Breaking the cycle of maltreatment: The role of safe, stable, and nurturing relationships

Purpose We examine two research questions. First, does a history of child maltreatment victimization significantly increase the likelihood of maltreatment perpetration during adulthood? Second, do safe, stable, and nurturing relationships (SSNRs) during early adulthood serve as direct protective factors, buffering protective factors, or both to interrupt intergenerational continuity in maltreating behaviors? Methods Data come from the Rochester Youth Development Study that followed a community sample from age 14 to 31 with 14 assessments. Maltreatment victimization records covering birth through age 17 were collected from Child Protective Services records as were maltreatment perpetration records from age 21 to 30. Data on five SSNRs were measured during three interviews from ages 21 to 23. Results There is a significant relationship between maltreatment victimization and maltreatment perpetration (odds ratio = 2.57; 95% confidence interval = 1.47–4.50). Three of the five SSNRs investigated—relationship satisfaction, parental satisfaction, and attachment to child—served as direct protective factors, significantly reducing risk for those who had been maltreated. However, none of the interaction terms—between maltreatment victimization and the SSNR—was statistically significant, indicating that the SSNRs did not serve as buffering protective factors Conclusions Although a history of maltreatment significantly increases the risk of subsequent perpetration of maltreatment, enhancing SSNRs with intimate partners and with children during early adulthood can decrease the odds that a victim of maltreatment will become a perpetrator. Mandated reporters and service providers should be aware of the risk posed by earlier maltreatment and be prepared to ameliorate that risk, in part by strengthening supportive social relationships

Reconstructing cancer genomes from paired-end sequencing data

<p>Abstract</p> <p>Background</p> <p>A cancer genome is derived from the germline genome through a series of somatic mutations. Somatic structural variants - including duplications, deletions, inversions, translocations, and other rearrangements - result in a cancer genome that is a scrambling of intervals, or "blocks" of the germline genome sequence. We present an efficient algorithm for reconstructing the block organization of a cancer genome from paired-end DNA sequencing data.</p> <p>Results</p> <p>By aligning paired reads from a cancer genome - and a matched germline genome, if available - to the human reference genome, we derive: (i) a partition of the reference genome into intervals; (ii) adjacencies between these intervals in the cancer genome; (iii) an estimated copy number for each interval. We formulate the Copy Number and Adjacency Genome Reconstruction Problem of determining the cancer genome as a sequence of the derived intervals that is consistent with the measured adjacencies and copy numbers. We design an efficient algorithm, called Paired-end Reconstruction of Genome Organization (PREGO), to solve this problem by reducing it to an optimization problem on an interval-adjacency graph constructed from the data. The solution to the optimization problem results in an Eulerian graph, containing an alternating Eulerian tour that corresponds to a cancer genome that is consistent with the sequencing data. We apply our algorithm to five ovarian cancer genomes that were sequenced as part of The Cancer Genome Atlas. We identify numerous rearrangements, or structural variants, in these genomes, analyze reciprocal vs. non-reciprocal rearrangements, and identify rearrangements consistent with known mechanisms of duplication such as tandem duplications and breakage/fusion/bridge (B/F/B) cycles.</p> <p>Conclusions</p> <p>We demonstrate that PREGO efficiently identifies complex and biologically relevant rearrangements in cancer genome sequencing data. An implementation of the PREGO algorithm is available at <url>http://compbio.cs.brown.edu/software/</url>.</p

Heterarchy of Transcription Factors Driving Basal and Luminal Cell Phenotypes in Human Urothelium

