Serial expression analysis of breast tumors during neoadjuvant chemotherapy reveals changes in cell cycle and immune pathways associated with recurrence and response

Abstract Introduction The molecular biology involving neoadjuvant chemotherapy (NAC) response is poorly understood. To elucidate the impact of NAC on the breast cancer transcriptome and its association with clinical outcome, we analyzed gene expression data derived from serial tumor samples of patients with breast cancer who received NAC in the I-SPY 1 TRIAL. Methods Expression data were collected before treatment (T1), 24–96 hours after initiation of chemotherapy (T2) and at surgery (TS). Expression levels between T1 and T2 (T1 vs. T2; n = 36) and between T1 and TS (T1 vs. TS; n = 39) were compared. Subtype was assigned using the PAM50 gene signature. Differences in early gene expression changes (T2 − T1) between responders and nonresponders, as defined by residual cancer burden, were evaluated. Cox proportional hazards modeling was used to identify genes in residual tumors associated with recurrence-free survival (RFS). Pathway analysis was performed with Ingenuity software. Results When we compared expression profiles at T1 vs. T2 and at T1 vs. TS, we detected significantly altered expression of 150 and 59 transcripts, respectively. We observed notable downregulation of proliferation and immune-related genes at T2. Lower concordance in subtype assignment was observed between T1 and TS (62 %) than between T1 and T2 (75 %). Analysis of early gene expression changes (T2 − T1) revealed that decreased expression of cell cycle inhibitors was associated with poor response. Increased interferon signaling (TS − T1) and high expression of cell proliferation genes in residual tumors (TS) were associated with reduced RFS. Conclusions Serial gene expression analysis revealed candidate immune and proliferation pathways associated with response and recurrence. Larger studies incorporating the approach described here are warranted to identify predictive and prognostic biomarkers in the NAC setting for specific targeted therapies. Clinical trial registration ClinicalTrials.gov identifier: NCT00033397 . Registered 9 Apr 2002

An Investigation of the Impact of Childhood Trauma on Quality of Caregiving in High Risk Mothers: Does Maternal Substance Misuse Confer Additional Risk?

The quality of caregiving is often compromised when mothers have co-occurring difficulties such as substance misuse\ua0and problems associated with extreme emotional dysregulation. These, in turn, are\ua0associated with poor child outcomes. The aim of the current study was twofold. First, to investigate the potential differences in risk factors associated with poor child outcome by comparing three groups: substance misusing mothers (Substance Misusing Mothers; SMM); mothers matched on demographic characteristics (Matched Comparison Mothers; MCM) and mothers recruited from the community (Matched Control Comparison; MCC). Second, to investigate the underlying mechanisms which are associated with poor child outcome by testing a mediated moderation model to ascertain (i) whether environmental risk and borderline psychopathology was a mediator between maternal childhood trauma and quality of caregiving and (ii) maternal substance misuse status moderated outcome. There were no significant differences found between the SMM and MCM groups on the key variables, but significant differences on all variables for both SMM and MCM compared to CCM. The moderated mediation analysis found that while there was significant mediation of environmental risk and borderline pathology between maternal childhood trauma and child outcome, this was not moderated by maternal substance abuse status. The importance of environmental-risk as a mechanism leading to reduced caregiving quality suggest treatment programs need to consider targeting these factors in high risk families

Quality of caregiving in mothers with illicit substance use: a systematic review and meta-analysis

The quality of caregiving in mothers with substance abuse problems appears to be compromised. However, divergent findings, methodological variability, and sample characteristics point to the need for research synthesis

Exploring parents' beliefs about their young child's physical activity and screen time behaviours

Drawing on the belief-based framework of the theory of planned behaviour, 20 adults living in Queensland, Australia participated in semi-structured interviews to elicit salient beliefs regarding their young child’s physical activity (PA) and screen time behaviours. Data were analysed separately for PA and screen time with a range of beliefs emerging that guided parents’ decisions for these important health behaviours. Underlying advantages (e.g., improve family interactions, improve child behaviour), disadvantages (e.g., mess and noise factor, increase in parental distress), barriers (e.g., lack of time, parental fatigue), and facilitators (e.g., access to parks, social support) to engaging their child in adequate PA and limited screen time emerged. Normative pressures were also identified as affecting parents’ decisions for their child in these contexts. Parents experience unique difficulties in engaging their child in adequate PA and limited screen time that interventions can draw on when designing and implementing programs aimed at modifying these important child health behaviours

Parents' role constructions for facilitating physical activity-related behaviours in their young children

Background The research explored parents' role constructions for themselves and other caregivers in promoting physical activity, limiting screen time, and ensuring their young child is not sedentary or restrained for extended periods. Method Using a qualitative social constructionist epistemological position, 10 mothers and 10 fathers (aged 22–49 years) from different households in South East Queensland, Australia, were interviewed. The interviews were transcribed verbatim and analysed using thematic analysis. Results Thirteen themes emerged in parents' descriptions of their role, aligning with three of the four key influences on parents' role constructions for involvement in their child's behaviour: beliefs about desired child outcomes, beliefs about who is responsible for the outcomes, and parental behaviours related to the beliefs and expectations. Conclusions Current findings indicate that parents commonly describe active manifestations of parent role constructions that are conducive to facilitating childhood physical activity‐related behaviours. Because many young Australian children are still not sufficiently active, future interventions should seek to target processes influencing parents' ability to fulfil their constructed roles and translate them into actions, including knowledge and skills, self‐efficacy for helping their child, and developing the ability to manage the mix of demands on their time

An investigation of the utility of the Australian Guide to the diagnosis of fetal alcohol spectrum disorder in young children.

BACKGROUND: Early diagnosis of children with fetal alcohol spectrum disorder (FASD) assists in implementing critical early support. The challenge lies in having a diagnostic process that enables valid and reliable assessment of domains of functioning in young children, with the added complexity that many children will also have co-occurring exposure to childhood adversity that is likely to impact these domains. METHODS: The aim of this study was to test a diagnostic assessment of FASD in young children using the Australian Guide to the Diagnosis of FASD. Ninety-four children (aged 3 to 7 years) with confirmed or suspected prenatal alcohol exposure were referred to two specialist FASD clinics for assessment in Queensland, Australia. RESULTS: There was a significant risk profile with 68.1% (n = 64) children having had contact with child protection services, and most children living in kinship (n = 22, 27.7%) or foster (n = 36, 40.4%) care. Forty-one percent of the children were Indigenous Australians. The majority (64.9%, n = 61) of children met criteria for FASD, 30.9% were classified as "At Risk" for FASD (n = 29), and 4.3% received no FASD diagnosis (n = 4). Only 4 (4%) children were rated as severe for the brain domain. Over 60% of children (n = 58) had two or more comorbid diagnoses. Sensitivity analyses indicated that the removal of comorbid diagnoses in the Attention, Affect Regulation, or Adaptive Functioning domains resulted in a change in 7 of 47 cases (15%) to an "At Risk" designation. CONCLUSIONS: These results highlight the complexity of presentation and the extent of impairment in the sample. The use of comorbid diagnoses to substantiate a "severe" designation in specific neurodevelopmental domains raises the question of whether there were false-positive diagnoses. The complexity of determining causal relationships between exposure to PAE and early life adversity on developmental outcomes continues to be a challenge in this young population