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Supplementary Materials and Methods; Supplementary Figure 1: Effects of AMG 900 on nuclear morphology and centrosome features are consistent with aurora-B inhibition in MDA-MB-231 cell line; Supplementary Figure 2: Elevated expression of ABC transporter gene ABCB1 and ABCB4 in MDA-MB-231 (F11) PTX-r cell line; Supplementary Figure 3: Cell-cycle profiles of TNBC cell lines treated with paclitaxel or ixabepilone.

Breast cancer is the most prevalent malignancy affecting women and ranks second in cancer-related deaths, in which death occurs primarily from metastatic disease. Triple-negative breast cancer (TNBC) is a more aggressive and metastatic subtype of breast cancer that is initially responsive to treatment of microtubule-targeting agents (MTA) such as taxanes. Recently, we reported the characterization of AMG 900, an orally bioavailable, potent, and highly selective pan-Aurora kinase inhibitor that is active in multidrug-resistant cell lines. In this report, we investigate the activity of AMG 900 alone and in combination with two distinct classes of MTAs (taxanes and epothilones) in multidrug-resistant TNBC cell lines and xenografts. In TNBC cells, AMG 900 inhibited phosphorylation of histone H3 on Ser10, a proximal substrate of Aurora-B, and induced polyploidy and apoptosis. Furthermore, AMG 900 potentiated the antiproliferative effects of paclitaxel and ixabepilone at low nanomolar concentrations. In mice, AMG 900 significantly inhibited the growth of MDA-MB-231 (F11; parental), MDA-MB-231 (F11) PTX-r (paclitaxel-resistant variant), and DU4475 xenografts. The combination of AMG 900 with docetaxel enhanced tumor inhibition in MDA-MB-231 (F11) xenografts compared with either monotherapy. Notably, combining AMG 900 with ixabepilone resulted in regressions of MDA-MB-231 (F11) PTX-r xenografts, in which more than 50% of the tumors failed to regrow 75 days after the cessation of drug treatment. These findings suggest that AMG 900, alone and in combination with MTAs, may be an effective intervention strategy for the treatment of metastatic breast cancer and provide potential therapeutic options for patients with multidrug-resistant tumors. Mol Cancer Ther; 12(11); 2356–66. ©2013 AACR.

The Wittig reaction to synthesize olefins is a very attractive method in organic synthesis. Recently, this methodology has been achieved utilizing simple metal catalysts and diazo compounds in addition to a phosphine and an aldehyde. The following work investigates the use of a variety of metallophthalocyanines (MPc’s) to catalyze Wittig-like reactions from ethyldiazoacetate. We also examine the influence of substitution on the aromatic ring of the aldehyde as well as various phosphines, arsines and antimony complexes. We have been able to exclusively synthesize the trans-olefins in excellent yields in short periods of time (1 h).

Scholars and practitioners recognize that adaptation is necessary, and can enhance program outcomes, when scaling early interventions. This study used a framework for implementation that identified critical elements for understanding the adaptation process including: a) who made the adaptations, such as model developers and staff members, b) what elements were adapted, c) how adaptations occurred, such as adding or removing elements, d) when adaptations took place, such as at the beginning of implementation or as an on-going process, and e) why the adaptations occurred. Erikson Institute’s Fussy Baby Network ® (FBN) service program has been implemented in seven cities across the United States. Implementation of FBN in the New Orleans and Gulf Coast (NOGC) region began in 2012. Using a longitudinal phenomenological study design, FBNNOGC program and institutional staff were interviewed over three years at ten time points. This study identified five adaptations of FBN to NOGC: a) increasing length and intensity of services, b) adding a family advocate, c) integrating academic and clinical contexts, d) changing the program name, branding, and outreach materials, and e) networking with other providers. No adaptations were made to the program model or training, which ensured program fidelity.

