Navigating nutrition as a childhood cancer survivor: Understanding patient and family needs for nutrition interventions or education.

AIM: Nutrition challenges are common during childhood cancer treatment and can persist into survivorship, increasing the risk of non-communicable diseases. Evidence-based practice and implementation of nutrition interventions/education for childhood cancer survivors has been poorly investigated and may influence their future health. This study aimed to explore the nutrition interventions/education needs of childhood cancer survivors and the barriers and facilitators to delivering follow-up services in New Zealand. METHODS: Semi structured interviews were conducted with childhood cancer survivors and/or their families (n=22) and health professionals (n=9) from a specialist paediatric oncology centre in New Zealand. Interviews were audio-recorded and transcribed verbatim. Transcripts were analysed inductively using thematic analysis. A multi-level consensus coding methodology was used where each theme and associated subthemes were discussed with the study team for confirmation to ensure accurate coding and analysis. RESULTS: Three themes emerged from the analysis: (1) the current survivorship care pathway does not provide adequate interventions/education, (2) weight and dietary changes are common challenges and (3) requirements for interventions/education in survivorship are varied. Common nutrition-related concerns included fussy eating/limited dietary intake, poor diet quality, difficulties with tube weaning, and challenges with weight gain. Participants expressed a desire for education on healthy eating alongside information about cancer-related nutrition issues, such as learned food aversions. A preference for clear referral pathways and multifaceted interventions tailored to individual patient needs was identified. CONCLUSION: The trifecta of treatment side effects, negative feeding practices and poor messaging from health professionals creates a challenging environment to optimise nutrition. A stepped care model matching the intervention intensity with the childhood cancer survivors is required. Education for healthcare professionals will improve the delivery of timely interventions/education and monitoring practices.

Mouse ER+/PIK3CAH1047R breast cancers caused by exogenous estrogen are heterogeneously dependent on estrogen and undergo BIM-dependent apoptosis with BH3 and PI3K agents.

Estrogen dependence is major driver of ER + breast cancer, which is associated with PI3K mutation. PI3K inhibition (PI3Ki) can restore dependence on ER signaling for some hormone therapy-resistant ER + breast cancers, but is ineffective in others. Here we show that short-term supplementation with estrogen strongly enhanced Pik3caH1047R-induced mammary tumorigenesis in mice that resulted exclusively in ER + tumors, demonstrating the cooperation of the hormone and the oncogene in tumor development. Similar to human ER + breast cancers that are endocrine-dependent or endocrine-independent at diagnosis, tumor lines from this model retained ER expression but were sensitive or resistant to hormonal therapies. PI3Ki did not induce cell death but did cause upregulation of the pro-apoptotic gene BIM. BH3 mimetics or PI3Ki were unable to restore hormone sensitivity in several resistant mouse and human tumor lines. Importantly however, combination of PI3Ki and BH3 mimetics had a profound, BIM-dependent cytotoxic effect in PIK3CA-mutant cancer cells while sparing normal cells. We propose that addition of BH3 mimetics offers a therapeutic strategy to markedly improve the cytotoxic activity of PI3Ki in hormonal therapy-resistant and ER-independent PIK3CA-mutant breast cancer.

p53 Maintains Baseline Expression of Multiple Tumor Suppressor Genes.

TP53 is the most commonly mutated tumor suppressor gene and its mutation drives tumorigenesis. Using ChIP-seq for p53 in the absence of acute cell stress, we found that wild-type but not mutant p53 binds and activates numerous tumor suppressor genes, including PTEN, STK11(LKB1), miR-34a, KDM6A(UTX), FOXO1, PHLDA3, and TNFRSF10B through consensus binding sites in enhancers and promoters. Depletion of p53 reduced expression of these target genes, and analysis across 18 tumor types showed that mutation of TP53 associated with reduced expression of many of these genes. Regarding PTEN, p53 activated expression of a luciferase reporter gene containing the p53-consensus site in the PTEN enhancer, and homozygous deletion of this region in cells decreased PTEN expression and increased growth and transformation. These findings show that p53 maintains expression of a team of tumor suppressor genes that may together with the stress-induced targets mediate the ability of p53 to suppress cancer development. p53 mutations selected during tumor initiation and progression, thus, inactivate multiple tumor suppressor genes in parallel, which could account for the high frequency of p53 mutations in cancer.Implications: In this study, we investigate the activities of p53 under normal low-stress conditions and discover that p53 is capable of maintaining the expression of a group of important tumor suppressor genes at baseline, many of which are haploinsufficient, which could contribute to p53-mediated tumor suppression. Mol Cancer Res; 15(8); 1051-62. ©2017 AACR.

TRIM25 Enhances the Antiviral Action of Zinc-Finger Antiviral Protein (ZAP).

