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Basal p53 ChIP-seq peaks in MCF10A cells (after raw data analysis described in Materials in Methods section) ordered by significance of the peak call. Spreadsheet includes (columns left to right) peak locus (Chromosome, start, end), MACS2 significance, closest relevant gene (genes discussed in paper in red type), and original HOMER gene call (if relevant gene differs from called gene).

Supplementary Fig. S1. Basally expressed p53 may have important tumor suppressor targets. Supplementary Fig. S2. Binding targets of basal p53 in MCF10A cells. Supplementary Fig. S3. Exploring the binding targets of basal p53. Supplementary Fig. S4. Wild-type p53 maintains expression of tumor suppressor target genes. Supplementary Fig. S5. Long range chromatin interactions of enhancers with transcriptional start sites of basal p53 targets. Supplementary Fig. S6. Enhancer for PTEN is present in multiple cell types. Supplementary Fig. S7. The binding and regulation of the PTEN locus by basal p53. Supplementary Fig. S8. PTEN-eP53RE is a highly conserved p53 response element in a p53-dependent enhancer. Supplementary Fig. S9. Deletion of endogenous PTEN-eP53RE by CRISPR/Cas9. Supplementary Fig. S10. Depletion of p53 causes a PTEN-eP53RE-dependent decrease in PTEN expression, deletion of PTEN-eP53RE alters some tumor cell phenotypes. Supplementary Table S1. Information on tumor suppressor genes identified as basal p53 targets. Supplementary Table S2. Predicted p53 response elements within basal p53 binding sites using JASPAR. Supplementary Table S3. Chromatin properties of basal p53 binding sites near tumor suppressor genes. Legends for Supplementary Spreadsheets S1-S5. Additional Materials and Methods. References for Supplementary Material.

Purpose: Nutrition challenges are common during childhood cancer treatment and can persist into survivorship, increasing the risk of non-communicable chronic diseases. Evidence based practice and implementation of nutrition support for childhood cancer survivors (CCS) has been poorly investigated and may influence the future health of survivors. This study aimed to explore the nutrition support needs of CCS and the barriers and facilitators to delivering follow-up services in New Zealand (NZ).Methods: Qualitative thematic analysis of semi-structured interviews were performed at a specialist paediatric oncology centre in NZ with CCS and their family (N = 20 individuals) and health professionals (N = 9). Results: Three key themes emerged from the analysis: 1) the current survivorship care pathway does not provide adequate nutrition support, 2) weight and dietary changes are common challenges, and 3) requirements for nutrition support in survivorship are varied. Common nutrition-related concerns included fussy eating, poor diet quality, difficulties 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 were identified by CCS and health professionals. 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 CCS is required. Education for healthcare professionals will improve the delivery of timely nutrition support and monitoring practices.

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.

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.

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.

Tone, vowel and consonant production are described for a large group of Cantonese-speaking children assessed in speech and language therapy clinics in Hong Kong. The patterns of disability follow predictions made on the basis of work on normal phonological development in Cantonese, and on psychoacoustic factors in acquisition: consonants account for more disability than vowels, and tones are least problematic. Possible articulatory and auditory contributions to explanation of the observed patterns are discussed.

Apical nonselective cation channels with an average single-channel conductance of 34 +/- 2.3 pS were found in M-1 mouse cortical collecting duct cells. Channel activity is increased by depolarization and abolished by cytoplasmic calcium removal. Cytoplasmic application of 0.1 mM cGMP decreases channel open probability by 27%. cDNAs corresponding to approximately 40% of the coding region of the photoreceptor channel were isolated by the polymerase chain reaction from M-1 cells and a rat kidney cDNA library. The rat kidney-derived sequence differs by a single base, and the M-1-cell-derived sequence differs by only two bases, from the photoreceptor sequence. A second clone from M-1 cells differs by 20 out of 426 bases from the photoreceptor sequence. In all three clones, the deduced amino acid sequence is identical to that of the rat photoreceptor channel. Northern blot analysis of poly(A)+ RNA from M-1 cells reveals the presence of a 3.2-kilobase band hybridizing with a retinal cGMP-gated cation channel probe. The results suggest the expression in M-1 cells of more than one gene coding for nonselective cation channels or channel subunits, one of which is identical to the cGMP-gated cation channel gene of rod photoreceptors.

Purpose To report Propionibacterium acnes as a cause of vision-threatening infectious keratitis and to discuss culture isolation and antibiotic treatment. Methods Retrospective case series presentation collected from three academic medical centers. Results Six cases of P. acnes infectious keratitis are presented, all of which were associated with a compromised corneal barrier or environment. All cases were culture-positive on thioglycolate broth; none became positive before 7 days of growth. No other organisms were isolated from any culture, and the growth of P. acnes occurred in some cases despite negative gram stains. Conclusion P. acnes can produce vision-debilitating keratitis when the cornea is compromised. Growth in culture should be monitored for at least 10 days to ensure isolation of this fastidious organism. P. acnes may respond to several different antibiotics that have gram-positive coverage, but it should be treated with vancomycin to enhance clearance of the organism.