Objectives To clarify the effectiveness of perinatal social support interventions in reducing postpartum depression among minority, low-income women. Methods The Transdisciplinary Research Consortium for Gulf Resilience on Women's Health supported a community-based participatory research project to improve perinatal health among low-income, first-time pregnant women living in a vulnerable Gulf Coast region. Community health workers (CHWs) were partnered with recruited women, and used a mix of mobile technology and home visits to develop a supportive relationship during the perinatal period. Results Women enrolled in the CHW-led intervention had lower (F: 2.38, p = 0.04) average postpartum depression scores (EPDS) 6 months postpartum than a comparison population. The difference, however, was not seen among women in the intervention group who reported relatively poor relationships with their CHWs. Conclusions for Practice Results reinforce the evidence that perinatal social support can affect postpartum depression outcomes. CHWs are increasingly utilized by public programs to reach at-risk populations. We discuss the potential efficacy of CHW programs, but also, the need to pair outreach with effective monitoring and evaluation of the relationship development between CHW and clients.

Objective Unicompartmental knee arthroplasty (UKA) is a viable option for relieving pain and improving function in patients with isolated compartment knee osteoarthritis (OA). Certain surgeons prefer total knee arthroplasty (TKA) over UKA even when patients are candidates for UKA. Therefore, the decision to perform a UKA or a TKA when both are indicated is not straightforward. The goal of this study was to compare pre-operative and post-operative patient-reported outcome (PRO) scores for patients who underwent both a UKA and a contralateral TKA. Methods In this study, 17 patients were identified who underwent UKA in one knee and TKA in the contralateral knee either simultaneously or at different time points between 2003 and 2014. All procedures were performed by one of two fellowship trained surgeons at a large academic medical center. Patients were evaluated pre-operatively and then post-operatively using the validated PRO measurements Short Form 12 (SF12), Knee Society Functional Score (KSS), and the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) questionnaires. Student’s paired t-tests were conducted to compare PRO scores for UKA and TKA pre-operatively and post-operatively. Results Post-operatively, mean follow-up was 2.5 years (range, 3 months to 9 years). There was no significant difference in PRO scores between pre-operative values for UKA and TKA, and no significant difference between post-operative values for UKA and TKA (e.g. SF12 pre-operative difference between UKA and TKA mean = 1.6, p = 0.57; SF12 post-operative difference between UKA and TKA mean = 1.9, p = 0.51). Conclusion UKA and TKA are comparable in terms of PROs at mid-term follow-up. When choosing between UKA and TKA, the surgeon should expect similar PROs for each, and can therefore take into account other considerations when making a selection.

Assessment procedures for infants, toddlers, and preschoolers should include caregiver interviews, caregiver-report questionnaires, observational coding procedures, and collateral reports (i.e., medical, child care, etc.). This multimodal assessment approach provides clinicians a systematic means to incorporate the many factors that impact an infant’s clinical presentation. The prior chapter focuses on one aspect of a multimodal psychiatric evaluation, specifically observing the dyadic interaction. In this chapter, we outline key considerations regarding instrument selection, application and interpretation, and provide an in-depth list of dyadic observational measures which have been found to have useful clinical applications.

BACKGROUND: Beneficial roles for glucagon-like peptide 1 (GLP-1)/GLP-1R signaling have recently been described in diseases, where low-grade inflammation is a common phenomenon. We investigated the effects of GLP-1 in Brunner's glands and duodenum with abundant expression of GLP-1 receptors, as well as GLP-1 effect on colonic inflammation.METHODS: RNA from Brunner's glands of GLP-1R knockout and wild-type mice were subjected to full transcriptome profiling. Array results were validated by quantitative reverse transcription polymerase chain reaction in wild-type mice and compared with samples from inflammatory bowel disease (IBD) patients and controls. In addition, we performed a detailed investigation of the effects of exogenous liraglutide dosing in a T-cell driven adoptive transfer (AdTr) colitis mouse model.RESULTS: Analyses of the Brunner's gland transcriptomes of GLP-1R knockout and wild-type mice identified 722 differentially expressed genes. Upregulated transcripts after GLP-1 dosing included IL-33, chemokine ligand 20 (CCL20), and mucin 5b. Biopsies from IBD patients and controls, as well as data from the AdTr model, showed deregulated expression of GLP-1R, CCL20, and IL-33 in colon. Circulating levels of GLP-1 were found to be increased in mice with colitis. Finally, the colonic cytokine levels and disease scores of the AdTr model indicated reduced levels of colonic inflammation in liraglutide-dosed animals.CONCLUSIONS: We demonstrate that IL-33, GLP-1R, and CCL20 are deregulated in human IBD, and that prophylactic treatment with 0.6 mg/kg liraglutide improves disease in AdTr colitis. In addition, GLP-1 receptor agonists upregulate IL-33, mucin 5b, and CCL20 in murine Brunner's glands. Taken together, our data indicate that GLP-1 receptor agonists affect gut homeostasis in both proximal and distal parts of the gut.