The host factor and interferon (IFN)-stimulated gene (ISG) product, zinc-finger antiviral protein (ZAP), inhibits a number of diverse viruses by usurping and intersecting with multiple cellular pathways. To elucidate its antiviral mechanism, we perform a loss-of-function genome-wide RNAi screen to identify cellular cofactors required for ZAP antiviral activity against the prototype alphavirus, Sindbis virus (SINV). In order to exclude off-target effects, we carry out stringent confirmatory assays to verify the top hits. Important ZAP-liaising partners identified include proteins involved in membrane ion permeability, type I IFN signaling, and post-translational protein modification. The factor contributing most to the antiviral function of ZAP is TRIM25, an E3 ubiquitin and ISG15 ligase. We demonstrate here that TRIM25 interacts with ZAP through the SPRY domain, and TRIM25 mutants lacking the RING or coiled coil domain fail to stimulate ZAP's antiviral activity, suggesting that both TRIM25 ligase activity and its ability to form oligomers are critical for its cofactor function. TRIM25 increases the modification of both the short and long ZAP isoforms by K48- and K63-linked polyubiquitin, although ubiquitination of ZAP does not directly affect its antiviral activity. However, TRIM25 is critical for ZAP's ability to inhibit translation of the incoming SINV genome. Taken together, these data uncover TRIM25 as a bona fide ZAP cofactor that leads to increased ZAP modification enhancing its translational inhibition activity.

The "TSH Receptor Glo Assay" - A High-Throughput Detection System for Thyroid Stimulation.

BACKGROUND: To identify novel small molecules against the TSH receptor, we developed a sensitive transcription-based luciferase high-throughput screening (HTS) system named the TSHR-Glo Assay (TSHR-Glo). METHODS: This assay uses double-transfected Chinese hamster ovary cells stably expressing the human TSHR and a cAMP-response element (CRE) construct fused to an improved luciferase reporter gene. RESULTS: The assay was highly responsive toward TSH in a dose-dependent manner with a TSH sensitivity of 10(-10)M (10 ± 1.12 µU/ml) and thyroid-stimulating antibodies, a hallmark of Graves' disease, could also be detected. The assay was validated against the standard indicator of HTS performance - the Z-factor (Z') - producing a score of 0.895. Using the TSHR-Glo assay, we screened 48,224 compounds from a diverse chemical library in duplicate plates at a fixed dose of 17 µM. Twenty molecules with the greatest activity out of 62 molecules that were identified by this technique were subsequently screened against the parent luciferase stable cell line in order to eliminate false positive stimulators. CONCLUSION: Using this approach, we were able to identify specific agonists against the TSH receptor leading to the characterization of several TSH agonist molecules. Hence, the TSHR-Glo assay was a one-step cell-based HTS assay, which was successful in the discovery of novel small molecular agonists and for the detection of stimulating antibodies to the TSH receptor.

A high throughput Cre-lox activated viral membrane fusion assay identifies pharmacological inhibitors of HIV entry.

Enveloped virus entry occurs when viral and cellular membranes fuse releasing particle contents into the target cell. Human immunodeficiency virus (HIV) entry occurs by cell-free virus or virus transferred between infected and uninfected cells through structures called virological synapses. We developed a high-throughput cell-based assay to identify small molecule inhibitors of cell-free or virological synapse-mediated entry. An HIV clone carrying Cre recombinase as a Gag-internal gene fusion releases active Cre into cells upon viral entry activating a recombinatorial gene switch changing dsRed to GFP-expression. A screen of a 1998 known-biological profile small molecule library identified pharmacological HIV entry inhibitors that block both cell-free and cell-to-cell infection. Many top hits were noted as HIV inhibitors in prior studies, but not previously recognized as entry antagonists. Modest therapeutic indices for simvastatin and nigericin were observed in confirmatory HIV infection assays. This robust assay is adaptable to study HIV and heterologous viral pseudotypes.

Phonetic variations and sound changes in Hong Kong Cantonese: diachronic review, synchronic study and implications for speech sound assessment.

