

BackgroundIn order to measure and understand trajectories of parental feeding practices and their relationship with child eating and weight, it is desirable to perform assessment from infancy and across time, in age-appropriate ways. While many feeding practices questionnaires exist, none is presently available that enables tracking of feeding practices from infancy through childhood. The aim of the study was to develop a version of the Feeding Practices and Structure Questionnaire (FPSQ) for parents with infants and toddlers (MethodsConstructs and items for the FPSQ for infants and toddlers were derived from the existing and validated FPSQ for older children and supplemented by a review of the literature on infant feeding questionnaires. Following expert review, two versions of the questionnaire were developed, one for milk feeding parents and one for solid feeding parents. Data from two studies were combined (child ages 0–24 months) to test the derived constructs with Confirmatory Factor Analysis for the milk feeding (N = 731) and solid feeding (N = 611) versions.ResultsThe milk feeding version consisted of four factors (18 items) and showed acceptable model fit and good internal reliability: ‘feeding on demand vs. feeding routine’ (α = 0.87), ‘using food to calm’ (α = 0.87), ‘persuasive feeding’ (α = 0.71), ‘parent-led feeding’ (α = 0.79). The same four factors showed acceptable model fit for the solid feeding version (21 items), likewise with good internal reliability (α = 0.74, 0.86, 0.85, 0.84 respectively). Two additional factors (13 items) were developed for the solid feeding version that appeared developmentally appropriate only for children aged 12 months or older: ‘family meal environment’ (α = 0.81) and ‘using (non-)food rewards’ (α = 0.92). The majority of factor-factor correlations were in line with those of the original FPSQ.ConclusionsThe FPSQ milk and solid feeding versions are the first measures specifically developed as precursors to the FPSQ to measure parental feeding practices in children

Breastfeeding is beneficial to both the mother and infant, yet many infants are either partially or fully fed with formula milk. Those parents feeding with formula receive less support from professional sources than those breastfeeding and may rely on more non‐professional sources for advice, and this contributes to negative emotional experiences such as guilt. This paper explores the sources of advice for formula feeding, factors associated with using professional or non‐professional sources and compares these sources with those used for breastfeeding advice. A secondary analysis of Australian survey data from 270 mothers was performed. Mothers of six‐month‐old infants participated in an online survey, providing information on advice they received or read about formula feeding and/or breastfeeding from professional and non‐professional sources. A fifth of mothers who were formula feeding did not receive any formula feeding advice from professional sources, and only a small fraction (4.5%) of mothers breastfeeding did not received any breastfeeding advice from professional sources. Compared with those mothers breastfeeding receiving breastfeeding advice, fewer mothers formula feeding receive formula feeding advice from both professional and non‐professional sources. The tin of formula was the most used source of formula advice. Mothers feeding with formula at six months were more likely to have received formula feeding advice from professional sources if they had been fully formula feeding before their infant was under the age of three months. Further research is needed to understand the specific barriers to accessing formula feeding advice and what other factors influence access to formula feeding advice.