Cell differentiation is effected by complex networks of transcription factors that co-ordinate re-organisation of the chromatin landscape. The hierarchies of these relationships can be difficult to dissect. During in vitro differentiation of normal human uro-epithelial cells, formaldehyde-assisted isolation of regulatory elements (FAIRE-seq) and RNA-seq were used to identify alterations in chromatin accessibility and gene expression changes following activation of the nuclear receptor PPARG as a differentiation-initiating event. Regions of chromatin identified by FAIRE-seq as having altered accessibility during differentiation were found to be enriched with sequence-specific binding motifs for transcription factors predicted to be involved in driving basal and differentiated urothelial cell phenotypes, including FOXA1, P63, GRHL2, CTCF and GATA3. In addition, co-occurrence of GATA3 motifs was observed within sub-sets of differentiation-specific peaks containing P63 or FOXA1 after induction of differentiation. Changes in abundance of GRHL2, GATA3, and P63 were observed in immunoblots of chromatin-enriched extracts. Transient siRNA knockdown of P63 revealed that P63 favoured a basal-like phenotype by inhibiting differentiation and promoting expression of basal marker genes. GATA3 siRNA prevented differentiation-associated downregulation of P63 protein and transcript, and demonstrated positive feedback of GATA3 on PPARG transcript, but showed no effect on FOXA1 transcript or protein expression. This approach indicates that as a transcriptionally-regulated programme, urothelial differentiation operates as a heterarchy wherein GATA3 is able to co-operate with FOXA1 to drive expression of luminal marker genes, but that P63 has potential to transrepress expression of the same genes

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases

Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials

Mutational signatures of ionizing radiation in second malignancies

Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1-100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential.This work was supported by funding from the Wellcome Trust (grant reference 077012/Z/05/Z), Skeletal Cancer Action Trust, Rosetrees Trust UK, Bone Cancer Research Trust, the RNOH NHS Trust, the National Institute for Health Research Health Protection Research Unit in Chemical and Radiation Hazards and Threats at Newcastle University in partnership with Public Health England. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England. Tissue was obtained from the RNOH Musculoskeletal Research Programme and Biobank, co-ordinated by Mrs Deidre Brooking and Mrs Ru Grinnell, Biobank staff, RNOH. Support was provided to AMF by the National Institute for Health Research, UCLH Biomedical Research Centre, and the CRUK UCL Experimental Cancer Centre. S.N.Z. and S.B. are personally funded through Wellcome Trust Intermediate Clinical Research Fellowships, P.J.C. through a Wellcome Trust Senior Clinical Research Fellowship

From early dating violence to adult intimate partner violence: Continuity and sources of resilience in adulthood

Background: Previous literature has found continuity for intimate partner violence, but little research has explored continuity between dating violence and adult intimate partner violence (IPV) or whether protective factors may attenuate this relationship. Aims: This research hypothesised a positive relationship between dating violence in early adulthood and later adulthood IPV and that support and attachment would provide buffering and direct protection for this relationship. Methods: Data from the Rochester Youth Development Study were used to explore these questions through negative binomial regression. Results: Dating violence was statistically significantly related to an increase of adult IPV. Family support, parental reports of attachment to the subject, peer support and parenting-related social support all were protective factors that provided a direct effect for those respondents perpetrating dating violence. None of the protective factors provided buffering protection between dating violence and adult IPV. Conclusions: Results confirm significant continuity between dating violence and IPV and that support from peers and family, parenting-related support and parental reports of attachment protect an individual from continuing to engage in intimate partner violence throughout adulthood. Bolstering these supportive relationships may help provide points of intervention to interrupt the link between early dating violence and later adulthood IPV. Copyright © 2016 John Wiley & Sons, Ltd

Development of a gel-to-gel electro-kinetic pinched injection method for an integrated micro-fluidic based DNA analyser

An integrated gel supported micro-fluidic system is reported, in which PCR products can be efficiently injected into a capillary electrophoresis device. The gel supported system is designed to provide greater stability to reagents during long periods of dormancy, enabling the mass production of one use chips encapsulating all required reagents at the time of manufacturing. This simultaneously diminishes the risk of sample contamination, and reduces the amount of external hardware required for auxiliary flow control, thus increasing the potential for portability. After PCR amplification was performed in a polysaccharide gel matrix, the PCR product was injected into the separation gel polymer matrix by executing a capillary-based electro-kinetic pinched injection across a gel-to-gel interface. The gel-to-gel system delivered a precise and accurate plug into the separation polymer, which offered more stable electro-kinetic control of the sample compared to solution based methodology even when bubbles were present in the system. Suitable voltage control was proven to provide a repeatable electro-kinetic injection of PCR product sufficient for an on-chip separation of multiple loci by capillary electrophoresis. (C) 2009 Elsevier B.V. All rights reserved