The aim of this article was to describe phonetic variations and sound changes in Hong Kong Cantonese (HKC) to provide speech-language pathologists with information about acceptable variants of standard pronunciations for speech sound assessments. Study 1 examined the pattern of variations and changes based on past diachronic research and historical written records. Nine phonetic variations were found. Five in syllable-initial and syllabic contexts: (1) [n-] → [l-], (2) [ŋ-] → Ø-, (3) Ø- → [ŋ-], (4) [k(w)ɔ-] → [kɔ-], (5) syllabic [ŋ̍] → [mÌ©]; and four in syllable-final contexts: (6) [-ŋ] → [-n], (7) [-n] → [-ŋ], (8) [-k] → [-t], (9) [-t] → [-k]. Historical records demonstrated the pattern of variation and changes in HKC across time. In study 2, a large-scale synchronic study of speakers of differing ages was undertaken to determine acceptable phonetic variations of HKC for speech sound assessments. In the synchronic study, single-words were elicited from 138 children (10;8-12;4) and 112 adults (18-45 years) who spoke Cantonese and lived in Hong Kong. Synchronic evidence demonstrated five acceptable variants in syllable-initial and syllabic contexts: (1) [n-] → [l-], (2) [ŋ-] → Ø-, (3) Ø- → [ŋ-], (4) [k(w)ɔ-] → [kɔ-] and (5) syllabic [ŋ̍] → [mÌ©] and four incomplete sound changes in syllable-final contexts: (6) [-ŋ] → [-n], (7) [-n] → [-ŋ], (8) [-k] → [-t] and (9) [-t] → [-k]. The incomplete sound changes may still be accepted as variants in speech sound assessments unless related speech problems are indicated.

The impact of extrinsic demographic factors on Cantonese speech acquisition.

This study modeled the associations between extrinsic demographic factors and children's speech acquisition in Hong Kong Cantonese. The speech of 937 Cantonese-speaking children aged 2;4 to 6;7 in Hong Kong was assessed using a standardized speech test. Demographic information regarding household income, paternal education, maternal education, presence of siblings and having a domestic helper as the main caregiver was collected via parent questionnaires. After controlling for age and sex, higher maternal education and higher household income were significantly associated with better speech skills; however, these variables explained a negligible amount of variance. Paternal education, number of siblings and having a foreign domestic helper did not associate with a child's speech acquisition. Extrinsic factors only exerted minimal influence on children's speech acquisition. A large amount of unexplained variance in speech ability still warrants further research.

A population study of children's acquisition of Hong Kong Cantonese consonants, vowels, and tones.

PURPOSE: This study investigated children's acquisition of Hong Kong Cantonese. METHOD: Participants were 1,726 children ages 2;4 to 12;4 (years;months). Single-word speech samples were collected to examine 4 measures: initial consonants, final consonants, vowels/diphthongs, and lexical tones. A 2-way analysis of variance was performed to examine the effects of age and sex on phoneme acquisition. RESULTS: There was rapid acquisition of initial consonants from age 2;6 to age 4;6. All 19 initial consonants were acquired by age 6;0 (90% criterion): /p-/, /m-/, and /j-/ were acquired the earliest; the last were /ts(h)-/ and /s-/. Final consonants had a different acquisition time from their initial counterparts. Vowels were acquired by age 5;0 and diphthongs by age 4;0. All 9 tones were acquired by age 2;6. The main effect of age was significant for all 4 measures, whereas sex was significant for all measures except tone. Common phonological patterns (≥ 10%) for initial consonants were stopping, fronting, deaspiration, delabialization, affrication, and nasalization; patterns with 5.0%-9.9% occurrence were backing, deaffrication, gliding, and dentalization. CONCLUSIONS: The acquisition of Cantonese showed similarities with English acquisition yet also had specific characteristics. Factors that contributed to the acquisition rate were functional load, articulatory ease, consonant-vowel interactions, phonetic variations, and the behavior of vowels and their allophones.

Treatment intensity in everyday clinical management of speech sound disorders in Hong Kong.

Much evidence supports the efficacy of different treatment approaches for speech sound disorders (SSD) in children. Minimal research in the field has been conducted using treatment intensity as a research variable. This study examined the current practice of speech-language pathologists (SLPs) in Hong Kong regarding the treatment intensity prescribed to children with SSD and potential factors that were associated with the intensity. Participants were 102 SLPs working in different settings in Hong Kong who completed an online questionnaire. SLPs who had a heavier caseload offered significantly less frequent and shorter treatment duration to clients with SSD. Public and private settings differed significantly in treatment duration. Treatment approaches and clinicians' consideration about a client's conditions did not affect treatment intensity. SLPs in Hong Kong do not plan treatment duration and frequency in an evidence-based direction because of their heavy workloads and the dearth of research evidence on treatment intensity to guide their clinical practice.

Face mask use and control of respiratory virus transmission in households.

Many countries are stockpiling face masks for use as a nonpharmaceutical intervention to control virus transmission during an influenza pandemic. We conducted a prospective cluster-randomized trial comparing surgical masks, non-fit-tested P2 masks, and no masks in prevention of influenza-like illness (ILI) in households. Mask use adherence was self-reported. During the 2006 and 2007 winter seasons, 286 exposed adults from 143 households who had been exposed to a child with clinical respiratory illness were recruited. We found that adherence to mask use significantly reduced the risk for ILI-associated infection, but <50% of participants wore masks most of the time. We concluded that household use of face masks is associated with low adherence and is ineffective for controlling seasonal respiratory disease. However, during a severe pandemic when use of face masks might be greater, pandemic transmission in households could be reduced.