Copyright © 2019 Taki, Russell, Lymer, Laws, Campbell, Appleton, Ong and Denney-Wilson. Purpose: Mobile health (mHealth) interventions have great potential to promote health. To increase consumer engagement in mHealth interventions it is necessary to address factors that influence the target demographic. The Growing healthy (GH) program is the first obesity prevention program delivered via a smartphone app and website offering evidence-based information on infant feeding from birth until 9 months of age. This sub-study aimed to explore how the design features, quality of the app and participant characteristics influenced parents' engagement with the GH app. Methods: A sequential mixed methods design was used. The GH app participants (225/301) were considered for this sub-study. Participant app engagement was measured through a purpose-built Engagement Index (EI) using app metrics. Participants were categorized as low, moderately or highly engaged based on their EI score upon completing the 9 months program and were then invited to participate in semi-structured telephone interviews. Participants who used the app program, given an EI score and expressed interest to participate in these interviews were eligible. The interviews explored factors that influenced app engagement including delivery features and quality. Thematic analysis networks was used for analysis. Results: 108/225 expressed interest and 18 interviews were conducted from low (n = 3), moderately (n = 7), or highly (n = 8) engaged participants based on purposeful sampling. Participants defined as highly engaged were likely to be a first-time parent, felt the app content to be trustworthy and the app design facilitated easy navigation and regularly opened the push notifications. Participants defined as having low or moderate engagement were likely to have experience from previous children, felt they had sufficient knowledge on infant feeding and the app did not provide further information, or experienced technological issues including app dysfunction due to system upgrades. Conclusions/Implications: This study demonstrated a novel approach to comprehensively analyse engagement in an mHealth intervention through quantitative (Engagement Index) and qualitative (interviews) methods. It provides an insight on maximizing data collected from these programs for measuring effectiveness and to understand users of various engagement levels interaction with program features. Measuring this can determine efficacy and refine programs to meet user requirements.

Purpose Child and family health (CAFH) services in Australia initially provide at least one nurse-home-visit following the birth of a child. Planning and referral then commences for the on-going provision of appropriate services to families. Unfortunately, services in rural and regional communities in Australia can be fragmented and poorly resourced. Little is known about CAFH nurses’ experiences of working with families in these communities. The purpose of this paper is to examine the way CAFH nurses work within a universal health service model that may be compromised by isolation, discontinuity and fragmentation. Design/methodology/approach Focus groups with 26 CAFH nurses from five rural, two regional and one urban community in New South Wales (NSW), Australia were conducted. A secondary, thematic analysis of the qualitative data were undertaken to reflect on change and continuity in the field of universal CAFH services. Analysis was driven by two key research questions: How do CAFH nurses experience their role in universal home-based CAFH services within rural and regional areas of Australia and, what unique factors are present in rural and regional areas that impact on their CAFH nursing role? Findings The experience of the CAFH nurses as presented by these data revealed a role that was family centred and concerned for the welfare of the family, yet compromised by the need to meet the disproportionately complex needs of families in the absence of a strong network of services. The opportunity to present the findings provides insight into the way in which families engage with available services in isolated communities. CAFH nurses in the study attempted to maintain service integrity by adapting to the unique context of their work. Originality/value It is important to understand the mechanisms through which CAFH nurses operate to work effectively with families referred to their service. This paper describes the way in which CAFH nurses work with families not meeting the threshold for more intensive and targeted home-visiting service delivery in rural and regional communities of NSW, Australia.

© 2018 John Wiley & Sons Ltd Excess or rapid weight gain during the first 2 years of life is associated with an increased risk of later childhood and adult overweight and obesity. When compared with breastfed infants, formula fed infants are more likely to experience excess or rapid weight gain, and this increased risk in formula fed infant populations may be due to a number of different mechanisms. These mechanisms include the nutrient composition of the formula and the way formula is prepared and provided to infants. This systematic literature review examines the association between formula feeding practice and excess or rapid weight gain. This review explores these different mechanisms and provides practical recommendations for best practice formula feeding to reduce rapid weight gain. Eighteen studies are included in this review. The findings are complicated by the challenges in study design and accuracy of measurements. Nevertheless, there are some potential recommendations for best practice formula feeding that may reduce excess or rapid weight gain, such as providing formula with lower protein content, not adding cereals into bottles, not putting a baby to bed with a bottle, and not overfeeding formula. Although further well designed studies are required before more firm recommendations can be made.