The foundations of social-emotional development are based in the primary caregiving relationship. In the first months of life, development in this area is primarily influenced by the infant’s relationship(s) with his primary caregiver(s), and in turn these relationships are influenced by the infant’s development and behavior. This chapter briefly reviews typical infant development month by month and the bi-directional impact of the relationship and infant behavior on social-emotional development. The ways in which multiple individuals and systems can influence parenting decisions typically formulated during this age period, such as breastfeeding, sleep arrangements, and childcare placement, are highlighted. The chapter ends with a brief review of the assessment process and social-emotional assessment tools that can be used with very young infants and their caregivers.

Significance A core question in evolutionary biology is how mutation and selection adapt and constrain species to specialized habitats. We sequenced the genome of the sand rat, a desert rodent susceptible to nutritionally induced diabetes, and discovered an unusual chromosome region skewed toward G and C nucleotides. This region includes the Pdx1 homeobox gene, a transcriptional activator of insulin , which has undergone massive sequence change, likely contributing to diabetes and adaptation to low caloric intake. Our results imply that mutation rate varies within a genome and that hotspots of high mutation rate may influence ecological adaptation and constraint. In addition, we caution that divergent regions can be omitted by conventional short-read sequencing approaches, a consideration for existing and future genome sequencing projects.

Current literature indicates that risk for maternal depression is substantial in low-income families. A large body of research also indicates that when mothers are depressed, children are at risk for a number of developmental difficulties. While mutual influence between child and parental difficulties has been noted, few studies examine risk factors for both depression and child aggression within ecological models. The present cross-site study examined the unique and additive contributions of contextual factors, including SES and family functioning, on maternal depression and child aggression in Early Head Start families. A multiethnic sample of parents and their children, between the ages of 12 and 43 months, participated in this study. Families came from five Early Head Start programs across the United States, representing both urban and rural areas. Structural equation models (SEM) demonstrate mutual links between depression and aggression, mediated at least in part by ecological factors. SEM indicated that 36.4% of the variance in child aggression is accounted for in a model linking aggressive behavior to parent depression, stress, and couple-level functioning, as well as other family interaction variables. A second model focusing on maternal depression revealed that 44.5% of the variance in maternal depression was accounted for through family factors, including couple-related support and satisfaction and parenting stress. In this second model, child aggression was indirectly linked to maternal depression. These data have important implications for programs serving at-risk families.

The sand ratPsammomys obesusis a gerbil native to deserts of North Africa and the Middle East1. Sand rats survive with low caloric intake and when given high carbohydrate diets can become obese and develop type II diabetes2which, in extreme cases, leads to pancreatic failure and death3,4. Previous studies have reported inability to detect thePdx1gene or protein in gerbils5–7, suggesting that absence of this key insulin-regulating homeobox gene might underlie diabetes susceptibility. Here we report sequencing of the sand rat genome and discovery of an extensive, mutationally-biased GC-rich genomic domain encompassing many essential genes, including the elusivePdx1.The sequence ofPdx1has been grossly affected by GC-biased mutation leading to the highest divergence observed in the animal kingdom. In addition to molecular insights into restricted caloric intake in a desert species, the discovery that specific chromosomal regions can be subject to elevated mutation rate has widespread significance to evolution.