Background Infant formula feeding practices are an important consideration for obesity prevention. An infant’s diet is influential on their later risk of developing overweight or obesity, yet very little is known about infant formula feeding practices. It is plausible that certain modifiable practices may put children at higher risk of developing overweight or obesity, for example how much and how often a baby is fed. Understanding how parents use infant formula and what factors may influence this practice is therefore important. Moreover, parents who feed their infants formula have identified a lack of support and access to resources to guide them. Therefore this study aimed to explore parents’ infant formula feeding practices to understand how parents use infant formula and what factors may influence this practice. Methods Using an explorative qualitative design, data were collected using semi-structured telephone interviews and analysed using a pragmatic inductive approach to thematic analysis. Results A total of 24 mothers from across Australia were interviewed. Mothers are influenced by a number of factors in relation to their infant formula feeding practice. These factors include information on the formula tin and marketing from formula manufacturers, particularly in relation to choosing the type of formula. Their formula feeding practices are also influenced by their interpretation of infant cues, and the amount of formula in the bottle. Many mothers would like more information to aid their practices but barriers exist to accessing health professional advice and support, so mothers may rely on informal sources. Some women reported that the social environment surrounding infant feeding wherein breastfeeding is promoted as the best option leads a feeling of stigma when formula feeding. Conclusions Additional support for parents’ feeding their infants with formula is necessary. Health professionals and policy around infant formula use should include how formula information may be provided to parents who use formula in ways that do not undermine breastfeeding promotion. Further observational research should seek to understand the interaction between advice, interpretation of cues and the amount formula fed to infants. Electronic supplementary material The online version of this article (10.1186/s12887-017-0977-7) contains supplementary material, which is available to authorized users.

© 2017 Informa UK Limited, trading as Taylor & Francis Group. Background: Childhood obesity is an increasing concern for parents and health professionals alike. Parents’ perception of obesity as a current health issue for their children is important for the everyday parenting and health choices parents make. As parents are frequently going online to seek and exchange information about parenting and child health, asynchronous online discussion forums provide an opportunity to investigate their perceptions and concerns. Understanding parents’ perceptions, beliefs and attitudes is important in any childhood obesity prevention and intervention. Aim: To explore parents’ perceptions, perspectives and concerns regarding childhood obesity expressed on asynchronous online discussion forums. Methods: A qualitative descriptive approach using template analysis to analyse a novel data collection strategy of 34 purposefully sampled threads from two Australian-based asynchronous online discussion forums. Results: Parents on the discussion forum displayed an understanding of childhood obesity as a public health concern, the discussion incorporated issues such as providing a healthy diet and lifestyle for children. Parents shared their own opinions and experiences that challenged or conceded to the status quo of the discussion. Parents discussed the role of health professionals in obesity prevention. There were varied opinions on the relevance of health professionals, particularly nurses, monitoring of growth and risk of obesity. Conclusion: This exploratory study highlights that parents perceive childhood obesity as an important public health concern, and that they understand the key public health messages of prevention and intervention. Yet, for many it is difficult to successfully implement these messages into their everyday lives. Health professionals need to play a key role in providing non-judgemental, innovative support and advice to parents to successfully implement prevention and intervention strategies.

We have previously shown that Wnt5A drives invasion in melanoma. We have also shown that Wnt5A promotes resistance to therapy designed to target the BRAF(V600E) mutation in melanoma. Here, we show that melanomas characterized by high levels of Wnt5A respond to therapeutic stress by increasing p21 and expressing classical markers of senescence, including positivity for senescence-associated β-galactosidase (SA-β-gal), senescence-associated heterochromatic foci (SAHF), H3K9Me chromatin marks, and PML bodies. We find that despite this, these cells retain their ability to migrate and invade. Further, despite the expression of classic markers of senescence such as SA-β-gal and SAHF, these Wnt5A-high cells are able to colonize the lungs in in vivo tail vein colony-forming assays. This clearly underscores the fact that these markers do not indicate true senescence in these cells, but instead an adaptive stress response that allows the cells to evade therapy and invade. Notably, silencing Wnt5A reduces expression of these markers and decreases invasiveness. The combined data point to Wnt5A as a master regulator of an adaptive stress response in melanoma, which may contribute to therapy resistance.

Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression, we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in β-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly.

Quality of life after pulmonary rehabilitation: assessing change using quantitative and qualitative methods [Physical Therapy 2000;80:986-95]

Metastatic melanoma is highly aggressively and often therapy resistant. Signaling pathways which promote invasion of metastatic melanoma, also promote therapy resistance. Therapy resistant melanomas are characterized by high levels of the pro-invasive non-canonical Wnt molecule, Wnt5A. Previously, we described an adaptive stress response in highly invasive melanoma cells, which is characterized by a growth arrest and an increase in senescence markers, yet these cells retain the ability to invade and form colonies. These highly invasive cells do not undergo apoptosis following treatment with DNA damaging agents such as doxorubicin and are resistant to BRAFV600E targeted therapy. Recently, Lukin et al. have shown that p53 expression promotes survival of colorectal cancer cells via p21 expression and a reversible cell cycle arrest, allowing for repair of damaged DNA. Here, we show that highly invasive and therapy resistant melanoma cells express Wnt5A, p53 and p21, which regulate proliferation and slow cycling in invasive melanoma cells. The expression of p53 is promoted by Wnt5A, knock down of Wnt5A decreases p53 and p21 expression in these cells and decreases the number of cells arrested in G2/M following DNA damage. The cell cycle and apoptotic functions of p53 are highly regulated. iASPP, MDMX, and MDM2 have been shown to regulate the function of wild type p53 in melanoma cells. MDM2, an E4 ubiquitin ligase, regulates p53 by shuttling it out of the nucleus and targeting it for proteasomal degradation. We found that MDM2 expression increases in invasive melanoma cells following DNA damage, however, in these cells it is phosphorylated at serine 395. Phosphorylation of MDM2 at ser395 blocks its ability to export p53 from the nucleus, leading to increased p53 expression. Even with increased p53 expression, invasive melanoma cells undergo a cell cycle arrest following stress instead of apoptosis. The apoptotic function of p53 has been shown to be inhibited by nuclear iASPP, which is enriched in metastatic melanoma. We found that knocking down Wnt5A in invasive melanoma cells decreases the expression of iASPP. These data suggest that Wnt5A promotes MDM2 Ser395 phosphorylation and iASPP expression, blocking down regulation of p53 and its apoptotic function, while promoting cell cycle arrest and survival following stress. These data may reveal a mechanism by which highly invasive melanoma cells evade therapy to form therapy resistant sub-colonies at distant sites. Citation Format: Marie R. Webster, Amanpreet Kaur, Abibatou Ndoye, Curtis Kugel, Subhasree Basu, Alexander Valiga, Jessica Appleton, Ying-Jie Wang, Maureen Murphy, Ashani T. Weeraratna. Invasive melanoma cells commandeer p53 activity to promote the survival of a therapy resistant subpopulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4913. doi:10.1158/1538-7445.AM2017-4913

Background: The use of Internet and social media is increasing in every area of life. Parents are increasingly using online mediums to seek information about their children's health. Therefore, this is becoming an increasingly important topic area for health professionals to acknowledge. Developing an understanding about the dissemination of child health information through these online mediums will assist health professional to continue to engage and support parents to seek and share accurate and safe child health information. Aim: To explore parents' use of asynchronous online discussion boards for child health information seeking, advice and social support. Method: A qualitative descriptive approach using an a priori template analysis was used to explore 34 discussions threads sampled from two Australian based online parenting discussion forums. To contain the scope of this study the threads chosen focused on childhood obesity in the Australian context. Results: Four major themes related to parents' use of asynchronous online discussion boards were found. These were seeking advice, sharing advice, social support and making judgement. This final theme of making judgements included parents' perceptions of health professionals' advice. Conclusion: Asynchronous online discussion boards are online mediums being utilised for seeking and sharing child health related information and support between parents. The notion that these online communities are usually supportive and provide accurate health information is challenged by the results of this study. This study found the forum environment can provide inaccurate information and in some instances can be judgemental and foster defensive attitudes. © 2014 Australian College of Nursing Ltd.

Nature 532, 250–254 (2016); doi:10.1038/nature17392 In Fig. 5a of this Letter, the labels PBS and PLX4720 were inadvertently reversed. The corrected Fig. 5a is shown in Fig. 1 of this Corrigendum.

Melanoma is one of the few cancer types where p53 is not often mutated. Cancers which have not mutated TP53, often attenuate p53 activity by affecting upstream regulators or downstream effectors of p53. As melanoma progresses, it by passes senescence, proliferates, and switches from a proliferative phenotype to a more invasive phenotype. We have found that invasive melanomas, characterized by high levels of the pro-invasive Wnt molecule, Wnt5A, express active p53. Conversely, melanomas with a more proliferative phenotype, characterized by increased MITF signaling and low Wnt5A expression, do not express active p53. We show that the expression of p53 appears to be controlled by Wnt5A, and this may occur via CAMKII. By Western blot, we have observed that more proliferative melanoma cells express a high molecular weight p53 (∼250 kDa). This high molecular weight p53 does not break down on an SDS-PAGE gel. Knocking down p53 in proliferative and invasive melanoma cells, using siRNA, decreases the high molecular weight band in the proliferative cells, and the 53 kDa band in the more invasive cells. When we over express HA-tagged p53 in proliferative cells, we see multiple bands for p53 by Western blot, including the high molecular weight bands, suggesting that p53 is being post-translationally modified in these cells. We confirmed that ubiquitination is involved in the formation of the high molecular weight p53, by treating proliferative cells with SMER3, an E3 ligase inhibitor. Following two hours of treatment, the high molecular weight p53 band decreased and this decrease persists for 16 h. Next, we transfected an E6 ligase into invasive melanoma cells, which express active p53. Expression of the E6 ligase increased the expression of the high molecular weight p53 band (250 kDa), but these cells also continued to express active p53 (53 kDa). To determine if ubiquitination is targeting p53 for degradation in proliferative cells, we treated invasive and proliferative cells with MG132, a proteasome inhibitor. Following treatment with MG132, p53 (53 kDa) increased in invasive cells, suggesting that p53 is degraded via the proteasome in these cells. However, when we treated proliferative cells with MG132 we did not see an increase in the high molecular weight band, suggesting that p53 is not being degraded via the proteasome in these cells. By immunofluorescence, we found that p53 is in the cytoplasm of proliferative cells, suggesting that ubiquitination may be playing a role in sequestration of p53 in proliferative cells. In invasive cells, p53 remains largely nuclear, and we demonstrate that this plays critical roles in response to therapy, counter-intuitively driving resistance, by allowing cells to undergo an adaptive stress response that we term “pseudosenescence” Citation Format: Marie R. Webster, Subhasree Basu, Amanpreet Kaur, Jessica Appleton, Maureen E. Murphy, Ashani T. Weeraratna. p53 is differentially regulated in proliferative and invasive melanoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3775. doi:10.1158/1538-7445.AM2015-3775

Senescence is a cytostatic cell fate that can be induced by oncogene activation, replicative stress or therapy-induced stress. Therapy-induced senescence (TIS) of tumor cells can be initiated by anti-cancer compounds or radiation. TIS is generally considered to be irreversible, and as such this process is believed to be a desirable therapeutic outcome. In this study, we show that melanomas characterized by high levels of the signaling molecule Wnt5A respond to irradiation by undergoing growth arrest, and by expressing classical markers of senescence, including positivity for senescence-associated beta-galactosidase (SA-β-gal), senescence associated heterochromatic foci (SAHF), H3K9Me chromatin marks, and PML bodies. Even though these cells are positive for classical markers of senescence, we find that they retain their ability to migrate and invade. Further, these Wnt5A-high cells are able to proliferate following metastasis and form new tumors in the lung, while expressing increased markers of senescence. Silencing Wnt5A reduces expression of these senescence markers and decreases invasiveness. Finally, Wnt5A-high melanoma cells treated with PLX4720, a BRAFV600E targeted therapy, also increase markers of a TIS response, while remaining invasive. The combined data challenge the paradigm that TIS is a desirable therapeutic endpoint. They also point to Wnt5A as a master regulator of this senescence-like stress-induced phenotype in melanoma. Citation Format: Marie R. Webster, Mai Xu, Kathryn Kinzler, Amanpreet Kaur, Jessica Appleton, Michael P. O'Connell, Katie Marchbank, Alexander Valiga, Vanessa Dang, Michela Perego, Gao Zhang, Ana Slipicevic, Frederick Keeney, Elin Lehrmann, William Wood, III, Kevin Becker, Andrew V. Kossenkov, Meenhard Herlyn, Maureen Murphy, Ashani T. Weeraratna. Wnt5A-expressing melanoma cells show classical markers of senescence following radiation and therapeutic stress, but retain the ability to metastasize and proliferate at distant sites. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B27.

The incidence of melanoma rises dramatically after the age of 55. Due to an increase in aging population, it is important to study the change in molecular mechanisms due to aging that would allow development of therapies that are tailored to the age of the patients. The role of the tumor microenvironment in modulating cancer characteristics is widely recognized and it also provides targets for therapeutic intervention. Due to this, we hypothesized that changes in tumor microenvironment due to aging could affect the progression of the melanoma. We obtained skin fibroblasts from healthy donors aged 25-35, as well as skin fibroblasts from healthy donors aged 55-65. We cultured these fibroblasts and used conditioned media from them to affect the invasion of melanoma cells in 3D spheroid invasion assays, where aged fibroblasts promoted invasion of melanoma cells into collagen. We also built artificial skin (reconstructs) using young and aged fibroblasts and demonstrated that skin built with aged fibroblasts promoted melanoma cell invasion. Finally using a transgenic mouse model of melanoma (Yumm1.7, BRAFV600E/PTEN-/-) we observed that the injection of melanoma cells into the tail vein of aged mice (52 weeks) formed metastastic colonies much more rapidly than those injected into the tail vein of young mice (8 weeks). To study the factors involved in the aging microenvironment, we performed a proteomics study of the secretome from young and aged fibroblasts. From this study, we observed that aged fibroblasts secreted inhibitors of canonical Wnt signaling, as well as increased deposition of extracellular matrix components in the aging microenvironment. Since inhibition of canonical Wnt signaling has been linked to decreased sensitivity towards BRAF inhibitors in melanoma, we injected Yumm 1.7 cells subcutaneously into aged and young mice. These mice were then treated with BRAF inhibitors. We observed an increased resistance in response to therapy in the aged mice. We also prepared skin reconstruct from fibroblasts with knockdown of the proteins that we identified from secretome and treated them with PLX4720. These results indicated the role of these extracellular matrix proteins in melanoma. We are exploring the mechanisms of how these extracellular matrix proteins affect the sensitivity towards chemotherapeutics. We concluded that aging could alter tumor microenvironment thus resulting in increased metastasis and therapy resistance. It is important that the studies in cancer therapies take into account the age of the patient to achieve better response in patients. Citation Format: Amanpreet Kaur, Katie Marchbank, Vanessa Dang, Michael O'Connell, Marie Webster, Jessica Appleton, Phil Cheng, Alexander Valiga, Rachel Morissette, Nazli McDonnell, Luigi Ferrucci, Andrew Kossenkov, Katrina Meeth, Marcus Bosenberg, Hsin-Yao Tang, Xiangfan Yin, William Wood, III, Elin Lehrmann, Kevin Becker, Keith Flaherty, Dennie Frederick, Jennifer Wargo, Katherine Aird, Rugang Zhang, Xiaowei Xu, Qin Liu, David Speicher, Ashani Weeraratna. Aging microenvironment modulates melanoma invasion and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A04.